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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, 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 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 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.
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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 [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 includ-
ed searching the Cochrane Library and PubMed using the
terms: recurrent herpes labialis,herpes simplex virus 1
infection,HSV-1,andoral 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 simplexclassification, 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, Mollarets
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
4660 % 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 110 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 [10,1619].
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 57 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 recur-
rences affect the patientsqualityoflife,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 [7,3033].
Essential to a successful therapeutic intervention for RHL
is an accurate anamnesis for assessment of the patients
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 phototherapymechanisms 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
defocusedhigh-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 phototherapyclinical 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/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 [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 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 [5457].
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 (HeNe 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
group37.5 weeks×control
group3 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
group0.116 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 Japplied
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
C2C3 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 135, year 242,
year 3149, year 441, year 522
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×/weekduring 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:YSGG2.78 μm, 20 Hz,
0.75 W (vesicles drainage)
PDTMethylene 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 PDTMethylene 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
LPTdiode 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 PDTMethylene 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
LPTdiode 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:YAG2.94 μm, 80 mJ/pulse,
24 Hz (vesicles drainage)
Contact mode, punctual applications Pain was discontinued in the
first session
LPTdiode 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 [4851,
5356,58].
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 [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]. 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 780808 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
[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 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 [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 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
hostcell 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
[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 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 microorganismsresistance 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.
References
1. Embil JA, Stephens RG, Manuel FR (1975) Prevalence of recur-
rent herpes labialis and aphthous ulcers among young adults on six
continents. Can Med Assoc J 113(7):627630
2. Lowhagen GB, Bonde E, Eriksson B, Nordin P, Tunback P, Krantz
I (2002) Self-reported herpes labialis in a Swedish population.
Scand J Infect Dis 34(9):664667
3. Spruance SL (1992) The natural history of recurrent oral-facial
herpes simplex virus infection. Semin Dermatol 11(3):200206
4. Cernik C, Gallina K, Brodell RT (2008) The treatment of herpes
simplex infections: an evidence-based review. Arch Intern Med
168(11):11371144. doi:10.1001/archinte.168.11.1137
5. Glenny AM, Fernandez Mauleffinch LM, Pavitt S, Walsh T (2009)
Interventions for the prevention and treatment of herpes simplex
virus in patients being treated for cancer. Cochrane Database Syst
Rev. doi:10.1002/14651858.CD006706.pub2
6. Harmenberg J, Oberg B, Spruance S (2010) Prevention of ulcera-
tive lesions by episodic treatment of recurrent herpes labialis: a
literature review. Acta Derm Venereol 90(2):122130.
doi:10.2340/00015555-0806
7. Woo SB, Challacombe SJ (2007) Management of recurrent oral herpes
simplex infections. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
103(Suppl):S12 e11S12 e18. doi:10.1016/j.tripleo.2006.11.004
8. Opstelten W, Neven AK, Eekhof J (2008) Treatment and preven-
tion of herpes labialis. Can Fam Physician 54(12):16831687
9. Miller CS, Danaher RJ, Jacob RJ (1998) Molecular aspects of
herpes simplex virus I latency, reactivation, and recurrence. Crit
Rev Oral Biol Med 9(4):541562
10. Arduino PG, Porter SR (2008) Herpes simplex virus type 1
infection: overview on relevant clinico-pathological features. J
Oral Pathol Med 37(2):107121
11. Chayavichitsilp P, Buckwalter JV, Krakowski AC, Friedlander SF
(2009) Herpes simplex. Pediatr Rev 30(4):119129. doi:10.1542/
pir.30-4-119
12. Axell T, Liedholm R (1990) Occurrence of recurrent herpes labialis
in an adult Swedish population. Acta Odontol Scand 48(2):119123
13. Reichart PA (2000) Oral mucosal lesions in a representative
cross-sectional study of aging Germans. Community Dent Oral
Epidemiol 28(5):390398
14. Crumpacker CS (2004) Use of antiviral drugs to prevent herpes-
virus transmission. N Engl J Med 350(1):6768. doi:10.1056/
NEJMe038189
15. Esmann J (2001) The many challenges of facial herpes simplex
virus infection. J Antimicrob Chemother 47(Suppl T1):1727
16. Arduino PG, Porter SR (2006) Oral and perioral herpes simplex
virus type 1 (HSV-1) infection: review of its management. Oral
Dis 12(3):254270
Lasers Med Sci
17. Fatahzadeh M, Schwartz RA (2007) Human herpes simplex virus
infections: epidemiology, pathogenesis, symptomatology, diag-
nosis, and management. J Am Acad Dermatol 57(5):737763,
quiz 764-736
18. Raborn GW, Grace MG (2003) Recurrent herpes simplex labialis:
selected therapeutic options. J Can Dent Assoc 69(8):498503
19. Spruance SL, Kriesel JD (2002) Treatment of herpes simplex
labialis. Herpes 9(3):6469
20. Fatahzadeh M, Schwartz RA (2007) Human herpes simplex
labialis. Clin Exp Dermatol 32(6):625630
21. Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding
T (2002) Acyclovir cream for treatment of herpes simplex
labialis: results of two randomized, double-blind, vehicle-
controlled, multicenter clinical trials. Antimicrob Agents
Chemother 46(7):22382243
22. Birek C (2000) Herpesvirus-induced diseases: oral manifestations
and current treatment options. J Calif Dent Assoc 28(12):911921
23. Su CT, Hsu JT, Hsieh HP, Lin PH, Chen TC, Kao CL, Lee CN,
Chang SY (2008) Anti-HSV activity of digitoxin and its possi ble
mechanisms. Antiviral Res 79(1):6270
24. Baker D, Eisen D (2003) Valacyclovir for prevention of recurrent
herpes labialis: 2 double-blind, placebo-controlled studies. Cutis
71(3):239242
25. Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL
(1998) Oral famciclovir for the suppression of recurrent genital
herpes: a randomized controlled trial. Collaborative Famciclovir
Genital Herpes Research Group. JAMA 280(10):887892
26. Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R, Frost P,
Crumpacker C, Rabinovich S, Peacock JE Jr, Herndon J et al
(1991) Prolonged continuous acyclovir treatment of normal
adults with frequently recurring genital herpes simplex virus
infection. The Acyclovir Study Group. JAMA 265(6):747751
27. Koelle DM, Ghiasi H (2005) Prospects for developing an effec-
tive vaccine against ocular herpes simplex virus infection. Curr
Eye Res 30(11):929942. doi:10.1080/02713680500313153
28. De Clercq E, Walker RT (1984) Synthesis and antiviral properties
of 5-vinylpyrimidine nucleoside analogs. Pharmacol Ther
26(1):144
29. Shinkai I, Ohta Y (1996) New drugsreports of new drugs
recently approved by the FDA. Dirithromycin. Bioorg Med
Chem 4(4):521522
30. Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D (2003)
Herpes simplex virus resistance to acyclovir and penciclovir after
two decades of antiviral therapy. Clin Microbiol Rev 16(1):114
128
31. Datema R, Ericson AC, Field HJ, Larsson A, Stenberg K (1987)
Critical determinants of antiherpes efficacy of buciclovir and
related acyclic guanosine analogs. Antiviral Res 7(6):303316
32. Earnshaw DL, Bacon TH, Darlison SJ, Edmonds K, Perkins RM,
Vere Hodge RA (1992) Mode of antiviral action of penciclovir in
MRC-5 cells infected with herpes simplex virus type 1 (HSV-1),
HSV-2, and varicella-zoster virus. Antimicrob Agents Chemother
36(12):27472757
33. Morfin F, Thouvenot D (2003) Herpes simplex virus resistance to
antiviral drugs. J Clin Virol 26(1):2937
34. Huber MA (2003) Herpes simplex type-1 virus infection. Quin-
tessence Int 34(6):453467
35. Karu TI (1986) Molecular mechanism of the therapeutic effect of
low-intensity laser irradiation. Dokl Akad Nauk SSSR
291(5):12451249
36. Lito P, Pantanowitz L, Marotti J, Aboulafia DM, Campbell V,
Bower M, Dezube BJ (2009) Gastroenteropancreatic neuroendo-
crine tumors in patients with HIV infection: a trans-Atlantic series.
Am J Med Sci 337(1):14. doi:10.1097/MAJ.0b013e31817d1cb7
37. Zungu IL, Hawkins Evans D, Abrahamse H (2009) Mitochondrial
responses of normal and injured human skin fibroblasts following
low level laser irradiation-an in vitro study. Photochem Photobiol
85(4):987996. doi:10.1111/j.1751-1097.2008.00523.x
38. Tunér J (2011) Laser phototherapy (LPT) in dentistry. Int CE
Mag Laser Dent 1(817)
39. Karu T (1989) Photobiology of low-power laser effects. Health
Phys 56(5):691704
40. Ramalho KM, Luiz AC, de Paula EC, Tunér J, Magalhaes RP,
Gallottini Magalhaes M (2011) Use of laser phototherapy on a
delayed wound healing of oral mucosa previously submitted to
radiotherapy: case report. Int Wound J 8(4):413418.
doi:10.1111/j.1742-481X.2011.00788.x
41. Schindl A, Schindl M, Pernerstorfer-Schon H, Schindl L (2000)
Low-intensity laser therapy: a review. J Investig Med 48(5):312
326
42. Schaffer M, Bonel H, Sroka R, Schaffer PM, Busch M, Reiser M,
Duhmke E (2000) Effects of 780 nm diode laser irradiation on
blood microcirculation: preliminary findings on time-dependent
T1-weighted contrast-enhanced magnetic resonance imaging
(MRI). J Photochem Photobiol B 54(1):5560
43. Kudo HC, Inomata K, Okajima K, Moteji M, Oshiro T (1998)
Low-level laser therapy: pain attenuation mechanisms. Laser
Therapy 2:36
44. Hagiwara S, Iwasaka H, Okuda K, Noguchi T (2007) GaAlAs
(830 nm) low-level laser enhances peripheral endogenous opioid
analgesia in rats. Lasers Surg Med 39(10):797802. doi:10.1002/
lsm.20583
45. Mizutani K, Musya Y, Wakae K, Kobayashi T, Tobe M, Taira K,
Harada T (2004) A clinical study on serum prostaglandin E2 with
low-level laser therapy. Photomed Laser Surg 22(6):537539.
doi:10.1089/pho.2004.22.537
46. Chow RT, David MA, Armati PJ (2007) 830 nm laser irradiation
induces varicosity formation, reduces mitochondrial membrane
potential and blocks fast axonal flow in small and medium
diameter rat dorsal root ganglion neurons: implications for the
analgesic effects of 830 nm laser. J Peripher Nerv Syst 12(1):28
39. doi:10.1111/j.1529-8027.2007.00114.x
47. Donnarumma G, De Gregorio V, Fusco A, Farina E, Baroni A,
Esposito V, Contaldo M, Petruzzi M, Pannone G, Serpico R
(2010) Inhibition of HSV-1 replication by laser diode-
irradiation: possible mechanism of action. Int J Immunopathol
Pharmacol 23(4):11671176
48. de Carvalho RR, de Paula EF, Ramalho KM, Antunes JL,
Bezinelli LM, de Magalhaes MH, Pegoretti T, de Freitas PM,
de Paula EC (2010) Effect of laser phototherapy on recurring
herpes labialis prevention: an in vivo study. Lasers Med Sci
25(3):397402. doi:10.1007/s10103-009-0717-9
49. Sanchez PJM, Femenias JLC, Tejeda AD, Tunér J (2012) The of
670-nm low laser therapy on herpes simplex type 1. Photomed
Laser Surg 30(1):3740
50. Schindl A, Neumann R (1999) Low-intensity laser therapy is an
effective treatment for recurrent herpes simplex infection. Results
from a randomized double-blind placebo-controlled study. J Invest
Dermatol 113(2):221223. doi:10.1046/j.1523-1747.1999.00684.x
51. Vélez-González M, Urrea-Arbeláez A, Nicolas M, Serra-Baldrich
E, Perez JL, Pavesi M, Camarasa JMG, Trelles MA (1995)
Treatment of relapse in herpes simplex on labial & facial areas
and of primary herpes simplex on genital areas and area puden-
dawith low power laser (He-Ne) or Acyclovir administered
orally. SPIE Proc 2630:4350
52. Eduardo CP, Bezinelli LM, Eduardo FP, Lopes RMG, Ramalho
KM, Bello-Silva MS, Esteves-Oliveira M (2012) Prevention of
recurrent herpes labialis outbreaks through low-intensity laser
therapy. A clinical protocol with 3 years follow-up. Lasers Med
Sci 27(5):10771083
53. Marotti J, Aranha AC, Eduardo Cde P, Ribeiro MS (2009) Pho-
todynamic therapy can be effective as a treatment for herpes
Lasers Med Sci
simplex labialis. Photomed Laser Surg 27(2):357363.
doi:10.1089/pho.2008.2268
54. Marotti J, Sperandio FF, Fregnani ER, Aranha AC, de Freitas
PM, Eduardo Cde P (2010) High-intensity laser and photody-
namic therapy as a treatment for recurrent herpes labialis.
Photomed Laser Surg 28(3):439444. doi:10.1089/
pho.2009.2522
55. Sperandio FF, Marotti J, Aranha AC, Eduardo Cde P (2009)
Photodynamic therapy for the treatment of recurrent herpes
labialis: preliminary results. Gen Dent 57(4):415419
56. Bello-Silva MS, de Freitas PM, Aranha AC, Lage-Marques JL,
Simoes A, de Paula EC (2010) Low- and high-intensity lasers in
the treatment of herpes simplex virus 1 infection. Photomed Laser
Surg 28(1):135139. doi:10.1089/pho.2008.2458
57. Navarro R, Marquezan M, Cerqueira DF, Silveira BL, Correa MS
(2007) Low-level-laser therapy as an alternative treatment for
primary herpes simplex infection: a case report. J Clin Pediatr
Dent 31(4):225228
58. de Paula EC, de Freitas PM, Esteves-Oliveira M, Aranha AC,
Ramalho KM, Simoes A, Bello-Silva MS, Tuner J (2010) Laser
phototherapy in the treatment of periodontal disease. A review
Lasers Med Sci 25(6):781792. doi:10.1007/s10103-010-0812-y
59. Tunér J, Hode L (2007) The Laser Therapy Handbook. Prima
Books, Grangesberg
60. Eduardo CP, Bezinelli LM, Eduardo FP, Lopes RMG, Ramalho
KM, Bello-Silva MS, Esteves-Oliveira M (2012) Prevention of
recurrent herpes labialis outbreaks through low-intensity laser
therapy. A clinical protocol with 3 years follow-up. Las Med
Sci 27(5):10771083
61. Gilioli G, Taparelli F, Fornaciari A, Palmieri B, Celani M (1985)
Studio ultrastrutturale di colture cellulari veroinfettate con
virus Herpes Simplex e sottoposte all- azione Laser [In Italian].
[Ultrastructural study of cell cultures infected with herpes sim-
plex virus and subjected to the action of laser]. Med Laser Rep
3:2831
62. Novoselova EG, Glushkova OV, Cherenkov DA, Chudnovsky
VM, Fesenko EE (2006) Effects of low-power laser radiation on
mice immunity. Photodermatol Photoimmunol Photomed
22(1):3338. doi:10.1111/j.1600-0781.2006.00191.x
63. Dougal G, Kelly P (2001) A pilot study of treatment of herpes
labialis with 1072 nm narrow waveband light. Clin Exp Dermatol
26(2):149154
64. Landthaler M, Haina D, Waidelich W (1983) Behandlung von
zoster, postzosterischen schmerzen und herpes simplex recidivans
in loco mit laser-licht. Fortsch Med 101:1039
65. Ackermann G, Hartmann M, Scherer K, Lang EW, Hohenleutner
U, Landthaler M, Baumler W (2002) Correlations between light
penetration into skin and the therapeutic outcome following laser
therapy of port-wine stains.LasersMedSci17(2):7078.
doi:10.1007/s101030200013
66. Tunér J, Hode L (1999) Low level laser therapy: clinical practice
and scientific background. Prima Books, Grangesberg
67. Niemz MH (1996) Laser-tissue interactions: fundamentals and
applications, 1st edn. Springer, Berlin
68. Azevedo LH, de Paula EF, Moreira MS, de Paula EC, Marques
MM (2006) Influence of different power densities of LILT on
cultured human fibroblast growth: a pilot study. Lasers Med Sci
21(2):8689. doi:10.1007/s10103-006-0379-9
69. Hamblin MR, Zahra T, Contag CH, McManus AT, Hasan T
(2003) Optical monitoring and treatment of potentially lethal
wound infections in vivo. J Infect Dis 187(11):17171725.
doi:10.1086/375244
70. Wainwright M (1998) Photodynamic antimicrobial chemotherapy
(PACT). J Antimicrob Chemother 42(1):1328
71. Bhatti M, MacRobert A, Meghji S, Henderson B, Wilson M
(1998) A study of the uptake of toluidine blue O by
Porphyromonas gingivalis and the mechanism of lethal photo-
sensitization. Photochem Photobiol 68(3):370376
72. Bhatti M, Nair SP, Macrobert AJ, Henderson B, Shepherd P,
Cridland J, Wilson M (2001) Identification of photolabile outer
membrane proteins of Porphyromonas gingivalis. Curr Microbiol
43(2):9699. doi:10.1007/s002840010268
73. Harris F, Chatfield LK, Phoenix DA (2005) Phenothiazinium
based photosensitisersphotodynamic agents with a multiplicity
of cellular targets and clinical applications. Curr Drug Targets
6(5):615627
74. Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE,
Nesland JM (1997) 5-Aminolevulinic acid-based photodynamic ther-
apy. Clinical research and future challenges. Cancer 79(12):2282
2308. doi:10.1002/(SICI)1097-0142(19970615)79:12<2282::
AID-CNCR2>3.0.CO;2-O
75. Bandyopadhyay-Ghosh S, Reaney IM, Johnson A, Hurrell-
Gillingham K, Brook IM, Hatton PV (2008) The effect of invest-
ment materials on the surface of cast fluorcanasite glasses and
glass-ceramics. J Mater Sci Mater Med 19(2):839846.
doi:10.1007/s10856-007-3207-2
76. Wainwright M (2003) Local treatment of viral disease using
photodynamic therapy. Int J Antimicrob Agents 21(6):510520
77. Schulz EW (1928) Inactivation of Staphyloccus bacteriophage by
Methylene Blue. Proc Soc Exp Biol Med 26:100101
78. Felber TD, Smith EB, Knox JM, Wallis C, Melnick JL (1973)
Photodynamic inactivation of herpes simplex. J Am Med Assoc
223(3):289292
79. Rapp F, Kemeny BA (1977) Oncogenic potential of herpes sim-
plex virus in mammalian cells following photodynamic inactiva-
tion. Photochem Photobiol 25(4):335337
80. Myers MG, Oxman MN, Clark JE, Arndt KA (1975) Failure of
neutral-red photodynamic inactivation in recurrent herpes sim-
plex virus infections. N Engl J Med 293(19):945949.
doi:10.1056/NEJM197511062931901
81. Owens JW, Robins M (2000) The role of second generation
organometallic complexes in the photodynamic therapeutic treat-
ment of cancer. Recent Res Dev Inorg Chem 2:4155
82. Ackroyd R, Brown N, Vernon D, Roberts D, Stephenson T,
Marcus S, Stoddard C, Reed M (1999) 5-Aminolevulinic acid
photosensitization of dysplastic Barretts esophagus: a pharma-
cokinetic study. Photochem Photobiol 70(4):656662
83. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ (1996) The
risk of transfusion-transmitted viral infections. The retrovirus
epidemiology donor study. N Engl J Med 334(26):16851690.
doi:10.1056/NEJM199606273342601
84. Muller-Breitkreutz K, Mohr H (1998) Hepatitis C and human
immunodeficiency virus RNA degradation by methylene blue/
light treatment of human plasma. J Med Virol 56(3):239245.
doi:10.1002/(SICI)1096-9071(199811)56:3<239::AID-
JMV11>3.0.CO;2-9
85. Smetana Z, Malik Z, Orenstein A, Mendelson E, Ben-Hur E
(1997) Treatment of viral infections with 5-aminolevulinic acid
and light. Lasers Surg Med 21(4):351358. doi:10.1002/
(SICI)1096-9101(1997)21:4<351::AID-LSM6>3.0.CO;2-P
86. Wagner SJ, Skripchenko A, Robinette D, Foley JW, Cincotta L
(1998) Factors affecting virus photoinactivation by a series of
phenothiazine dyes. Photochem Photobiol 67(3):343349
87. Schnipper LE, Lewin AA, Swartz M, Crumpacker CS (1980)
Mechanisms of photodynamic inactivation of herpes simplex
viruses: comparison between methylene blue, light plus electric-
ity, and hematoporhyrin plus light. J Clin Invest 65(2):432438.
doi:10.1172/JCI109686
88. Lambrecht B, Mohr H, Knuver-Hopf J, Schmitt H (1991)
Photoinactivation of viruses in human fresh plasma by phenothia-
zine dyes in combination with visible light. Vox Sang 60(4):207
213
Lasers Med Sci
89. Tuite EM, Kelly JM (1993) Photochemical interactions of meth-
ylene blue and analogues with DNA and other biological sub-
strates. J Photochem Photobiol B 21(23):103124
90. Muller-Breitkreutz K, Mohr H (1997) Infection cycle of herpes
viruses after photodynamic treatment with methylene blue and
light. Beitr Infusionsther Transfusionsmed 34:3742
91. Muller-Breitkreutz K, Mohr H, Briviba K, Sies H (1995) Inacti-
vation of viruses by chemically and photochemically generated
singlet molecular oxygen. J Photochem Photobiol B 30(1):6370
92. Wainwright M (2002) The emerging chemistry of blood product
disinfection. Chem Soc Rev 31(2):128136
93. Wagner SJ, Skripchenko A, Robinette D, Mallory DA, Cincotta L
(1998) Preservation of red cell properties after virucidal
phototreatment with dimethylmethylene blue. Transfusion
38(8):729737
94. Wainwright M, Phoenix DA, Rice L, Burrow SM, Waring J
(1997) Increased cytotoxicity and phototoxicity in the methylene
blue series via chromophore methylation. J Photochem Photobiol
B 40(3):233239
95. Ben-Hur E, Hoeben RC, Van Ormondt H, Dubbelman TM, Van
Steveninck J (1992) Photodynamic inactivation of retroviruses by
phthalocyanines: the effects of sulphonation, metal ligand and
fluoride. J Photochem Photobiol B 13(2):145152
96. Van Lier JE (1990) Phthalocyanines as sensitizers for PDT of
cancer. In: Kessel D (ed) Photodynamic therapy of neoplasis
diseases, vol 1. CRC Press, Boca Raton, pp 279291
97. Smetana Z, Mendelson E, Manor J, van Lier JE, Ben-Hur E, Salzberg
S, Malik Z (1994) Photodynamic inactivation of herpes viruses with
phthalocyanine derivatives. J Photochem Photobiol B 22(1):3743
98. Smetana Z, Ben-Hur E, Mendelson E, Salzberg S, Wagner P,
Malik Z (1998) Herpes simplex virus proteins are damaged
following photodynamic inactivation with phthalocyanines. J
Photochem Photobiol B 44(1):7783. doi:10.1016/S1011-
1344(98)00124-9
99. Rywkin S, Lenny L, Goldstein J, Geacintov NE, Margolis-Nunno
H, Horowitz B (1992) Importance of type I and type II mechanisms
in the photodynamic inactivation of viruses in blood with aluminum
phthalocyanine derivatives. Photochem Photobiol 56(4):463469
100. Javaly K, Wohlfeiler M, Kalayjian R, Klein T, Bryson Y, Grafford
K, Martin-Munley S, Hardy WD (1999) Treatment of mucocuta-
neous herpes simplex virus infections unresponsive to acyclovir
with topical foscarnet cream in AIDS patients: a phase I/II study.
J Acquir Immune Defic Syndr 21(4):301306
101. Lytle CD, Carney PG, Felten RP, Bushar HF, Straight RC (1989)
Inactivation and mutagenesis of herpes virus by photodynamic
treatment with therapeutic dyes. Photochem Photobiol
50(3):367371
102. Ackroyd R, Kelty C, Brown N, Reed M (2001) The history of
photodetection and photodynamic therapy. Photochem Photobiol
74(5):656669
103. Kvacheva ZB, Shukanova NA, Votyakov VI, Lobanok ES,
Vorobei AV, Nikolaeva SN (2003) Photodynamic inhibition of
infection caused by drug-resistant variants of herpes simplex
virus type I. Bull Exp Biol Med 135(4):384387
104. Hsi RA, Rosenthal DI, Glatstein E (1999) Photodynamic therapy
in the treatment of cancer: current state of the art. Drugs
57(5):725734
105. Chan Y, Lai CH (2003) Bactericidal effects of different laser wave-
lengths on periodontopathic germs in photodynamic therapy. Lasers
Med Sci 18(1):5155. doi:10.1007/s10103-002-0243-5
106. Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL,
Scholl DR, Balfour HH Jr (1990) Herpes simplex virus resistant
to acyclovir. A study in a tertiary care center. Ann Intern Med
112(6):416422
107. Komerik N, Curnow A, MacRobert AJ, Hopper C, Speight PM,
Wilson M (2002) Fluorescence biodistribution and
photosensitising activity of toluidine blue o on rat buccal mucosa.
Lasers Med Sci 17(2):8692. doi:10.1007/s101030200015
108. Eduardo CP (2010) Laser in contemporary clinical dentistry. In:
Fernandes CP (ed) A world class dentistry, FDI 2010. Livraria
Santos, Brazil, pp 237264
109. Ohshiro T, Fujino T (1993) Laser applications in plastic and
reconstructive surgery. Keio J Med 42(4):191195
110. Meister J (2007) Basic research. In: Gutknecht N (ed) Pro-
ceedings of the 1st International Workshop of Evidence
Based Dentistry on Lasers in Dentistry. Quintessence, Berlin,
pp 327
111. Calderhead RG (1991) Simultaneous LLLT in laser surgery:
the phenomenon explained. In: Ohshiro T, Calderhead RG
(eds) Progress in laser therapy. Wiley, Chichester, pp 209
213
112. Kaufmann R, Hibst R (1990) Pulsed 2.94-microns erbium-YAG
laser skin ablationexperimental results and first clinical appli-
cation. Clin Exp Dermatol 15(5):389393
113. Hohenleutner U, Hohenleutner S, Baumler W, Landthaler M
(1997) Fast and effective skin ablation with an Er:YAG laser:
determination of ablation rates and thermal damage zones. Lasers
Surg Med 20(3):242247. doi:10.1002/(SICI)1096-
9101(1997)20:3<242::AID-LSM2>3.0.CO;2-Q
114. Hughes PS, Hughes AP (1998) Absence of human papillomavirus
DNA in the plume of erbium:YAG laser-treated warts. J Am Acad
Dermatol 38(3):426428
115. Trevor M (1987) Presence of virus in CO2 laser plumes raises
infection concern. Hospital Infection Control 14:166167
116. Kotlow L (2011) Lasers in pediatric dentistry. In: Convissar RA
(ed) Principles and practice of laser dentistry. Mosby, Elsevier, St.
Louis, pp 202224
117. Tunér J, Beck-Kristensen PH (2011) Low-level lasers in dentistry.
In: Convissar RA (ed) Principles and practice of laser dentistry.
Mosby, Elsevier, St. Louis, pp 263286
Lasers Med Sci
... Photosensitizers with affinity for the virus envelope such as merocyanine 540 and hematoporphyrin derivatives inhibit virus infectivity, whereas those with affinity for the virus nucleic acid such as toluidine blue and MB inactivate viral genetic material. 20 For recurrent herpes simplex, what matters is to inactivate the viral DNA because the viral infection has already occurred. Hence, all studies included in the review used MB, which is an FDA-approved dye that absorbs red light at an absorption peak of 660 nm and is able to inhibit virus activity through oxidative damage to virus DNA, 21-23 via a type II photochemical reaction. ...
... For effective sensitization, consideration should be given to the preirradiation time. 20 In the studies included in this review, the preirradiation time took 3-5 min with reference to the application of the photosensitizer several times during the preirradiation time. All studies emphasized the necessity of draining the vesicular content via a sterile needle before performing PDT due to the possibility that the low-power laser used in PDT might compromise prognosis. ...
... 39 In contrast to viral resistance to antiviral drugs, no resistance to lethal oxidative effects has been developed. 20 In addition, PDT has no adverse effects on adjacent tissues. Due to the short-term effective action of oxidizing molecules, the damage is limited to viral structures close to the photosensitizer activation site, 19 and thus considered a safe antimicrobial method. ...
Article
Background: This systematic review aims to analyze the effectiveness of the association of photodynamic therapy (PDT) and photobiomodulation (PBM) in the treatment of recurrent herpes labialis and to analyze the very many variables of parameters applied, number of sessions, photosensitizer concentration, and the timing of the intervention to offer clinicians an indication of the most likely optimal techniques and parameters required to achieve clinical success. Methods: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA Checklist and registered at the International Prospective Register of Systematic Reviews (PROSPERO). We searched and identified articles of the subsequent bibliographic databases: PubMed and Cochrane. Results: Since there are no clinical trials regarding the association of PDT and PBM in the treatment of herpes labialis, we only included case reports in our review. All studies used methylene blue solution as the photosensitizer and the laser (diode laser or low-power laser) with a wavelength of 660 nm as the light source. Power output, power density, number of irradiation points, number of PBM sessions, and irradiation duration varied between the included studies. Despite the diversity in parameters between studies, all case reports showed good results regarding relieving symptoms, accelerating healing, as well as reducing the incidence of recurrence without side effects. Conclusions: The association of PDT in the vesicular phase and PBM in the crust phase can be considered a promising solution for recurrent labial herpes. Despite the many successful cases reported, establishing an effective clinical protocol for the treatment of herpes labialis using PDT followed by PBM will only be possible through double-blind placebo studies that would elucidate the exact action of this treatment modality, the appropriate irradiation parameters for both therapies, optimal timing, and number of PBM sessions following PDT. This review has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD42021290757.
... These drugs have limited efficacy in prevent recurrence of lesions. However, they can promote painful relieve and block the progression of the lesion by restricting viral multiplication [6][7][8]. A complicated factor, which has hindered treatment, refers to the emergence of strains resistant to antiviral drugs [1,2,9,10]. ...
... The literature shows photodynamic therapy as a promising technique, with no side effects. However, there are still some divergences, such as choice of photosensitizer, its concentration, usage time, power, energy density, irradiation time, and the molecular mechanisms involved in the phototherapy action of low power laser [6,8,12,13]. So, the aim of this study was to analyze in vitro the interference of photodynamic therapy with methylene blue on the replication or herpes simplex virus type 1 in Vero cells culture (cells from the lineage of monkey kidneys), aiming at the reduction or elimination of viral replication with satisfactory cell viability. ...
... Thus, it shows no specificity regarding the biomolecular target, reacting rapidly with a variety of substrates. Photodynamic therapy can be indicated for patients within viral resistance to the gold standard drug, acyclovir, offering an alternative in immunocompromised patients with a high occurrence of herpetic lesions or in patients that should avoid drug administration by organ impairment where acyclovir is metabolized [8,10,35]. ...
Article
Full-text available
Purpose The aim of this study was to perform in vitro assays using epithelial cell culture of monkey kidney (Vero cell line) and herpes simplex virus type 1 (HSV-1) to evaluate the effect of photodynamic therapy in this virus infection. Methods It was used a culture of epithelial cells infected (I) or not infected with HSV-1 (NI). The experimental groups were defined: control cell (G1), cell with methylene blue (G2), the control HSV-1 (G3), photodynamic therapy in the cell by the virus inoculated with laser irradiation 30 J/cm² (8 s) (G4) and irradiation 100 J/cm², 70s (G5), cell inoculated by virus with laser irradiation 30 J/cm² (8 s) (G6), and cell inoculated by virus with laser irradiation 100 J/cm² (70s) (G7). The irradiation was carried out by a GaAlAs diode laser – 660 nm, and methylene blue concentration of 0.0001%. Cell viability was investigated by inverted optical microscope (Leitz). Titer was evaluated using the 50/Ml TCID (the dose that produces cytopathic effect (CPE) in 50% of cell culture) by the method of Reed and Muench. Results The methylene blue and photodynamic therapy were effective in viral inhibiting. The low power laser with energy densities of 30 J/cm² and 100 J/cm² showed no effect in inhibiting HSV-1. The results of cell viability were G4 > G5 = G6˃G7 > G2. Conclusion Photodynamic therapy proved to be effective in inhibiting HSV-1 virus. The low power laser with wavelength of 660 nm and energy density of 30 J/cm² showed better viral inhibition with higher viable cells.
... Herpes simplex is a viral disease caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) [1]. Most middle-aged individuals have antibodies to HSV in their serum and about a third of the world population has a recurrence of HSV infection [2]. ...
... Most middle-aged individuals have antibodies to HSV in their serum and about a third of the world population has a recurrence of HSV infection [2]. Reactivation of the virus in the sensory ganglion causes recurrent herpetic infection in the skin and mucosa [1]. This viral reactivation can be spontaneous or caused by several local or systemic factors [3]. ...
... It is worth mentioning that PDT is effective in cases in the vesicle phase, as shown in the present case. Low-power lasers can be used in the treatment of recurrent HSV manifestations in other periods of manifestation, such as in the latent, prodromal, and crust phases [1]. In these cases, the action of the laser is the result of its interaction with biological tissues and is based on the therapeutic effects of biomodulation, analgesia and modulation of the inflammatory process [1]. ...
Article
The aim of the present study is to describe a case report on the treatment of recurrent herpes using Photodynamic therapy (PDT) and Photobiomodulation as the treatments of choice. A 21-year-old white man checked in in the clinic for evaluation of vesicles arranged in the lower lip skin region. The clinical diagnosis was recurrent herpes and, for treatment, PDT was chosen, using 0.1% methylene blue as a photosensitizer and a pre-irradiation time of five minutes. The Therapy XT laser was used, with a wavelength of 660 nm, power of 100 mW, in a spot area of 0.028 cm 2 , using 4 J energy per point, having been applied on 4 points, one in the center of the lesion and three on its laterals, so that it involved the entire extension of the lesion, totaling 16 J. After 24 hours after the application of the PDT, the patient returned for photobiomodulation with a low-power laser with a wavelength of 660 nm, power of 100 mW, using energy of 1 J per point, for 10 s, being applied on 4 points, totaling 4 J. It was possible to observe complete healing after 10 days of treatment, and the patient remains in follow-up for eight months without any recurrences.
... PBMT at red, near-infrared and infra-red wavelengths reduced the recurrence of infectious episodes in vivo on patients and contributed to the healing process of the HSV-1 oral vesicles [6]. Interestingly, Eduardo et al. treated patients with multiple PBMT sessions on oral and perioral areas in the prodromic stages when the virus was in a latent phase. ...
Article
Full-text available
Herpes simplex virus 1 (HSV-1) is wide-spread virus that triggers painful and recurrent infections, as herpes labialis, causing blister lesions on the lip. HSV-1 infection can be a lifelong condition starting from childhood due to the latency of the virus hidden in the trigeminal ganglia. Despite the use of antiviral treatments, there is not a resolutive cure for herpes. In our study, we tested blue light against HSV-1 in a neuronal cellular model, aimed at mimicking the neuronal tropism of HSV-1. Two laser protocols employing continuous wave and pulse modalities were delivered to infected cell cultures and to the virus alone. A significant reduction of viral replication was observed when the beam was directly applied to the virus, along with an increase in cell survival. Our findings, considering the limitation of the still-unknown mechanisms by which the blue light acts on the virus, suggested a potential use of photobiomodulation therapy for clinical applications against herpes labialis in pediatric patients.
Article
Aim To assess the clinical periodontal and microbiological parameters in patients having chronic necrotizing ulcerative periodontitis (NUP) after the administration of adjunctive photodynamic therapy and non-surgical periodontal therapy in smokers, mal-nutrition and HIV positive individuals. Materials and Methods A total of 30 individuals with NUP were selected for the present clinical trial, where both Group I and Group II had equal number of patients respectively (15 each). The groups were divided on the basis of provision of treatment where patients in Group I underwent scaling and root planing (SRP). Furthermore, Group II patients were subjected to adjunctive phtotodynamic therapy and SRP (aPDT + SRP). Full mouth plaque scores (fmpS), full mouth bleeding on probing (fmBOP), periodontal pocket depth (PPD) and clinical attachment levels (CAL) were the clinical periodontal parameters that were carefully evaluated. Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg) and Tannerella forsythia (Tf) were the bacteria species which were evaluated. The assessments were done at baseline, three (3) months and six (6) months respectively. Results All periodontal parameters including fmpS, fmBOP, PPD and CAL significantly improved in both Group I and Group II respectively. Group II patients subjected to aPDT + SRP reported higher reduction in mean PPD in comparison to Group I patients at follow up (p<0.05). At follow-up, similar results were also reported for CAL gain where Group II (aPDT +SRP) patients reported higher CAL gain in comparison to patients who underwent SRP only (p<0.05). From baseline to follow-up, all the bacterial levels exhibited reduction in both study groups i.e Group I (SRP) and Group II (aPDT + SRP) respectively (p<0.05). However, Group II patients prominent reduction in the counts of Aa and Tf at the three-month interval, whereas Aa seem to reduce in HIV and smoking individuals at the six-month interval. Moreover, the levels of Pg and Tf significantly reduced at 3 months and only Aa at 6 months in patients with mal-nutrition respectively (p<0.05). Conclusion The use of photodynamic treatment as an adjunct to scaling and root planing enhanced clinical periodontal results and reduced bacterial content in patients having NUP.
Article
The current viral pandemic has highlighted the compelling need for effective and versatile treatments, that can be quickly tuned to tackle new threats, and are robust against mutations. Development of such treatments is made even more urgent in view of the decreasing effectiveness of current antibiotics, that makes microbial infections the next emerging global threat. Photodynamic effect is one such method. It relies on physical processes proceeding from excited states of particular organic molecules, called photosensitizers, generated upon absorption of visible or near infrared light. The excited states of these molecules, tailored to undergo efficient intersystem crossing, interact with molecular oxygen and generate short lived reactive oxygen species (ROS), mostly singlet oxygen. These species are highly cytotoxic through non-specific oxidation reactions and constitute the basis of the treatment. In spite of the apparent simplicity of the principle, the method still has to face important challenges. For instance, the short lifetime of ROS means that the photosensitizer must reach the target within a few tens nanometers, which requires proper molecular engineering at the nanoscale level. Photoactive nanostructures thus engineered should ideally comprise a functionality that turns the system into a theranostic means, for instance, through introduction of fluorophores suitable for nanoscopy. We discuss the principles of the method and the current molecular strategies that have been and still are being explored in antimicrobial and antiviral photodynamic treatment.
Article
Introduction: Herpesvirus infection has a variety of clinical forms and is extremely widespread in the world while existing treatment methods are not always quite effective. The search for new treatment modalities is a relevant problem and numerous studies show the therapeutic effect of low-level laser therapy (LLLT) on different herpesvirus types. Methods: The mechanisms of laser light action and the impact of LLLT on the pathological pathways of herpes infections are described. A narrative review of the relevant papers is conducted. Results: The reviewed studies confirm that LLLT is a potential prospective treatment method for patients infected with the herpesvirus. However, it is necessary to improve the methodology and optimize the combination of laser action with antiviral medications. Conclusion: The review shows that it is most effective to combine laser impact on skin lesions with the application of topical antiviral gels or creams, additionally using a combined procedure of laser ultraviolet blood illumination (LUVBI, 365-405 nm) + intravenous laser blood irradiation (ILBI, 525 nm).
Article
Full-text available
Although oral human herpesvirus 1 (HHV‐1) affects approximately 75% of the general population, recurrent infections are more often encountered in immunocompromised patients. Such infections become a serious concern especially following allogeneic bone marrow transplantation (BMT), as the lesions are more extensive, aggressive, slow‐healing, and painful in comparison to those in healthy individuals.¹ Furthermore, oral herpes lesions in patients submitted to allogeneic BMT may also predispose to secondary bacterial and fungal infections that, in turn, could lead to disseminated viral infection with severe organ involvement.² The reactivation of herpesvirus has been also associated with graft‐versus‐host disease (GVHD), a condition caused by the reactivity of transplanted immunocompetent cells against host cells and considered the major problem after allogeneic BMT.³ Recent literature data suggest that herpesvirus reactivation is predictive of subsequent severe grades of GVHD; however, the available clinical studies on the role of herpesvirus in GVHD are still limited and show an association but not causation.¹ Antimicrobial photodynamic therapy (aPDT) has been recently proposed to treat viral infections, and a combination of aPDT and photobiomodulation therapy has already been used for the management of oral GVHD.4,5 So, the present study reports a clinical case in which this therapy was used to manage an ulcerative lesion of recurrent herpes labialis in a patient with chronic GVHD.
Article
Full-text available
Introduction: Given the inconsistencies in the literature regarding laser performance in non-surgical treatments, this study investigated the available literature to determine the advantages and disadvantages of low-power lasers in treating non-surgical complications and diseases. Methods: Authentic information from articles was extracted and evaluated to assess low-power laser performance for non-surgical treatments. A systematic search of studies on low-level laser therapy (LLLT) for non-surgical treatments was conducted mainly in PubMed and google scholar articles. Results: Four categories of diseases, including brain-related diseases, skin-related diseases, cancers, and bone-related disorders, which were treated by LLLT were identified and introduced. The various types of LLLT regarding the studied diseases were discussed. Conclusion: Positive aspects of LLLT versus a few disadvantages of its application imply more investigation to find better and efficient new methods.
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Background Herpes Simplex Virus Type 1 (HSV-1) is one of the most widespread infections that can effect the orofacial region. Recurrent infection is considered a life-long oral health problem, leading to pain, discomfort, and social restriction due to esthetic features when active. Effective therapies are needed. This study aimed to compare photodynamic therapy (PDT), Topical Acyclovir (AC), and the association of both in the healing process and self-reported symptomologies of HSV-1 recurrences. Methods Patients were randomly assigned into 3 groups (n = 25): PDT (low-power laser, 660 nm, 40 mW, 120 J/cm², 4.8 J, 120 s per point) and methylene blue (0.005 %) as photosensitizer; AC (5%); PDT + AC.Data concerning lesion size, healing time, and self-reported healing parameters, such as pain, tingling, and edema were taken every day up to complete healing for all studied groups. Results There was no significant difference in healing time and pain between groups. AC group showed a significant minor reduction of the lesion compared to the AC-PDT group on day 1. Regarding edema and tingling, the comparison of treatments showed a statistical difference only on day 1, where PDT showed better results. Conclusion With all the limitations of this study, it can be concluded that only on day 1 PDT showed positive effects in the treatment of herpes lesions in comparison to AC.
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Photodynamic therapy (PDT) of neoplasms using photosensitizers and red light, is currently undergoing clinical trials throughout the world.1 The sensitizer preparation used almost exclusively in PDT consists of a mixture of hematoporphyrin derivatives (HPD) obtained from alkaline hydrolysis of hematoporphyrin acetates.2 The most active compounds in this mixture are believed to be dihematoporphyrin ethers3 and/or esters,4 known as DHE. A commercial preparation enriched in the latter (Photofrin IItm) has been made available for research and clinical trials by Photomedica Inc. The effectiveness of DHE in PDT results from two important properties: (a) selective retention by neoplasms, and (b) induction of cellular damage upon light excitation, most likely through 1O2 formation.5 Advantages of this procedure as compared to conventional cancer treatment modalities include selectivity and low systemic toxicity. A particular advantage of PDT is that it can be applied to recurrences in regions which have already received maximal doses of conventional radiotherapy.
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In this 3-year study of suppressive acyclovir for recurrent genital herpes, patients with more than six recurrences per year were randomized initially to 400 mg of acyclovir or placebo orally two times per day, with recurrences treated with 200 mg of acyclovir five times per day for 5 days. In the second year of the study, all patients received acyclovir as a daily suppressive or intermittent acute therapy; in the third year, all received daily acyclovir. Among 525 patients completing 3 study years, 289 received 3 years of suppressive therapy and 236 received 1 year of acute therapy followed by 2 years of suppressive therapy. Of those who completed the third year, 61% were recurrence free that year; 25% of the suppressive therapy—only group were recurrence free for all 3 years. The annual recurrence rate dropped from more than 12 recurrences per year at baseline to 1.0 (suppressive therapy) and 1.4 (acute and suppressive therapy) recurrences during the third year. No significant toxic effects were detected. Daily suppressive acyclovir therapy was effective and well tolerated. (JAMA. 1991;265:747-751)