Lasers in Medical Science

, Volume 29, Issue 4, pp 1517–1529

Laser treatment of recurrent herpes labialis: a literature review

Authors

    • Special Laboratory of Lasers in Dentistry (LELO), Department of Restorative DentistrySchool of Dentistry of the University of São Paulo (USP)
  • Ana Cecilia Corrêa Aranha
    • Special Laboratory of Lasers in Dentistry (LELO), Department of Restorative DentistrySchool of Dentistry of the University of São Paulo (USP)
  • Alyne Simões
    • Laboratory of Oral Biology, Department of Biomaterials and Oral BiologySchool of Dentistry of the University of São Paulo (USP)
  • Marina Stella Bello-Silva
    • Special Laboratory of Lasers in Dentistry (LELO), Department of Restorative DentistrySchool of Dentistry of the University of São Paulo (USP)
    • School of DentistryNove de Julho University
  • Karen Muller Ramalho
    • Special Laboratory of Lasers in Dentistry (LELO), Department of Restorative DentistrySchool of Dentistry of the University of São Paulo (USP)
    • Department of Stomatoloy, Discipline of Integrated Dental ClinicSchool of Dentistry of the University of São Paulo (USP)
  • Marcella Esteves-Oliveira
    • Special Laboratory of Lasers in Dentistry (LELO), Department of Restorative DentistrySchool of Dentistry of the University of São Paulo (USP)
    • Department of Operative Dentistry, Periodontology and Preventive DentistryRWTH Aachen University
  • Patrícia Moreira de Freitas
    • Special Laboratory of Lasers in Dentistry (LELO), Department of Restorative DentistrySchool of Dentistry of the University of São Paulo (USP)
  • Juliana Marotti
    • Department of Prosthodontics and Dental MaterialsMedical Faculty, RWTH Aachen University
  • Jan Tunér
    • Private Dental Clinic
Review Article

DOI: 10.1007/s10103-013-1311-8

Cite this article as:
de Paula Eduardo, C., Aranha, A.C.C., Simões, A. et al. Lasers Med Sci (2014) 29: 1517. doi:10.1007/s10103-013-1311-8

Abstract

Recurrent herpes labialis is a worldwide life-long oral health problem that remains unsolved. It affects approximately one third of the world population and causes frequent pain and discomfort episodes, as well as social restriction due to its compromise of esthetic features. In addition, the available antiviral drugs have not been successful in completely eliminating the virus and its recurrence. Currently, different kinds of laser treatment and different protocols have been proposed for the management of recurrent herpes labialis. Therefore, the aim of the present article was to review the literature regarding the effects of laser irradiation on recurrent herpes labialis and to identify the indications and most successful clinical protocols. The literature was searched with the aim of identifying the effects on healing time, pain relief, duration of viral shedding, viral inactivation, and interval of recurrence. According to the literature, none of the laser treatment modalities is able to completely eliminate the virus and its recurrence. However, laser phototherapy appears to strongly decrease pain and the interval of recurrences without causing any side effects. Photodynamic therapy can be helpful in reducing viral titer in the vesicle phase, and high-power lasers may be useful to drain vesicles. The main advantages of the laser treatment appear to be the absence of side effects and drug interactions, which are especially helpful for older and immunocompromised patients. Although these results indicate a potential beneficial use for lasers in the management of recurrent herpes labialis, they are based on limited published clinical trials and case reports. The literature still lacks double-blind controlled clinical trials verifying these effects and such trials should be the focus of future research.

Keywords

Herpes simplex virusHSV-1High-power laserLow-power laserLaser phototherapyPhotodynamic therapy

Introduction

Recurrent herpes labialis (RHL) remains an unsolved, life-long oral health problem, affecting approximately one third of the world population [1, 2]. Although the disease itself is not life-threatening, it causes frequent pain and discomfort episodes, as well as social restriction due to its compromise of esthetic features [3, 4]. In addition, it can be even more aggressive in immunocompromised patients, resulting in the presentation of painful recurrences and slower healing that may compromise quality of life [5]. Considering the fact that the currently available antiviral drugs demonstrate only a limited effect on reducing healing time and ulcerative lesion occurrence [69], the purpose of this review article is to present the available scientific evidence that supports or contraindicates the clinical use of lasers for the management of oral manifestations of the herpes simplex virus. The search methodology for identifying scientific reports included searching the Cochrane Library and PubMed using the terms: “recurrent herpes labialis”, “herpes simplex virus 1 infection”, “HSV-1”, and “oral herpes simplex infection” alone or in combination with one or more of the following terms: “low power laser”, “low level laser”, “low intensity laser”, “LLLT”, “laser phototherapy”, “photodynamic therapy”, “PDT”, “high intensity laser”, “high power laser”, “Nd:YAG”, “Er:YAG”, “Er,Cr:YSGG”, “CO2”, “diode”, and “laser”. The studies and articles were searched to identify effects on healing time, pain relief, duration of viral shedding, viral inactivation, and interval of recurrences.

Herpes simplex—classification, diagnosis, and stages

Herpes simplex is a viral disease caused by both herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Both are alpha-herpes viruses that are neurotropic and have a rapid replication cycle and broad host and cell range [10]. HSV-1 primarily causes infections in the mouth, throat, face, eye, and central nervous system, while HSV-2 primarily causes genital infections. However, each of them may cause infections in varied areas [11]. Oral herpes is the most common form of HSV infection manifestation. Genital herpes is the second most common form. Other disorders, such as herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret’s meningitis, and neonatal herpes, are all caused by herpes simplex virus. HSV is rarely fatal, but patients with immature or suppressed immune systems are prone to severe complications from HSV infections. The prevalence of RHL increases gradually from childhood, reaching 70–80 % in later adult years [10], but demographic factors may affect its acquisition [2, 12, 13].

Most primary infections are acquired through direct contact with a lesion or with infected body fluids such as saliva or the exudates of active lesions [10]. The appearance and distribution of sores in these individuals typically occurs as multiple, round, superficial oral ulcers, accompanied by acute gingivitis [10]. After initial infection, the viruses are transported along sensory nerves to the sensory nerve cell bodies, where they become latent and reside life-long [10]. Reactivation of the virus in the sensory ganglion causes cutaneous and mucocutaneous recurrent herpetic infection. The causes of recurrence are uncertain, though some potential triggers have been identified and related to immunosuppressive factors, such as UV exposure, trauma, and others [14]. In reactivation, the previously latent virus multiplies new virus particles in the nerve cell, and these are transported along the axon of neurons to the nerve terminals in the skin, where they are released [10].

Clinically, the recurrent lesions progress through several stages: prodrome, redness, papule, vesicle, ulcer, hard crust, dry flaking/residuals swelling, and normal healed skin. Some of these stages may be short lasting and unnoticeable [3, 6].

The prodromic symptoms, such as paresthesia, tenderness, pain, burning sensation, or itching sensation arise in 46–60 % of patients, lasting approximately 6 h. Approximately 25 % of facial recurrences do not progress beyond the prodromic or papular stage [15]. The lesions of recurrent infections are usually red macules that rapidly become vesicular, being highly infective at this stage, later forming pustular ulcers. Healing occurs within 1–10 days of the onset of the initial symptoms [15].

It is important to emphasize that HSV is never eradicated from the host body by the immune system. In the past 20 years, a great variety of antiviral drugs has become available for the treatment of RHL. These will be detailed next.

Conventional antiviral therapy

The conventional treatment for RHL is based on the prescription of antiviral compounds. The available treatments do not cure latent HSV infections, but rather palliate symptoms or prevent recurrences. Most drugs developed to act against HSV are antiviral agents called nucleosides and nucleotide analogs, which block viral reproduction. The most prescribed medications against RHL include acyclovir, valacyclovir, and famciclovir. The antiviral drugs are effective and reasonably safe when properly administrated. However, these medications differ in their chemical structure, dosage and cost [10, 1619].

Topical and systemic acyclovir, at a variety of concentrations and dosages, has been used in the treatment of RHL with variable outcomes. For most dentists, selecting an appropriate type and drug delivery format (intravenous, oral, or topical) can present a dilemma because the intermittent administration of antiviral medications does not alter the frequency of recurrences and usually only demonstrates a good response when applied before the onset of vesicles [14, 16, 18, 20, 21].

There are antiviral medications available in pill form that were particularly developed for genital herpes treatment but are also used for herpes labialis [10]. The oral medication acts by stopping virus growth [10]. These medications may also significantly decrease the severity of a primary outbreak and the number of days that the virus can be transmitted. In addition, the medications reduce the healing time, which consequently decreases painful symptoms. Nevertheless, antiviral medication is most effective if it is taken when the patient first notices the prodromic symptoms (tingling and pain) of RHL outbreak and if medication is taken for the next 5–7 days or until the symptoms are gone [10, 1820, 22, 23].

Although most patients with RHL do not have a need for systemic medication, it can be prescribed to patients with frequent recurrences (>6 per year) who experience severe pain or disfigurement, have difficulty in swallowing, or have experienced a protracted disease course [24]. Of all patients with herpes labialis, 5–10 % have frequent recurrences [25]. When the recurrences affect the patient’s quality of life, administration of systemic medication may be appropriate for those psychologically distressed by their disease [4, 26].

The development of new compounds that are effective against HSV is still a challenge for the scientific community and pharmaceutical industry. The development of a vaccine would be the most effective management of HSV infections [27]. Nevertheless, the HSV candidate vaccines developed until now have mostly been purified subunit vaccines and/or recombinant envelope glycoproteins (such as gB and gD) that, in different animal model experiments, resulted in protection against acute virus challenge along with a reduction in latency [27]. The immunotherapeutic effects of herpes vaccines are still not reliable. Therefore, the addition of adjutants that shift cytokine production of helper T cells towards stimulation of cytotoxic T cells (TH1-type cytokine response) may be more promising [27]. Existing efforts for the most favorable combination of HSV-1 glycoproteins, presented as recombinant proteins or DNA vaccines, with immunostimulatory cytokines are yielding incremental, yet significant, gains in biological activity in animal models [10, 27].

Antiviral agents reduce viral replication by inhibiting viral DNA synthesis, which is essential for viral reproduction. Limiting reproduction helps to keep the virus inactive or latent. Acyclovir and penciclovir have a similar mechanism of antiviral action against HSV, as extensively reported in the literature [16, 28, 29].

The resistance of HSV to acyclovir can happen, and almost all resistance occurs as a result of a deficiency in thymidine kinase [7]. Nearly all clinical HSV isolated with resistance to acyclovir have been obtained from patients who have received prolonged acyclovir therapy [7, 3033].

Essential to a successful therapeutic intervention for RHL is an accurate anamnesis for assessment of the patient’s overall health and the extent of clinical disease [20, 34]. There is a requirement for additional randomized-controlled trials to establish the most appropriate means of treating and preventing HSV-1 infection in both immunocompetent and immunocompromised individuals [10]. As mentioned previously, many antiviral agents are available for the treatment of HSV-1 infection. Despite these treatments being effective, drug-resistant strains have been found, and there is no available vaccine for this troublesome viral infection. Recently, laser phototherapy has been suggested as a promising therapeutic measure for both the prevention and episodic management of outbreaks.

Laser phototherapy—mechanisms of action

HSV treatment with lasers is based either on heat production (high-power lasers) or on the photochemical and photobiological effects of laser light (low-power lasers or “defocused” high-power lasers). Regarding laser phototherapy (LPT; without heating), it has been suggested that its effect is based on its capacity to modulate various metabolic processes by the conversion of the laser light energy into useful energy to the cell. Visible laser light is absorbed by chromophores in the respiratory chain of the mitochondria, leading to fundamental changes, such as increasing reactive oxygen species (ROS), ATP synthesis, cell membrane permeability changes, and nitric oxide release [35]. These effects produce a number of secondary effects: changes in extracellular matrix synthesis, increased action potential of nerve cells and new formation of capillaries through the release of growth factors, local effects on components of the immune, vascular and nervous system, and an increase in intracellular Ca2+ and cyclic adenosine monophosphate levels [36], which are related to various biological processes such as RNA and DNA synthesis, cell mitosis, and protein secretion [37, 38]. This cascade of cellular events accelerates cell proliferation, which promotes healing.

The effect of LPT depends on the physiological state of the cell at the moment of irradiation [39, 40]. This suggests that laser therapy works with a considerable effect in cases of stressed cells. Injuries can be induced in many ways, including physical agents (e.g. skin incisions) and infections [37]. LPT can be advantageous because its therapeutic window for anti-inflammatory actions overlaps with its ability to improve tissue repair and pain relief. In addition to these benefits, LPT has been shown to be a simple and atraumatic technique in the treatment of oral lesions and is well tolerated by patients.

The anti-inflammatory effect of LPT could be partially due to an increase in circulation and inhibition of PGE2 synthesis [41, 42]. The analgesic effect of LPT is still not totally clear in the literature. It has been shown that peripheral nerve stimulation by a laser alters the hyperpolarization of the cellular membrane and increases the concentration of ATP, which could contribute to maintaining the stability of the membrane and increase the pain threshold [43]. The enhancement of ATP production has also been shown to lead to the restoration of neuronal membranes and decreasing pain transmission. Moreover, LPT can enhance peripheral endogenous opioid production [44] and decrease serum prostaglandin E2 [45]. In addition, Chow et al. have shown that infrared laser light is able to block fast axonal flow, providing a mechanism for a neural basis of laser-induced pain relief [46].

The mechanism of action of laser therapy for both the prevention and reduction of the severity of the oral manifestation of the herpes labialis virus is not completely understood. Dannarumma et al. [47] investigated the effect of LPT on HSV-1 replication and evaluated the modulation of expression of certain proinflammatory cytokines (TNF-α, IL-1β, and IL-6), antimicrobial peptide HBD2, chemokine IL-8 and the immunosuppressive cytokine IL-10. The authors suggested that LPT acts in the final stage of HSV-1 replication by limiting viral spread from cell to cell and that laser therapy also acts on the host immune response, unblocking the suppression of pro-inflammatory mediators induced by the accumulation of progeny virus in infected epithelial cells.

It is important to note that LPT follows the Arndt–Schultz law, which means that low doses of irradiation cause no reaction and high doses can elicit an inhibition. Still, a reasonable knowledge of the various parameters involved in LPT is necessary to obtain consistent clinical results [38]. Table 1 lists the relevant reports from the literature (clinical studies, brief reports, and clinical cases) published in or before September 2012.
Table 1

Reports of the literature until September 2012 (clinical studies, brief reports, and clinical cases)

Reference

Study type

Patients

Follow-up

Laser parameters

Irradiation mode

Results

Clinical studies (in PubMed and SPIE Proc until September 2012)

Vélez-González et al. [51]

Randomized double-blind placebo-controlled trial design

36 Suffering from labial and facial herpes (3 or more times/year)

Daily (during HSV lesion manifestation)

632.8 nm (He–Ne laser)

Labial herpes: 6 laser applications. The first 2 given in consecutive days and the last 4 every second day

Statistically reduce of relapses of herpes infection in the lips and face in patients treated with laser and laser plus acyclovir. The interim between the relapses increased significantly in patients treat with laser in relation to patients treated to acyclovir

24 Suffering from genital herpes (3 or more times/year)

1 Year (for recurrences observations)

20, 445 mW/cm2, 8 J/cm2

Genital herpes: 8 laser applications. The first 3 given in consecutive days and the last 5 every second day

The duration of herpetic eruptions were reduced in patients treated with laser plus acyclovir (A probable therapeutic synergism took place)

Spot of optic fiber = 2 mm

The number of relapses in herpes infection in the genital and the interim between the relapses were not modified with the treatment of laser

Schindl and Neuman [50]

Randomized double-blind placebo-controlled trial design

50

Weekly (52 weeks)

690 nm (diode laser)

Daily irradiations during 2 weeks

No side effect reported

80 mW, 10 min, 1 cm2, 80 mW/cm2, 48 J/cm2, Irradiation in recurrence free period at the site of original chronic herpes infection

Median recurrence-free interval: laser group—37.5 weeks × control group—3 weeks

de Carvalho et al. [48]

Uncontrolled study

71

Monthly (during 16 months)

780 nm (diode laser)

Contact mode punctual application

Statistically decrease in lesions dimension and inflammatory edema in laser group patients

60 mW, 2 s/point, 7.2 J, 3 J/cm2 in latent phase

Weekly irradiations during 10 weeks

Decrease in recurrences periods in laser group (but the difference showed no statistically results). After 16 months: laser group—0.076 recurrence/month; control group—0.116 recurrence/month

60 mW, 3 s/point, 10.8 J, 4.5 J/cm2, in infected phase

Spot size = 0.04 cm2

Sanchez et al. [49]

Semiblind study

232

Daily (during 1 week), monthly (during 1 year)

670 nm (diode laser)

No side effect reported

40 mW, 40 s, 1.6 J, 2.04 J/cm2, 51 mW/cm2—applied in prodromal stage and stages of vesicles (per blister)

Positive effect of LPT on initial healing and also in the length of recurrences periods

40 mW, 2 min, 4.8 J—applied in crust and secondarily infected stages (per blister)

After day 7 ,no patients in laser group had any visible signs of bluster, whereas in control group (acyclovir cream and tablets) 77 patients still had vesicles, 29 crust and 10 secondary infection

322

Monthly (during 5 years)

40 mW, 30 s, 1.2 J at the C2–C3 vertebral

 

After 1: 84 recurrences (laser group) × 114 recurrences (control group)

Spot size = 0.79 cm2

Noncontact

After 5 years recurrences in laser group: year 1–35, year 2–42, year 3–149, year 4–41, year 5–22

Clinical brief report (in PubMed until September 2012)

Eduardo C.P. [52]

Brief report uncontrolled

3

Monthly (during 3 years)

780 nm (diode laser)

Contact mode, punctual application

Pain relief. Provide initial clinical evidence supporting the efficacy of laser therapy on Prevention of herpes labialis outbreaks.

70 mW, 5 s/point, 8.75 J/cm2, 1.75 W/cm2, 50/60 points, 21 J

Spot size = 0.04 cm2

(5 min total irradiation time) in recurrence-free period

10 sessions 2×/week—during 5 weeks

660 nm (diode laser)

50 mW, 20 J/cm2 (in prodromic phase)

50 mW, 4 J/cm2 (in crust phase)

After 6 months: 5 sessions every 2 days

1,064 nm (Nd:YAG laser)

After 12 months: 5 sessions every 2 days

1.5 W, 100 mJ, 1 5 Hz in vesicle

Clinical cases (in PubMed until September 2012)

Navarro et al. [57]

Clinical case

1 (19 months diagnosis of herpetic gingivostomatitis)

1 Week

660 nm (diode laser) 10 mW, 7.5 J/cm2

Contact mode

Immediately pain relief. The child was able to eat again. 1 week later, the wound was completely healed

Spot size = 0.04 cm2

2 Irradiations with interval of 3 days between them

Marotti et al. [54]

Clinical case

Four patients in the vesicle phase of HSV-1 Infection (2 patients treated with HILT + LPT and 2 treated with PDT + LPT)

6 Months

Er,Cr:YSGG—2.78 μm, 20 Hz, 0.75 W (vesicles drainage) PDT—Methylene Blue 0.01 % for 5 min + diode laser, 660 nm, 100 J/cm2, 100 mW, 28 

Contact mode punctual applications

Immediate pain relief

s/point, 2.8 J/point, 3 points

With exception of Er,Cr:YSGG irradiation

No recurrences reported during the monitored time

LPT - diode laser, 660 nm; 3.8 J/cm2; 15 mW

Marotti et al. [53]

Clinical case

Four patients in the vesicle phase of HSV-1 Infection treated with PDT + LPT

6 Months

PDT—Methylene Blue 0.01 % for 5 min + diode laser, 660 nm, 120 J/cm2, 40 mW, 2 min/point, 4.8 J/point, 4 points

Contact mode, punctual applications

No side effects reported

LPT—diode laser, 660 nm, 3.8 J/cm2, 15 mW, 0.6 J/session, 4 points

Accelerated wound healing (complete healing after 1 week) Recurrences reported by patient 1 after 4 months, and no recurrences reported in the other cases during the monitored time

Sperandio et al. [55]

Clinical case

Two patients in the vesicle phase of HSV-1 Infection treated with PDT + LPT

6 months

PDT—Methylene Blue 0.01 % for 5 min + diode laser; 660 nm; 100 J/cm2; 100 mW, 28 s/point; 2.8 J/point; 3 points

Contact mode, punctual applications

Immediate pain relief

LPT—diode laser, 660 nm; 60 J/cm2 per session, 40 mW; 14 s/point, 1.69 J/session, 1 or 3 points

 

Accelerated wound healing No recurrences reported during the monitored time

Bello-Silva et al. [56]

Clinical Case

1 Patient treated with HILT and LPT

Not informed

Er:YAG—2.94 μm, 80 mJ/pulse, 2–4 Hz (vesicles drainage)

Contact mode, punctual applications

Pain was discontinued in the first session

LPT—diode laser, 660 nm; 0.04 J/cm2; 3.8 J/cm2; 10 mW; 10 s/point

With exception of Er:YAG irradiation

Complete healing after 10 days

Laser phototherapy—clinical studies and clinical case reports

Despite the fact that few clinical studies have been published concerning laser phototherapy and the treatment of RHL (Table 1), all of them described some gain from the use of laser therapy [4851]. A negative point of the studies is the divergence in laser parameters, which makes it difficult to compare their results. The laser power used in the studies varied between 20 and 80 mW, the wavelength varied from 632.8 to 780 nm, and the fluence varied from 2.04 to 48 J/cm2. The studies also vary in regards to the RHL (latent, prodromic, vesicle, or crust) to which laser therapy was applied. Nevertheless, some positive points of these studies can be pointed out. They had a high sampling of patients (minimum (50)–maximum (322)), and almost all of the studies were designed as randomized-controlled clinical trials (Table 1). Interesting results can be extracted from the results of the studies.
  • All of the clinical studies described a significantly reduced interval between the herpes labialis recurrences in laser groups, with the exception of de Carvalho et al. [48], who observed a decrease (average of 0.076 recurrences/month in the laser group and 0.116 recurrences/month in the control group), but the difference was not significant. Schindl and Neuman [50] found a recurrence-free interval of 37.5 weeks after LPT in the laser group in comparison to 3 weeks in the placebo group. Sanchez et al. found 84 recurrences in the laser group and 114 recurrences in the control group after 1 year of treatments. Vélez-González et al. [51] demonstrated a significant reduction in the relapses of RHL, and the interim between the relapses in the laser group were significantly longer compared to the acyclovir group. Thus, the studies that compared LPT with acyclovir found a beneficial effect of LPT in comparison to acyclovir with respect to the interval between recurrences. Several case reports were also examined. de Paula Eduardo et al. [52] found that in three patients treated with LPT, there was a reduction in outbreaks after 3 years of follow-up. In the other three case reports cited [5355], at a 6-month follow-up of 10 patients after LPT, only one presented a recurrence episode.

  • All the clinical studies that examined the duration of HSV manifestations found a significant reduction in the duration of herpetic eruptions in patients treated with LPT in comparison to placebo or control groups [48, 49, 51, 56]. Curiously, Vélez-González et al. [51] found a probable therapeutic synergism in the association of acyclovir and LPT. Case reports also note improved wound healing of lesions reported by patients [54, 55, 57].

  • Pain relief was discussed mostly in case reports examining the immediate post-LPT treatment period [5457].

  • No side effects associated with LPT were reported in any of the clinical studies or case reports [4851, 5356, 58].

Infection phases and indication of laser phototherapy

HSV-1 infection, as described earlier, manifests itself clinically in different phases. Interesting results are observed when LPT is used in the prodromic phase [59]. In this case, LPT may cause a suppression of the infection and lesions may not occur [60]. The later LPT is used in the management of HSV-1 infection, the milder the preventive effect obtained [59]. However, even in the later stages of HSV-1 infection, LPT can provide relief of symptoms and the acceleration of the healing process [5457, 59].

It has been speculated that during the vesicle phase, LPT could benefit virus proliferation [61] and cause a negative effect on the healing process of the lesions [47]. Considering that the viruses are proliferating and that LPT results in an increase of nucleic acids and ATP synthesis in the cells [39], this therapy should be used with caution during this phase. On the other hand, it is important to note that the innate immune system is also influenced by LPT [61, 62]. Although the virus proliferation may be stimulated after LPT irradiation, the immune cells will also proliferate and act against HSV-1 infection, as suggested by some authors [48, 63]. De Carvalho et al. [48] used LPT independently of the infection phase, and promising results were found with reduced edema and lesion size. Dougal et al. [63] utilized a 1,072-nm laser after 36 h of symptom onset and demonstrated a reduced healing time. Vélez-González et al. [51] applied LPT after the diagnosis of herpes infections, and no side effect was reported after the irradiation, apart from the herpes infection phase. None of the two studies reported any side effects of the laser irradiation during the referred infection phases. LPT applied during the vesicle phase of HSV-1 infection, leading to the stimulation of virus replication, is only speculative, and no published study has investigated this possible side effect. However, in the clinical experience of our group, some patients irradiated in the vesicle phase have returned to the dental office with an increased number of vesicles (data not published). Therefore, drainage of the vesicle content with a high-power laser or sterile needle before LPT is strongly recommended [55, 56].

Regarding the preventive effects of LPT, it can be used in the perioral area during the latent phase, when no signs of infection are present, and in this case, an increase of the interval between successive HSV-1 infections is expected [49, 50]. Landthaler et al. [64] also achieved significant prolongation of remission intervals, from 30 to 73 days, in patients with recurrent HSV-1 infection. Similar results have also been shown recently [49, 60].

According to the literature, infrared low-power laser light of approximately 780–808 nm presents a lower superficial absorption and penetrates deeper into soft tissues [65]. Therefore, it reaches deeper skin portions and is able to act on neural endings and the terminal circulatory system [60, 66, 67]. For this reason, this wavelength is indicated for the preventive treatment of HSV-1 infection during the latent phase [48, 60], although Schindl and Neuman [50] have already described interesting results in the prevention of human herpes labialis using a 690-nm wavelength. The literature indicates that visible-red laser light may be more effective in the prodromic and crust phases [49, 50, 60]. The former presents erythema, and therefore, hemoglobin, which is the main chromophore for this wavelength. In the crust phase, laser light is used to accelerate wound healing and reduce pain [68]. This is based on the superficial absorption of the visible-red wavelength [6567], which acts efficiently on superficial lesions.

In conclusion, LPT may be used in the prodromic phase to avoid lesion exteriorization, as well as in the latent phase to increase the interval between recurrences. Likewise, LPT may be used in the crust phase to accelerate lesion healing and provide symptom relief. These actions are based on its therapeutic effects, as already discussed.

Photodynamic therapy

Low-power lasers can be used in the treatment of oral manifestations of HSV recurrences at different manifestation times, such as the prodromic, latent, and crust phases. In these cases, the laser action is a result of its interaction with biological tissues and is based on the therapeutic effects of biomodulation, analgesia, and the modulation of the inflammatory process. Alone, low-power lasers do not have significant antimicrobial effects [69]. However, when associated with photosensitizers, the main effects of LPT are not fully based on biomodulation, but rather on cell death. The association of a light source with a resonant extrinsic photosensitizer is called photodynamic therapy (PDT) and aims to produce highly reactive oxygen species [70] that will damage the membrane, mitochondria, and DNA, culminating in the death of microorganisms or host cells [7173].

The literature presents two type of PDT. The first type, antineoplastic PDT, aims to treat tumors and skin diseases and is based on the use of a light source associated with an extrinsic photosensitizer, mostly derivatives of hematoporphyrin [74]. This photodynamic process is generally unspecific and depends on the affinity of these photosensitizers to structures of both host and microorganism cells. In the second type of PDT, the photosensitizer used is mainly a dye, and in this case, it is more specific for targeting microorganisms such as bacteria, fungi, and viruses. Because of its lethal effects on microorganisms, this type of PDT is also called antimicrobial photodynamic therapy, photoactivated disinfection [75], lethal photosensitization, and photodynamic antimicrobial chemotherapy.

The lethal effects of PDT are mediated by either the production of singlet oxygen through oxygen triplet excitation by light (photochemical reaction type II) or by excitation of the photosensitizer, which interacts directly with the substrate to produce highly reactive free radicals (reaction type I). In both reactions, the photodynamic process occurs due to the triplet light-excited state of the photosensitizer [8] [76].

Virucidal effects of PDT

The virucidal effects of PDT were first reported in 1928 [77]. In the early 1970s, the first clinical study of PDT on HSV infection was reported. This double-blind study on herpes infection found that PDT was able to improve the healing time of lesions and decrease recurrence rates [78]. However, the dye used was reported to cause important side effects in human beings, either via host–cell mutation or photodamage to uninfected host cells surrounding the target tissue [79], leading to the discouragement of PDT practice [80]. Fortunately, the development of photodynamic techniques was possible due to a better understanding of photosensitizers and improvement of light delivery and its sources [81], leading to the establishment of reliable protocols that culminated with the Food and Drug Administration approval of PDT for esophageal tumor treatment [82].

The increasing concerns regarding the risk of virus infection have raised the importance of photodynamic inactivation of viruses, mainly in blood and its components [83]. The use of PDT in viral infections include both in vitro and in vivo inactivation of DNA viruses (HSV, retro virus) and RNA viruses (human immunodeficiency virus and hepatitis C virus) [84, 85]. HSV seems to be significantly suppressed by PDT under different environmental conditions (virus suspension, infected cell cultures, blood plasma, and infected animals) [86, 87].

Several photosensitizers can be successfully used for PDT. The use of cationic charged photosensitizers for HSV inactivation such as toluidine blue and methylene blue (MB) [1] [88] has been frequently reported in the literature [86]. The latter is one of the most used photosensitizers for PDT. This phenothiazine dye absorbs red light and can photo-inactivate viruses via oxidative damage to virus DNA [89, 90] in media, red cells, and plasma [87, 88, 91], mostly through a type II photochemical reaction [76]. Because of this, MB has been used for plasma decontamination in several European agencies [92]. The photo-inactivation of HSV infection with MB has demonstrated favorable results, and its clinical use enables the conduction of a local, effective and comfortable photodynamic management of oral herpes manifestations [53, 55, 91]. New MB derivatives are being developed to favor the photodynamic inactivation of viruses. Despite the favorable results observed [86, 93], MB is still considered to be safer than other photosensitizing dyes [94].

Phthalocyanines (Pc) have also been used as photosensitizers for virus inactivation [95]. This porphyrin-like second-generation sensitizer also absorbs red light efficiently and has been used in cancer treatment [96]. Because intracellular viruses are more resistant to PDT than free virions, the use of an amphiphilic dye such as Pc can penetrate the cell plasma membrane easier, acting more efficiently in the inactivation of intracellular HSV [97]. The inactivation of HSV with Pc is thought to be caused by oxidative damage to the virus envelope, specifically to glycoprotein D, which leads to inhibition of virus adsorption, penetration into host cells, and virus infectivity [97, 98]. This inactivation process is thought to be primarily related to a type II singlet oxygen mechanism [99]. Because Pc targets the virus envelope and not viral nucleic acids, non-enveloped viruses such as adenovirus are not photo-inactivated with this dye [97].

In addition, 5-aminolevulinic acid [100] is one of the most commonly used photosensitizers for PDT for both antitumor treatment and antimicrobial therapy. It is a precursor of protoporphyrin IX, and its use in virus inactivation has been extensively studied. Its action in HSV was demonstrated in an in vivo study and was effective for both experimental animals and human patients [85].

It is possible to conclude that each photosensitizer presents a different mechanism of virus inactivation, according to its affinity for either the virus envelope (merocyanine 540, rose Bengal hematoporphyrin derivatives) or the virus nucleic acid (heterocyclic dyes such as MB and toluidine blue). The former acts to inhibit virus infectivity, whereas the latter inactivates virus DNA. It is important to emphasize that for sensitization to be efficient, the inoculation time of virus in the dye (pre-irradiation time) should be carefully respected, and inoculation may take a few minutes (as performed in clinical studies) to several hours (as performed in in vitro studies) [53, 84].

Virus photoinactivation requires adequate interaction between the light source and photosensitizer. The photosensitizer type and concentration play an important role in the photodynamic mechanisms. Likewise, the light characteristics and its delivery should be adequate to provide photoexcitiational energy that will enable the virucidal effects [76]. Fluence, irradiance, and power are examples of irradiation parameters that must be taken into account when establishing a reliable protocol for PDT procedures. Different light sources have been studied for virus inactivation by PDT, such as tungsten lamps [86] and quartz halogen lights [98] (both coupled to filters emitting red light), xenon lamps [85], UV light [101], and low-power lasers [53, 55]. The latter is the most commonly used light source for photosensitization in viral infections because they present a single wavelength, which favors a better interaction with the resonant photosensitizer, as well as the possibility of calculating irradiation dosimetry more precisely [102]. Low-power red laser light is well absorbed by all the aforementioned photosensitizers and is considered very appropriate for use in virus photoinactivation [76].

The clinical use of PDT for the treatment of HSV-1 infections is mainly presented in the literature as case reports [5355]. The use of PDT is indicated in the vesicle phase [53] and aims to reduce the viral titer of vesicles and reduce their duration [53, 85, 103]. The relief of infection signals and symptoms are already noticeable a few hours after the PDT [53]. As noted in the literature, it is important to emphasize that PDT should only be conducted after leakage of all vesicles with a sterile needle because the use of the low-power laser during PDT may compromise prognosis [53, 55]. After PDT, the daily use of LPT alone is indicated. PDT aims to reduce viral titer, while LPT will help with lesion healing [53]. This association of PDT in the vesicle phase with LPT in the crust phase has been shown to produce infection resolution within a few days [55].

The treatment of HSV-1 oral manifestations with PDT may be considered a promising alternative when used in the vesicle phase to reduce viral titer and infection duration. Its potential effect on improving wound healing has also been reported and may help with the reduction of infection duration [54, 55]. The topical application of PDT allows a local and specific action at the disease active site [104], and the microbiota at other sites of the oral cavity is preserved [105]. In contrast to the antiviral-resistant HSV prevalence of up to 14 % in immunocompromised patients [106], resistance to singlet-oxygen-mediated PDT is unlikely to occur in such a specific population, as microorganisms’ resistance to oxidative lethal effects has not yet been reported in the literature. In addition, PDT does not exert harmful effects on adjacent tissues and therefore is considered a safe antimicrobial approach [107].

The literature still lacks controlled clinical studies on the use of PDT for the treatment of HSV-1 oral manifestations. However, there are many in vitro studies in the literature describing the beneficial effects of PDT for the management of HSV-1 infection. Despite the many successful cases reported, the establishment of an effective clinical protocol for HSV inactivation with PDT would only be possible via double-blind placebo studies that would be able to elucidate the exact action of this treatment modality in the clinical manifestations of HSV-1, as well as the adequate irradiation parameters to be used for an optimized association of the photosensitizer with low-power laser light.

High-power laser treatment

High-power lasers (HPLs) have been widely used in different dental specialties [108]. Unlike low-power lasers, HPLs induce a temperature increase on the target tissue and can lead to photothermally destructive reactions such as vaporization, coagulation, ablation, and tissue protein degradation/denaturation [109].

The mechanism of action of these lasers on oral tissues depends on the interaction between the laser light and the biological components (chromophores) of soft and hard tissues. The current literature reports some factors that can influence the effectiveness of laser interaction with the target tissue, including different wavelengths, energy densities, exposure time, and tissue composition [110].

Many HPLs produce beams with a Gaussian distribution, with the greatest power at the peak of the curve, gradually diminishing toward the periphery [109, 111]. Some authors have proposed that a range of roughly concentric bioreactions can occur simultaneously at the surface of the target tissues (with the most heat) and at a subcellular level, where light has penetrated with very low-power densities. The effects verified at the periphery of the beam are able to alter the energy level of the cell, influencing its metabolism and modulating its function. This concept is referred to as simultaneous low level laser therapy [111].

There are two main indications for the use of HPLs during a herpes simplex manifestation in the oral cavity. The main indication is to cause the lesion drainage during the vesicle phase of herpes lesions, in which the use of LPT should be avoided, as mentioned previously. Another indication would be to use HPLs in a defocused mode, where they act as low-power lasers. During the prodromic and/or repairing stages, it is expected that laser treatment can benefit both tissue healing and pain reduction, and laser treatment is also indicated for the prevention of herpes recurrence.

High-power laser treatment in the vesicle phase

HPLs have been shown to be effective for the rupture and drainage of vesicles clinically [54, 56]. Authors have reported the use of erbium lasers for this purpose because their wavelengths are resonant with the peak of the water absorption spectrum [112]. When the laser energy is absorbed by water molecules present in the tissue, there is a quick increase in temperature, followed by tissue vaporization and its high-pressure expansion [113]. This phenomenon is called ablation, and when considering its effects on herpes labialis, it is expected to cause the disruption of the virus structure such that it is no longer detectable, as investigated by Hughes and Hughes [114]. Marotti et al. [54] have also suggested that HPLs can reduce the amount of virus present in the fluid by increasing the local temperature and, consequently, decreasing the duration of the infection.

Using erbium lasers (Er:YAG or Er,Cr:YSGG), vesicles can be easily ruptured with minimal residual thermal damage and minimal pain [56]. Bello-Silva et al. [56] highlighted the possible presence of viable cells in laser-derived aerosol and noted that, during clinical procedures, lesions should be isolated with a fenestrated drape and a smoke evacuator should be positioned close to the irradiating site (approximately 1 cm) with the aim of preventing the dispersion of ablated particles [115].

Considering its potential to increase temperature, HPLs associated with water/air cooling are preferable because cooling is related to pain reduction during irradiation. Lasers without a cooling system may result in more discomfort for the patient during irradiation and may require the use of topical anesthesia [56]. The use of a diode laser at a low-power setting in a defocused mode has also been reported in the literature. The laser beam defocusing was not aimed at tissue ablation but rather modification of the epithelium of the lesion [116] and reduction of the need for anesthesia. Other researchers have mentioned the use of surgical lasers, including CO2 lasers, to open large blisters and empty the fluid inside before the application of low-power laser light [117].

The pain reduction and modulation of the healing process usually related to the use of defocused HPLs [109] is intimately related to its potential to penetrate into subsurface tissues, as cited previously (simultaneous low level laser therapy). It is important to state that the depth of tissue penetration by infrared lasers will depend on the wavelength used, the absorption coefficient of the tissues, and the irradiation parameters employed.

HPL effects on the healing phase

There are still no reports on the use of HPLs in the defocused mode for aiding in the healing of herpes labialis lesions. However, studies have already shown that defocusing the laser beam (increasing the irradiated spot diameter) decreases energy density [109], and low-power effects can therefore be achieved. There is also a lack of studies reporting on HSV-1 inactivation with HPLs. Likewise, there is a need for further clinical studies to investigate adequate irradiation protocols, as well as their effects on the frequency and recurrence of HSV-1 infections.

Final considerations

The main advantages of laser treatment appear to be the absence of side effects and drug interactions, which are especially useful for older and immunocompromised patients. Although these results indicate a potentially beneficial use of lasers in the management of HSV-1 oral manifestations, they are based mostly on case reports. The literature still lacks double-blind controlled clinical trials verifying these effects, and such trials should be the focus of future research. Because the first reports have already shown the potential of several types of laser therapy, it is worthwhile to invest more time and effort on developing high-quality clinical trials to produce stronger evidence of the effects of laser treatment in comparison to placebo and conventional antiviral drugs.

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© Springer-Verlag London 2013