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REVIEW ARTICLE
Laser treatment of recurrent herpes labialis:
a literature review
Carlos de Paula Eduardo &Ana Cecilia Corrêa Aranha &
Alyne Simões &Marina Stella Bello-Silva &
Karen Muller Ramalho &Marcella Esteves-Oliveira &
Patrícia Moreira de Freitas &Juliana Marotti &
Jan Tunér
Received: 25 October 2012 /Accepted: 12 March 2013
#Springer-Verlag London 2013
Abstract Recurrent herpes labialis is a worldwide life-long
oral health problem that remains unsolved. It affects approx-
imately one third of the world population and causes fre-
quent 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 suc-
cessful in completely eliminating the virus and its recur-
rence. 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 shed-
ding, viral inactivation, and interval of recurrence.
According to the literature,noneofthelasertreatment
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 caus-
ing 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
C. de Paula Eduardo (*):A. C. C. Aranha :M. S. Bello-Silva :
K. M. Ramalho :M. Esteves-Oliveira :P. M. de Freitas
Special Laboratory of Lasers in Dentistry (LELO), Department of
Restorative Dentistry, School of Dentistry of the University of São
Paulo (USP), Av. Prof. Lineu Prestes, 2227,
05508-000 São Paulo, SP, Brazil
e-mail: cpeduard@usp.br
A. Simões
Laboratory of Oral Biology, Department of Biomaterials and Oral
Biology, School of Dentistry of the University of São Paulo (USP),
Av. Prof. Lineu Prestes, 2227,
05508-000 São Paulo, SP, Brazil
M. S. Bello-Silva
School of Dentistry, Nove de Julho University, Rua Vergueiro 249,
01504-001 São Paulo, SP, Brazil
K. M. Ramalho
Department of Stomatoloy, Discipline of Integrated Dental Clinic,
School of Dentistry of the University of São Paulo (USP), Av.
Prof. Lineu Prestes, 2227,
05508-000 São Paulo, SP, Brazil
M. Esteves-Oliveira
Department of Operative Dentistry, Periodontology and Preventive
Dentistry, RWTH Aachen University, Pauwelsstraße 30,
52074 Aachen, Germany
J. Marotti
Department of Prosthodontics and Dental Materials, Medical
Faculty, RWTH Aachen University, Pauwelsstraße 30,
52074 Aachen, Germany
J. Tunér
Private Dental Clinic, Spjutvagen 9,
77232 Grangesberg, Sweden
C. P. Eduardo (*):A. C. C. Aranha :M. S. Bello-Silva :
Lasers Med Sci
DOI 10.1007/s10103-013-1311-8
indicate a potential beneficial use for lasers in the manage-
ment 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 virus .HSV-1 .High-power
laser .Low-power laser .Laser phototherapy .Photodynamic
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 [6–9], 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 includ-
ed 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 ther-
apy”,“PDT”,“high intensity laser”,“high power laser”,
“Nd:YAG ”,“Er:YA G”,“Er,Cr:YSGG”,“CO
2
”,“diode”,
and “laser”. The studies and articles were searched to iden-
tify 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 in-
fections in varied areas [11]. Oral herpes is the most com-
mon 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 imma-
ture 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 con-
tact 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 poten-
tial triggers have been identified and related to immunosup-
pressive 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, tender-
ness, pain, burning sensation, or itching sensation arise in
46–60 % of patients, lasting approximately 6 h. Approxi-
mately 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 ve-
sicular, 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 pre-
scription of antiviral compounds. The available treatments
do not cure latent HSV infections, but rather palliate symp-
toms or prevent recurrences. Most drugs developed to act
against HSV are antiviral agents called nucleosides and
Lasers Med Sci
nucleotide analogs, which block viral reproduction. The
most prescribed medications against RHL include acyclovir,
valacyclovir, and famciclovir. The antiviral drugs are effec-
tive and reasonably safe when properly administrated. How-
ever, these medications differ in their chemical structure,
dosage and cost [10,16–19].
Topical and systemic acyclovir, at a variety of concentra-
tions 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 out-
break and the number of days that the virus can be trans-
mitted. In addition, the medications reduce the healing time,
which consequently decreases painful symptoms. Neverthe-
less, 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 [10,18–20,
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 recur-
rences affect the patient’squalityoflife,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 reduc-
tion in latency [27]. The immunotherapeutic effects of her-
pes 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 reproduc-
tion. Limiting reproduction helps to keep the virus inactive
or latent. Acyclovir and penciclovir have a similar mecha-
nism 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 [7,30–33].
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 pre-
viously, many antiviral agents are available for the treatment
of HSV-1 infection. Despite these treatments being effec-
tive, drug-resistant strains have been found, and there is no
available vaccine for this troublesome viral infection. Re-
cently, 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 photobio-
logical effects of laser light (low-power lasers or
“defocused”high-power lasers). Regarding laser photother-
apy (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 per-
meability changes, and nitric oxide release [35]. These ef-
fects 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 Ca
2+
and cyclic adenosine monophosphate
levels [36], which are related to various biological processes
such as RNA and DNA synthesis, cell mitosis, and
Lasers Med Sci
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 win-
dow 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 toler-
ated by patients.
The anti-inflammatory effect of LPT could be partially
due to an increase in circulation and inhibition of PGE
2
synthesis [41,42]. The analgesic effect of LPT is still not
totally clear in the literature. It has been shown that periph-
eral 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 decreas-
ing pain transmission. Moreover, LPT can enhance periph-
eral 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]investi-
gated the effect of LPT on HSV-1 replication and eval-
uated 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 1lists the relevant reports from the literature (clinical
studies, brief reports, and clinical cases) published in or
before September 2012.
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 [48–51]. 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/cm
2
.
The studies also vary in regards to the RHL (latent, prodromic,
vesicle, or crust) to which laser therapy was applied. Never-
theless, 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 re-
duced 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 differ-
ence 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 com-
parison 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 [53–55], 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 dura-
tion 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 exam-
ining the immediate post-LPT treatment period [54–57].
Lasers Med Sci
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/cm
2
, 8 J/cm
2
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 cm
2
,
80 mW/cm
2
, 48 J/cm
2
,
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/cm
2
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/cm
2
, in infected phase
Spot size= 0.04 cm
2
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/cm
2
, 51 mW/cm
2
—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 cm
2
Lasers Med Sci
Table 1 (continued)
Reference Study type Patients Follow-up Laser parameters Irradiation mode Results
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/cm
2
,
1.75 W/cm
2
, 50/60 points, 21 J
Spot size= 0.04 cm
2
(5 min total irradiation time) in
recurrence-free period
10 sessions 2×/week—during 5 weeks
660 nm (diode laser)
50 mW, 20 J/cm
2
(in prodromic
phase)
50 mW, 4 J/cm
2
(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/
cm
2
Contact mode Immediately pain relief. The child
was able to eat again. 1 week later,
the wound was completely healed
Spot size= 0.04 cm
2
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/cm
2
, 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 timeLPT - diode laser, 660 nm; 3.8
J/cm
2
; 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/cm
2
, 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/
cm
2
,
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/cm
2
; 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/cm
2
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/cm
2
; 3.8 J/cm
2
; 10 mW; 10 s/
point
With exception of Er:YAG irradiation Complete healing after 10 days
Lasers Med Sci
–No side effects associated with LPT were reported in
any of the clinical studies or case reports [48–51,
53–56,58].
Infection phases and indication of laser phototherapy
HSV-1 infection, as described earlier, manifests itself clini-
cally 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 manage-
ment 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 [54–57,59].
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]. Al-
though 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 demon-
strated 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 infec-
tion 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 ves-
icle 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]. There-
fore, 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
[65–67], 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 inflam-
matory process. Alone, low-power lasers do not have sig-
nificant 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 [71–73].
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 hematopor-
phyrin [74]. This photodynamic process is generally
unspecific and depends on the affinity of these photosensi-
tizers 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 micro-
organisms such as bacteria, fungi, and viruses. Because of
Lasers Med Sci
its lethal effects on microorganisms, this type of PDT is also
called antimicrobial photodynamic therapy, photoactivated
disinfection [75], lethal photosensitization, and photody-
namic antimicrobial chemotherapy.
The lethal effects of PDT are mediated by either the pro-
duction 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 ap-
proval of PDT for esophageal tumor treatment [82].
The increasing concerns regarding the risk of virus infec-
tion have raised the importance of photodynamic inactiva-
tion 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]. Be-
cause 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, effec-
tive 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 photosensi-
tizers for virus inactivation [95]. This porphyrin-like
second-generation sensitizer also absorbs red light efficient-
ly 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 adsorp-
tion, 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 pre-
cursor of protoporphyrin IX, and its use in virus inactivation
has been extensively studied. Its action in HSV was dem-
onstrated in an in vivo study and was effective for both
experimental animals and human patients [85].
It is possible to conclude that each photosensitizer pre-
sents 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 be-
tween the light source and photosensitizer. The photosensi-
tizer type and concentration play an important role in the
photodynamic mechanisms. Likewise, the light characteris-
tics and its delivery should be adequate to provide
photoexcitiational energy that will enable the virucidal ef-
fects [76]. Fluence, irradiance, and power are examples of
irradiation parameters that must be taken into account when
establishing a reliable protocol for PDT procedures. Differ-
ent light sources have been studied for virus inactivation by
Lasers Med Sci
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 photosen-
sitization in viral infections because they present a single
wavelength, which favors a better interaction with the reso-
nant 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 pho-
tosensitizers 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
[53–55]. 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 ofinfection 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 immuno-
compromised patients [106], resistance to singlet-oxygen-
mediated PDT is unlikely to occur in such a specific popula-
tion, 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 there-
fore 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 differ-
ent 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 vapor-
ization, 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 tar-
get 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 vapori-
zation and its high-pressure expansion [113]. This phenom-
enon 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 inves-
tigated by Hughes and Hughes [114]. Marotti et al. [54]
have also suggested that HPLs can reduce the amount of
Lasers Med Sci
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 dam-
age and minimal pain [56]. Bello-Silva et al. [56] highlight-
ed 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 disper-
sion 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, includ-
ing CO
2
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 inti-
mately 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 irra-
diation 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. Like-
wise, 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 bene-
ficial use of lasers in the management of HSV-1 oral man-
ifestations, 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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