Acyclovir for treating primary herpetic gingivostomatitis (Review) The Cochrane Library

Transcription

Acyclovir for treating primary herpetic gingivostomatitis
(Review)
Nasser M, Fedorowicz Z, Khoshnevisan MH, Shahiri Tabarestani M
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 4
http://www.thecochranelibrary.com
Acyclovir for treating primary herpetic gingivostomatitis (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Acyclovir versus placebo, Outcome 1 The number of individuals with oral lesions (8 days after
the administration of the intervention). . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Acyclovir versus placebo, Outcome 2 The number of individuals who developed new extraoral
lesions after the administration of the intervention. . . . . . . . . . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Acyclovir versus placebo, Outcome 3 The number of individuals with eating difficulties (8 days
after the administration of the intervention). . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Acyclovir versus placebo, Outcome 4 The number of individuals with drinking difficulties (8
days after the administration of the intervention). . . . . . . . . . . . . . . . . . . . . .
Analysis 1.5. Comparison 1 Acyclovir versus placebo, Outcome 5 The number of individuals admitted to hospital after the
administration of the intervention. . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
2
3
4
6
12
12
13
13
14
18
18
19
19
20
20
20
24
25
25
25
25
25
i
[Intervention Review]
Mona Nasser1 , Zbys Fedorowicz2 , Mohammad H Khoshnevisan3 , Maryam Shahiri Tabarestani4
1 Department
of Health Information, Institute for Quality and Efficiency in Health care, Köln, Germany. 2 UKCC (Bahrain Branch),
Ministry of Health, Bahrain, Awali, Bahrain. 3 Community Oral Health, School of Dentistry of SBMU, Tehran, Iran, Islamic Republic
of. 4 App 2, 1st Floor, Babol, Iran, Islamic Republic of
Contact address: Mona Nasser, Department of Health Information, Institute for Quality and Efficiency in Health care, Dillenburger
Street, 27, D-51105, Köln, D-51105, Germany. [email protected]. [email protected].
Editorial group: Cochrane Oral Health Group.
Publication status and date: New, published in Issue 4, 2008.
Review content assessed as up-to-date: 25 June 2008.
Citation: Nasser M, Fedorowicz Z, Khoshnevisan MH, Shahiri Tabarestani M. Acyclovir for treating primary herpetic gingivostomatitis.
Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006700. DOI: 10.1002/14651858.CD006700.pub2.
ABSTRACT
Background
Primary herpetic gingivostomatitis is a highly contagious infection of the oral cavity which typically affects children but can also occur
in adults. Symptoms may vary widely from mild discomfort to life-threatening encephalitis.
Objectives
The objective of this review was to evaluate the effectiveness of systemic acyclovir for primary herpetic gingivostomatitis.
Search strategy
We searched the following databases: Cochrane Oral Health Group’s Trials Register (to 22 May 2008); the Cochrane Central Register
of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 2); MEDLINE (1950 to 22 May 2008); and EMBASE (1980 to
22 May 2008). There were no language restrictions.
Selection criteria
Randomised controlled trials comparing acyclovir to placebo in children and young adults < 25 years of age with a diagnosis of primary
herpetic gingivostomatitis with or without herpes labialis were considered.
Data collection and analysis
Two review authors independently and in duplicate screened and extracted information from, and assessed the risk of bias in the
included clinical trials. The Cochrane Collaboration statistical guidelines were followed for data synthesis.
Main results
Only two clinical trials, one with 72 participants and the other with 20 participants were included in this review. The second study
failed to report several methodological items and was inconsistent in its reporting of the outcomes measurement.
The first trial, with a moderate risk of bias, showed better results in the acyclovir group compared to the placebo group in children < 6
years of age in reducing the number of individuals with oral lesions (risk ratio (RR) 0.10 (95% confidence interval (CI) 0.02 to 0.38)),
new extraoral lesions (RR 0.04 (95% CI 0.00 to 0.65)), difficulty in eating (RR 0.14 (95% CI 0.03 to 0.58)), and drinking difficulties
(RR 0.11 (95% CI 0.01 to 0.83)) after 8 days of treatment.
1
Following the onset of treatment, three patients from the placebo group were admitted to hospital for rehydration (P = 0.11).
Four children (two from the acyclovir, and two from the placebo group) showed mild gastrointestinal symptoms that resolved spontaneously after 24 to 48 hours without a change in the study treatment.
Authors’ conclusions
We found two relevant trials in this systematic review, only one of them could provide some weak evidence that acyclovir is an effective
treatment in reducing the number of oral lesions, preventing the development of new extraoral lesions, decreasing the number of
individuals with difficulties experienced in eating and drinking and reducing hospital admission for children under 6 years of age with
primary herpetic gingivostomatitis.
PLAIN LANGUAGE SUMMARY
There is some weak evidence that acyclovir can be an effective treatment in decreasing some of the symptoms caused by primary herpetic
gingivostomatitis.
Primary herpetic gingivostomatitis is a highly contagious infection of the oral cavity which is caused by the herpes simplex virus.
It is prevalent in children and young adolescents and sometimes can cause uncomfortable symptoms including eating and drinking
difficulties and even life-threatening inflammation of the brain (encephalitis).
This review included two trials (92 participants) but only one of them provided some limited evidence to suggest that acyclovir is an
effective treatment in reducing the number of oral lesions, preventing the development of new extraoral lesions, decreasing the number
of individuals with difficulties experienced in eating and drinking and of those who are admitted to hospital for children under 6 years
of age with primary herpetic gingivostomatitis.
BACKGROUND
Primary herpetic gingivostomatitis (PHG) is an infection of the
oral cavity which is caused by the herpes simplex virus (HSV).
It is highly contagious, typically affects children but can also occur in adults, and has a high rate of recurrence of infection (
Chauvin 2002; Kolokotronis 2006). Symptoms may vary widely
from mild discomfort to life-threatening encephalitis (Amir 2001).
Only about 5% to 10% of patients initially infected with the herpes simplex virus develop clinical lesions. This is referred to as
primary herpetic gingivostomatitis.
Aetiology and prevalence
Many patients may remain undiagnosed because they are either
asymptomatic or have mild symptoms (Amir 2001). Ninety per
cent of Americans are said to have HSV-1 serum antibodies (Siegel
2002).
The herpes simplex virus is a double-stranded DNA virus of which
the HSV-1 type is responsible for oral, facial and ocular infections
including primary herpetic gingivostomatitis. Although HSV-2 is
primarily responsible for most genital and cutaneous lower body
herpetic lesions, it can also be the cause of primary herpetic gingivostomatitis.
The peak periods of PHG incidence are between the ages of 6
months and 5 years, and in young adults who are in their early
20s (Amir 1997a).
Although the virus is short lived on external surfaces it can readily
disrupt the integrity of skin or mucous membranes and viral replication occurs as soon as it penetrates the epithelial cell. It is at a
later stage that the virus travels along the sensory nerve endings to
the corresponding nerve ganglion (i.e. trigeminal ganglion) where
it enters a latent phase and can remain dormant until it is reactivated either spontaneously or by one or another of a number of
stimulants (e.g. infection, ultraviolet light, fever, cold) (Chauvin
2
2002; Kolokotronis 2006).
As the infection is highly contagious most patients acquire it
through direct contact (e.g. skin or via infected secretions (e.g.
saliva)). It can spread rapidly in a closed community setting such
as a daycare nursery or orphanage. Therefore, factors such as location and socio-economic status can influence the rate of HSV1 infection and it has been noted that individuals in developing
countries and from lower socio-economic groups become HSV1 seropositive at an earlier age than individuals from developed
countries (Amir 2001; Chauvin 2002; Kolokotronis 2006).
This is usually made by clinical presentation and history. In addition, the diagnosis may be confirmed via laboratory tests: serological assays (anti-HSV IgM and IgG), the Tzanck test and immunofluorescence, but the culture of viral isolates is still considered to be the gold standard (Neville 2002).
The differential diagnosis of primary herpetic gingivostomatitis
includes acute necrotizing ulcerative gingivitis, herpangina, aphthous stomatitis, candidiasis of the mouth, Steven-Johnson syndrome and hand, foot and mouth disease (Amir 2001; Chauvin
2002).
Symptoms
Treatment options
Primary herpetic gingivostomatitis is characterised by a sudden
onset and with the severity of symptoms related to the virulence
of the HSV and the host’s immune response (Chauvin 2002).
Non-specific symptoms may include cervical lymphadenopathy,
malaise and low grade fever, and can occur in the absence of any
discrete clinical lesions.
The general course of PHG infection is 10 to 14 days which is
usually preceded by an incubation period of 1 to 26 days (Faden
2006; Kolokotronis 2006).
Primary herpetic gingivostomatitis can include oral as well as extraoral lesions, swollen and bleeding gums, and symptoms such
as pain, fever, irritability, malaise, headache and upper respiratory
tract infection.
The oral lesions in PHG may start as vesicles on the tongue and
the buccal and gingival mucosa, and which rapidly rupture to
become ulcers. The ulcers, which are usually 1 to 3 mm in size,
may subsequently enlarge to form a large ulcerated area covered
by a yellowish-grey membrane. In some patients, especially adults,
the gingivae (gums) may also become swollen. Healing generally
occurs without scarring.
During the acute phase of PHG many children may refuse to eat
or drink because of the discomfort and pain from these lesions
and consequently become rapidly dehydrated. Extraoral lesions
(herpes labialis), which appear as erythematous papules on the
vermilion border and adjacent skin of the lips, may accompany
PHG (Kolokotronis 2006).
Complications are rare but do occur and usually as a result of viral shedding, and it is at this stage that HSV infection becomes
readily transmittable. During this phase with its high risk of direct
transmission, eye infections (ocular herpes or herpetic keratoconjunctivitis) and infections of the digits (herpetic whitlow) are not
infrequent complications. After the primary infection, the virus
may become dormant but can be readily reactivated producing
episodic bouts of recurrent infection which are generally considered to be less severe than the primary infection.
Individuals with symptoms such as pain, fever, and dehydration
may seek treatment (Amir 2001) including rehydration, analgesics
and oral lavage. Systemic analgesics (acetaminophen) may be adequate to manage the associated pain but topical applications of
diphenhydramine and Maalox, Kaopectate, viscous lidocaine are
also frequently prescribed.
Reduction of viral replication by using antivirals may shorten the
acute phase of the illness, relieve symptoms, stop the virus from
going into the latent phase and possibly prevent future recurrence
(Siegel 2002). A known selective inhibitor of replicating HSV is
acyclovir which is widely used for different forms of HSV infections.
Diagnosis
Antiviral therapy and acyclovir
Acyclovir, in either oral or topical form, is used fairly routinely for
HSV infections (e.g. herpes encephalitis, neonatal herpes, primary
herpes genitalis and recurrent herpes labialis) (Amir 2001). One of
the limitations of acyclovir is its poor gastrointestinal absorption
and bioavailability and therefore derivatives (e.g. valacyclovir and
famciclovir) have been developed with an apparently increased
bioavailability but these are not currently available as paediatric
suspensions.
A number of studies on the efficacy of acyclovir for treating primary
herpetic gingivostomatitis have shown promising results and this
systematic review sought to assess the available evidence.
OBJECTIVES
The objective of this review was to provide reliable evidence regarding the effectiveness of systemic acyclovir versus placebo or no
treatment for primary herpetic gingivostomatitis.
The following null hypothesis was tested: there is no difference
between acyclovir and placebo or no intervention for the treatment of primary herpetic gingivostomatitis against the alternative
hypothesis of a difference.
3
METHODS
Costs
Direct costs of medication, hospital bed days.
Criteria for considering studies for this review
Adverse effects
Types of studies
Any specific adverse effects related to any clinically diagnosed reactions to the active intervention or placebo were noted.
Only randomised controlled clinical trials (RCTs) were considered
in this review.
Search methods for identification of studies
Types of participants
Only studies, which had recruited children and young adults who
were under the age of 25 with a diagnosis of primary herpetic gingivostomatitis (PHG) with or without herpes labialis were considered. The diagnosis of PHG had been confirmed by clinical
history and laboratory investigation.
Types of interventions
The following interventions and controls were considered: systemic oral acyclovir in different doses, frequency and duration of
administration compared to placebo or nothing.
Studies which have permitted any analgesics to be administered
as concomitant therapy, provided they were distributed similarly
between the two groups, were included.
Types of outcome measures
Primary outcomes
(1) Duration and time of healing of all intraoral and extraoral
lesions and the change in the number of lesions from the time of
administration of the intervention. We also considered the number
of individuals with lesions from the time of administration of the
intervention.
(2) Pain/discomfort: patient-assessed using any recognised validated pain scale.
(3) Difficulty in eating/drinking: time to resumption of normal
feeding pattern or the number of individuals with eating and
drinking difficulties from the time of administration of the intervention.
(4) Fever.
Electronic searches
For the identification of studies included or considered for this
review, detailed search strategies were developed for each database
to be searched. These were based on the search strategy developed for MEDLINE but revised appropriately for each database.
For the MEDLINE search, the subject search was run using the
Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of the Cochrane Handbook for Systematic Reviews
of Interventions version 5.0.0 (updated February 2008) (Higgins
2008).
Databases to be searched
The following databases were searched:
The Cochrane Oral Health Group’s Trials Register (22 May 2008)
The Cochrane Central Register of Controlled Trials (CENTRAL)
(The Cochrane Library 2008, Issue 2)
MEDLINE (from 1950 to 22 May 2008)
EMBASE (from 1980 to 22 May 2008).
Details of the search strategies are provided in Appendix 1;
Appendix 2; Appendix 3 and Appendix 4.
Handsearches
We did not handsearch any specific journals but examined the
reference lists of potential clinical trials and the review authors’
personal database of trial reports in an attempt to identify any
additional studies or those not identified in the searches. We also
contacted experts in the field and requested information on unpublished and ongoing trials.
Secondary outcomes
(1) Hospital admission: length of stay to include intravenous rehydration and the number of individuals admitted to hospital from
the time of administration of the intervention.
(2) Quality of life as assessed by a validated questionnaire.
(3) Patient or parental satisfaction assessed by questionnaire.
Language
There were no language restrictions on included studies and we
either self translated or arranged to translate any of the relevant
non-English language papers.
4
We attempted to contact investigators of the included studies by
electronic mail to ask for details of additional published and unpublished trials.
Data collection and analysis
Assessment of search results
Two review authors, Mona Nasser (MN) and Maryam Shahiri
(MS), independently scanned the abstracts of studies resulting
from the initial electronic searches. Full copies of all relevant and
potentially relevant studies, those appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision, were obtained. The full
text papers were assessed independently by MN and MS and any
disagreement on the eligibility of included studies was resolved
through discussion and consensus or if necessary through a third
party (Zbys Fedorowicz (ZF)). All irrelevant records were excluded
and details of the studies and the reasons for their exclusion were
noted. After assessment any remaining studies that did not match
the inclusion criteria were eliminated from further review and the
reasons for their exclusion were noted in the Characteristics of
excluded studies table in RevMan 5 (RevMan 2008).
Data collection
Study details and outcomes data were collected using a predetermined form designed for this purpose. Study details were entered into the ’Characteristics of included studies’ table, and the
extracted outcomes data were entered separately by each of two
review authors (MN and ZF) into the Data and analyses section in
RevMan 5 and checked for differences. MN held the master copy.
Data were included if there was an independently reached consensus. Any disagreements were discussed and if required a third
review author was consulted.
The following details were extracted.
(1) Study methods: method of allocation, masking of participants,
exclusion of participants after randomisation and proportion of
follow-up losses.
(2) Participants: country of origin, sample size, age, sex, inclusion
and exclusion criteria.
(3) Intervention: time of administration relative to onset of symptoms, dose, frequency, and duration of acyclovir usage.
(4) Control: type, dose and frequency of any comparison or
placebo.
(5) Outcomes: primary and secondary outcomes.
If stated, the sources of funding of any of the included studies were
recorded.
This information was used to assess the clinical homogeneity and
the external validity of the trials.
Assessment of methodological quality
Two review authors (MN and ZF) graded the selected studies
independently. Every study was assessed following the criterion
grading system described in the Cochrane Handbook for Systematic
Reviews of Interventions version 5.0.0 (updated February 2008) (
Higgins 2008). The grading was compared and any inconsistencies between the review authors in the interpretation of inclusion
criteria and their significance to the selected studies were discussed
and resolved.
The following parameters of methodological quality were considered and used to help assess the risk of bias within the included
studies.
(1) Sequence generation:
This criterion was graded as adequate (A), unclear (B) or inadequate (C). Adequate (A) included any one of the following methods of randomisation: computer generated or table of random
numbers, drawing of lots, coin-toss, shuffling cards or throw of
a dice. The review authors judged as inadequate (C) methods of
randomisation utilising any of the following: case record number,
date of birth, or alternate numbers.
(2) Allocation concealment:
The review authors graded this criterion as adequate (A), unclear (B). Adequate (A) methods of allocation concealment included either central randomisation or sequentially numbered
sealed opaque envelopes.
(3) Blinding (of participants, researchers and outcome assessment):
Blinding was assessed using the following criteria (detection and
performance bias):
(a) blinding of participants (yes/no/unclear);
(b) blinding of caregiver (yes/no/unclear);
(c) blinding of outcome assessment (yes/no/unclear).
(4) Handling of withdrawals and losses:
The review authors graded this criterion as yes (A), unclear (B) and
no (C) according to whether there was a clear description given
of the difference between the two groups of losses to follow up
(attrition bias).
After assessment the included studies were to be grouped accordingly.
(A) Low risk of bias (plausible bias unlikely to seriously alter the
results): if all criteria were met.
(B) Moderate risk of bias (plausible bias that raises some doubt
about the results): if all criteria were at least partly met.
(C) High risk of bias (plausible bias that seriously weakens confidence in the results): if one or more criteria were not met as
described in Chapter 8 of the Cochrane Handbook for Systematic
Reviews of Interventions version 5.0.0 (Higgins 2008).
Data synthesis
In view of the paucity of trials and the limited amount of data
reported in the two included trials, pooling of results and meta-
5
analysis of extracted data were not feasible and therefore only data
relevant to some of the primary and secondary outcomes and a
descriptive summary of results is presented in addition to data
analysis for five relevant outcomes from one of the trials. The
paucity of included trials did preclude any planned attempts to
assess publication bias through the use of a funnel plot.
For future updates, when studies are identified for inclusion in this
review, the following methods will be applied.
We will pool the results of clinically homogeneous trials to provide
estimates of the efficacy of the interventions. Two review authors
(ZF and MN) will analyze the data found and report them as
suggested in Chapter 9 of the Cochrane Handbook for Systematic
Reviews of Interventions version 5.0.0 (Higgins 2008).
We will present risk ratios for beneficial outcomes, and odds ratios for adverse effect outcomes and calculate the number needed
to treat to benefit (NNTB) and number needed to treat to harm
(NNTH) for the whole pooled estimates. However, we will consider the length of follow up of the individual studies in interpreting NNT.
For the synthesis and meta-analysis of any quantitative data, we
will use the fixed-effect model. If we establish that there is heterogeneity between the studies, we will undertake a random-effects
model as appropriate but if the heterogeneity between the studies
is significant, we will not undertake a meta-analysis. If there are
few clinically homogenous trials or insufficient data for pooling,
we will present the results of the individual trials and perform a
descriptive analysis only.
If sufficient studies are included we plan to conduct sensitivity
analyses to assess the robustness of our review results by repeating
the analysis with the following adjustments: exclusion of studies
with unclear or inadequate allocation concealment, unclear or inadequate blinding of outcomes assessment and completeness of
follow up (Egger 1997).
Clinical homogeneity between the included trials will be assessed
by examining the characteristics of the participants and the outcomes reported.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Amir 1997a; Amir 1997b; Amir 2001; Amir 2002; Ducoulombier
1988; Jacobs 1998; Madigosky 2004; Mennemeyer 1997; Yarom
2006; Zhilina 1976) were eliminated and excluded from further review. Full text copies of these remaining studies were obtained and
subjected to further evaluation. Three of the remaining papers were
not in the English language but were in French (Ducoulombier
1988), Russian (Zhilina 1976), and Hebrew (Amir 2002), all of
which were translated and subsequently assessed for eligibility.
The bibliographical references of these studies were also examined
but did not provide any additional citations to potentially eligible
studies.
After further evaluation eight of these studies (Amir 1997a; Amir
2001; Amir 2002; Jacobs 1998; Madigosky 2004; Mennemeyer
1997; Yarom 2006; Zhilina 1976) were excluded and the reasons for their exclusion were noted (see Characteristics of excluded
studies).
Finally only two randomised controlled trials (RCTs), one including 72 participants (Amir 1997b) and one including 20 participants (Ducoulombier 1988) met our inclusion criteria and were
included in this review.
Summary of trial details
Amir 1997b
This was a randomised double blind placebo controlled trial which
included 72 participants and was conducted in Israel between
December 1993 and February 1995. The participants had been
referred to the paediatric day care unit of Hasharon Hospital Petah
Tiqva, or had been seen in the emergency room of Hasharon
Hospital and the Schneider Children’s Medical Centre, Israel.
Participants
A total of 72 patients aged 1 to 6 years (gender unspecified) were
enrolled in this study. They all had clinical symptoms of gingivostomatitis, and the diagnosis was confirmed by viral culture and
serological testing for herpes simplex virus prior to commencement of the study.
Eleven were subsequently excluded from further evaluation because their viral cultures were negative and all serological results remained negative during convalescence, however, their results were
reported.
Both groups were similar regarding the severity of clinical symptoms and demographic variables at baseline.
Interventions
Finding the trials
The search strategy, after de-duplication, retrieved 145 records (47
Cochrane Oral Health Group’s Trials Register, 53 CENTRAL, 56
EMBASE, 67 MEDLINE references to studies). After examination of the titles and abstracts of these references, all but 10 studies (
Randomisation was to a suspension of either acyclovir or placebo
which looked and smelled similar and were contained in identical
bottles. Acyclovir was administered in a dose of 15 mg/kg (0.375
ml/kg) 5 times a day (< 200 mg per dose) or placebo as an equal
volume, for a period of 7 days.
6
Compliance was measured by the volume of suspension left in
the bottle from which it was established that 29 children in the
acyclovir group and 24 in the placebo group received > 80% of
the prescribed treatment.
antiseptic solution), the quantity of which or mode of application
were not described.
No description was given of how compliance was evaluated and
was only judged as acceptable and good.
Outcomes
Outcomes
Clinical examination took place on days 0, 3, 6 and 8 as well as
the day after completion of treatment and thereafter every 2 or 3
days if symptoms persisted. This included an evaluation of fever,
the severity of oral lesions, presence of any extraoral skin lesions,
drooling and a note was made of any difficulties experienced in
drinking and eating. Oral lesions were categorised as mild (up to
10 lesions on the tongue or oral mucous membrane), moderate
(11 to 20 lesions with swelling of the gums), or severe (more than
20 tongue or oral lesions and gum lesions).
Swabs were taken for viral cultures at each clinical examination
and until all the oral or extraoral lesions had healed. Serum samples were obtained on days 0, 12 and 16 for serological testing
(serotyping for herpes simplex virus).
For additional trial details see Characteristics of included studies.
Ducoulombier 1988
This was a randomised double blind placebo controlled trial conducted on 20 patients and reported in the French language. Neither the time period of recruitment nor the setting were reported
in the paper, but it can be reasonably assumed that the study was
conducted in France.
The trialists recorded pain, hypersialorrhea (excessive drooling of
saliva), anorexia (loss of appetite), general health, body temperature and fever, lingual or labial lesions or a persistent cervical
adenopathy (large or swollen lymph nodes in the neck). The time
period needed to observe a negative virus culture was recorded and
the overall tolerability and acceptability of the drug by the patients
were also noted.
For additional trial details see Characteristics of included studies.
Risk of bias in included studies
Amir 1997b
Sequence generation and allocation concealment
The participants were assigned to the study using a random numbers table with a block size of eight and therefore sequence generation was graded as (A) adequate.
The assigned numbers were identical to the numbers on the treatment bottles. Concealment of allocation was judged as (A) adequate.
Participants
A total of 20 patients (11 boys and 9 girls) with a mean age of
2 years and mean weight of 12 kg were included in this trial. All
had clinical symptoms of primary herpetic infection which were
less than 4 days old and HSV-1 was isolated from human diploid
cell culture. The two groups were stated to be homogeneous in
terms of pathological and physical characteristics and signs and
symptoms of the infection. Fever was the only symptom which
was more prevalent in the acyclovir group (9) compared with the
placebo group (4).
The time interval between onset of symptoms and initiation of
treatment was different between the two groups but the mean time
interval for both was 2.5 days. Twelve out of the 20 participants
started their treatment in the first 48 hours of onset of symptoms.
Blinding (of participants, researchers and outcome
assessment)
The participants were given either placebo or acyclovir in bottles
which were identical in appearance and smell and therefore blinding of participants was graded as yes.
The researchers assigned the patients by a randomised table which
had identical numbers to those on the treatment bottles so blinding
of researchers was graded as yes.
Symptoms were recorded by the parent but the clinical examination in the follow-up evaluation was carried out by a single investigator. It was not clear from the text whether these outcomes
assessors were blinded to which intervention was received by the
participants, and therefore blinding of outcomes assessment was
graded as unclear.
Interventions
Randomisation was to either acyclovir tablets or placebo given in a
dose of five tablets per day for a period of 5 days. The dose was not
specified and there was no description of how participants or their
carers or the trialists were blinded to the intervention or placebo.
Fourteen patients, equally distributed between the two groups,
also received adjuvant topical treatment with Collu Hextril (an
Handling of withdrawals and losses
Ten children, out of the 72 enrolled in the study, whose viral cultures were negative for herpes simplex virus and whose serological results remained negative during convalescence were excluded
from the clinical evaluation. One additional child was excluded at
day 2 as his parents declined to attend for follow up. The authors
7
included all of the randomised patients in their analysis and performed an intention-to-treat analysis. Consequently, this criterion
was graded as (A) yes.
Assessment of risk of bias
As not all of the criteria were completely met, this study was assessed as at moderate risk of bias (plausible bias that raises some
doubt about the results).
Ducoulombier 1988
Sequence generation and allocation concealment
Participants were assigned using a random numbers table. Sequence generation was graded as (A) adequate.
There was no description of how the allocation sequence was concealed from the investigators so this was graded as (B) unclear.
Blinding (of participants and outcome assessment)
There was no description of how participants or their carers were
blinded to the interventions and therefore this criterion was graded
as unclear.
Handling of withdrawals and losses
Although 20 patients were enrolled, outcomes were only reported
for 18 and no explanation was provided for the two losses to follow
up. This criterion was graded as (B) unclear.
Assessment of risk of bias
As only some of the criteria were met, as described in Chapter 8
of the Cochrane Handbook for Systematic Reviews of Interventions
version 5.0.0, this study was assessed as at high risk of bias (plausible bias that seriously weakens confidence in the results).
Please refer to the Additional tables section of the review for further
information on the methodological quality of included studies
(Additional Table 1).
Table 1. Quality of included studies
Study ID
Sequence genera- Allocation
tion
concealment
Blinding
Intention-to-treat
Amir 1997b
(A) Adequate: ran- (A) Adequate
domised table with a
block size of 8
Participants (Yes),
researchers (Yes),
outcome assessment
(Unclear)
Yes:
the Yes: the drop outs
patients which were were described
later excluded from
the study, were included in the statistical analysis
Attrition
8
Table 1. Quality of included studies
Ducoulombier
1988
(Continued)
(A) Adequate: ran- (B) Unclear
domised table
Unclear:
described
not No: there were 2 No: there were 2
drop outs but no de- drop outs but no description was given scription was given
Effects of interventions
Clinical heterogeneity between the two trials included in this review precluded any possibility of synthesizing any of their data.
Only a limited amount of data relevant to some of the primary
outcomes, as specified in the inclusion criteria for this review, is
presented either within the text or in Additional Table 2. We have
contacted the authors of the Amir 1997b study to obtain further
details about the raw data of the review. Despite several attempts,
we were unsuccessful in obtaining new data.
Table 2. Results reported in the two included studies
Study ID
Results
Amir 1997b
Difference in median (95% CI) duration (in days) of clinical variables:
Oral lesions: (From 72: 5 (2.4 to 7.6)), (From 61: 6 (4.0 to 8.0)).
The time to healing was significantly shorter in the children receiving acyclovir (median: 4 days (range 212)) than in those receiving placebo (median: 10 days (3-15)). At the end of treatment on day 8, 2 out of 31
children in the acyclovir group still had oral lesions compared with 21 out of 30 in the placebo group.
Fever: (From 72: 1 (0.0 to 2.0)), (From 61: 2 (0.8 to 3.2)).
This disappeared significantly earlier in the acyclovir group (median 1 day) as opposed to placebo (median 3
days).
Extraoral lesions: (From 72: 3 (1.4 to 4.6)), (From 61: 5.5 (1.0 to 10.0)).
At enrolment one third of the children in each group had extraoral herpetic lesions. After commencing
treatment, 13 of the patients from the placebo as opposed to none in the acyclovir group developed additional
extraoral lesions. The median duration of extraoral lesions in the placebo group was reported as 5.5 days.
Hospital admission:
Before, inclusion in the study: Group 1: 2, Group 2: 3.
Among the rest of the children, after inclusion: Group 1: none, Group 2: 3 (2 to 3 days for rehydration (P =
0.11)).
At enrolment, 5 children (2 acyclovir, 3 placebo group) were admitted to hospital for rehydration. After
commencement of treatment a further 3 children (placebo group) were admitted for 2 to 3 days for rehydration
(P = 0.11).
Drooling: (From 72: 3 (1.4 to 4.5)), (From 61: 3.5 (2.0 to 5.0)).
Eating difficulties: (From 72: 3 (1.2 to 4.8)), (From 61: 3 (1.3 to 4.7)).
At enrolment all of the participants had difficulty with eating but by day 8 only 2 in the acyclovir group and
14 from the placebo group continued to have difficulties. The median duration of persisting difficulties in
9
(Continued)
eating was 4 days in the acyclovir and 7 days in the placebo group.
Drinking difficulties: (From 72: 2 (0.3 to 3.7)), (From 61: 3 (1.1 to 4.9)).
At entry all the participants had difficulty with drinking but by day 8, only 1 child in the acyclovir and 9
in the placebo group were still experiencing difficulties. The median duration was 3 days (acyclovir)versus 6
days (placebo).
Viral shedding: (From 72: 4 (2.7 to 5.3)), (From 61: 4 (2.9 to 5.1)).
Compliance: Group 1: 29 received > 80% of treatment, the rest (50-80%), Group 2: 24 received > 80% of
treatment, the rest (50-80%) (P = 0.117).
Side effects: Group 1: 2, Group 2: 2 mild gastrointestinal symptoms that resolved spontaneously after 24 to
48 hours without a change in the study treatment.
Ducoulombier 1988
Time to resolution of pain: Group 1 (1 day = 1, 2 days = 1, 3 days = 3, 4 days = 3, 5 days = 1, persistent =
0), Group 2 (1 day = 0, 2 days = 0, 3 days = 1, 4 days = 2, 5 days = 4, persistent = 2) (2 patients were not
reported) (P < 0.05).
The trialists reported the time to resolution of pain but did not describe how they assessed pain or its severity.
Considering the age of the participants, it is questionable whether they would be able to self report.
Time to resolution of hypersialorrhea (excessive drooling of saliva): Group 1 (1 day = 1, 2 days = 1, 3 days =
3, 4 days = 3, 5 days = 1, persistent = 0), Group 2 (1 day = 1, 2 days = 0, 3 days = 0, 4 days = 2, 5 days = 3,
persistent = 3) (2 patients were not reported) (P < 0.05).
Anorexia (loss of appetite): Group 1: in 5 patients disappeared after 4 days, Group 2: in 4 patients disappeared
after 5 days, 1 patient had persistent anorexia (comparable in 2 groups, P value not reported).
5 patients in the acyclovir group regained their appetite after 4 days, and 5 patients in the placebo group after 5
days. 1 patient continued to experience difficulties until the end of the treatment period. The trialists indicated
that this outcome was comparable between the 2 groups but did not report a P value or any additional details.
General physical health: Group 1: 7 patients were fine from the beginning to the end of the treatment, Group
2: 5 patients were fine from the beginning to the end of the treatment (comparable in 2 groups, P value not
reported).
Body temperature (time period to get to the normal temperature < 37 C): In the beginning of the study 9
children from Group 1 and 4 from Group 2 had fever and there was not significant different between the 2
groups to reach the normal temperature.
The trialists reported that at the beginning of the study 9 children from the acyclovir group and 4 from the
placebo group had fever and that there was no significant difference between the 2 groups in the time taken
to return to normal temperature, although no details were provided.
Physical symptoms: Group 1 and Group 2 had no statistically significant difference.
a) Labial lesions: persistent up to day 5 of the treatment in up to 50% of patients in both groups.
b) Lingual lesions: persistent up to day 5 of the treatment in up to 50% of patients in both groups.
c) Palatal lesions: disappeared in all of the patients.
d) Gingival lesions: mostly disappeared.
e) Buccal lesions: mostly disappeared.
f ) Pharyngeal lesions: mostly disappeared.
10
(Continued)
g) Peribuccal lesions: disappeared in more than half of the cases before 5 days.
Cervical adenopathy: This was persistent in all of the patients in the placebo group and disappeared in 3
patients from the acyclovir group in first 4 days of the treatment.
Viral culture: Negative culture 7 from 8 patients (acyclovir group) and 3 from 5 patients (placebo group). 5
patients were unknown. 2 patients were not reported.
Tolerance and acceptability of the drug was described as satisfactory but it was unclear how this was assessed
by the trialists.
Amir 1997b
Primary outcomes
administration of the intervention. Number of individuals with
lesions from the time of administration of the intervention.
(a) Oral lesions: The time to healing of oral lesions was reported
as median and consequently we were unable to enter the data into
the RevMan analysis and have entered these in Additional Table 2.
On day 8 after the treatment, 2 out of 31 children in the acyclovir
group still had oral lesions compared with 21 out of 30 in the
placebo group.
(b) Extraoral lesions: The duration of extraoral lesions was reported
the RevMan analysis and have entered these in Additional Table
2.
None of the children in the acyclovir group developed new lesions.
However, 12 of those in the placebo group continued to develop
extraoral lesions after the treatment.
No data were available.
(a) Eating ability: The duration of eating difficulties was reported
the RevMan analysis and have entered these in Additional Table
2.
At enrolment all of the participants had difficulty with eating but
8 days after the treatment, only two from the acyclovir group and
14 from the placebo group continued to have difficulties.
(b) Drinking ability: The duration of drinking difficulties was
reported as median and consequently we were unable to enter the
data into the RevMan analysis and have entered these in Additional
Table 2. At entry all the participants had difficulty with drinking
but 8 days after the treatment, only one child in the acyclovir and
nine in the placebo group were still experiencing difficulties.
(4) Fever.
The duration of fever was reported as median and consequently
we were unable to enter the data into the RevMan analysis and
have entered these in Additional Table 2.
Secondary outcomes
At enrolment, five children (two acyclovir, three placebo group)
were admitted to hospital for rehydration. After commencement of
treatment a further three children (placebo group) were admitted
for 2 to 3 days for rehydration (P = 0.11).
No data were available for either of these patient reported outcomes.
Costs
No data available.
Adverse effects
Two children in each group had mild gastrointestinal symptoms
which resolved spontaneously after 24 to 48 hours and which did
not entail any change in the study treatment.
Ducoulombier 1988
11
Primary outcomes
administration of the intervention. Number of individuals with
lesions from the time of administration of the intervention.
A limited amount of data addressed this outcome but due to inconsistencies in their reporting, we were unable to further evaluate
them and present the data as reported in the text. Further details
are provided in Additional Table 2.
The trialists reported the time to resolution of pain but did not
describe how they assessed pain or its severity. Considering the age
of the participants, it is questionable whether they would be able
to self report.
The only outcome relevant to eating difficulties that was evaluated
in this study was anorexia (loss of appetite). The details are available
in Additional Table 2.
(4) Fever.
The trialists reported that at the beginning of the study nine of
the children in the acyclovir group and four in the placebo group
had fever and that there was no significant difference between the
two groups in the time taken to return to normal temperature.
Unfortunately, no details were provided.
Secondary outcomes
No data available.
No data available.
Tolerance and acceptability of the drug was described as satisfactory but it was unclear how this was assessed by the trialists.
Costs
No data available.
Adverse effects
No significant adverse effects were reported.
DISCUSSION
Primary herpetic gingivostomatitis (PHG) is the most commonly
observed clinical manifestation of primary herpes simplex infection and can produce a range of symptoms (e.g. pain, drooling)
in addition to difficulties with eating and drinking. Acyclovir is
frequently prescribed for PHG and is presumed to be effective at
decreasing symptoms as a result of its capability of reducing viral
shedding.
This review sought high level evidence for the effectiveness of systemic acyclovir versus placebo or no treatment for primary herpetic gingivostomatitis but found only two eligible studies, one of
which (Ducoulombier 1988) provided very limited data on the
outcomes of interest and was not consistent in the reporting of its
results. It was also unclear to what extent the participants adhered
to the treatment reported in the study.
Although some of the limitations and side effects of acyclovir (i.e.
poor gastrointestinal absorption and bioavailability), have been
previously reported, none of the included studies in this review
illustrated any significant side effects. Mild gastrointestinal symptoms were reported in one of the included studies (Amir 1997b)
but these resolved spontaneously after 48 hours.
Whilst recognising the clinical heterogeneity, the methodological
limitations, the incompleteness of data and the likelihood of bias
and uncertainties in respect of outcomes assessment in both of
these studies, we have nevertheless chosen to include them but
advise caution in the interpretation of their results.
AUTHORS’ CONCLUSIONS
Implications for practice
Out of the two trials in this systematic review, only one was able
to provide some weak evidence that acyclovir is an effective treatment in reducing the number of oral lesions, preventing the development of new extraoral lesions, decreasing the number of individuals with difficulties experienced in eating and drinking and
of those who are admitted to hospital for children under the age
of 6 with primary herpetic gingivostomatitis.
Implications for research
The results of this systematic review confirm the necessity for
further larger sample, methodologically sound trials that are reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement (www.consort-statement.org/) and
provide means and standard deviations for important outcomes
measurements.
To help minimise the effects of systematic bias in outcomes assessment, it would be prudent if in future trials the trialists are not
included as evaluators of outcomes and that appropriate training is
given to independent assessors to ensure standardisation of criteria
to be used in any outcomes assessments.
12
The two included studies only provided data on children under
6 years of age and there is therefore a requirement for trials to be
conducted on patients in other age groups. Moreover, to enable
patients and carers to make better healthcare decisions it would
be beneficial if patient-reported outcomes (i.e. quality of life and
patient satisfaction) were included in future trials.
ACKNOWLEDGEMENTS
The review authors would like to thank Luisa Fernandez
Mauleffinch, Helen Worthingthon, Sylvia Bickley and Philip Riley of the Cochrane Oral Health Group for their support and
assistance with developing this review. We extend our thanks to
Leonard Leibovici for kindly translating the Hebrew language trial
for us and Vassily Vlassov for kindly translating the Russian language trial for us.
REFERENCES
References to studies included in this review
Amir 1997b {published data only}
Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex
gingivostomatitis with aciclovir in children: a randomised double
blind placebo controlled study. BMJ 1997;314(7097):1800–3.
Ducoulombier 1988 {published data only}
Ducoulombier H, Cousin J, Dewilde A, Lancrenon S, Renaudie M,
Steru D, et al.Herpetic stomatitis-gingivitis in children: controlled
trial of acyclovir versus placebo [La stomato–gingivite herpetique de
l’enfant: essai controle aciclovir versus placebo]. Annales de
Pédiatrie 1988;35(3):212–6.
Mennemeyer 1997 {published data only}
Mennemeyer ST, Cyr LP, Whitley RJ. Antiviral therapy for
neonatal herpes simplex virus: a cost-effectiveness analysis. The
American Journal of Managed Care 1997;3(10):1551–8.
Yarom 2006 {published data only}
Yarom N, Buchner A, Dayan D. Herpes simplex infection--Part II:
Management of HSV infections. Refuat Hapeh Vehashinayim 2006;
23(2):6–13.
Zhilina 1976 {published data only}
Zhilina VV, Medvedeva II, Maksimova ZhI, Novikova NI.
Effectiveness of the overall treatment of acute herpetic stomatitis in
children. Stomatologiia 1976;55(5):78–82.
References to studies excluded from this review
Additional references
Amir 1997a {published data only}
Amir J, Harel L, Smetana H, Varsano I. Aciclovir for herpetic
gingivostomatitis in children. New Zealand Medical Journal 1997;
110(1053):369.
Amir 2001 {published data only}
Amir J. Clinical aspects and antiviral therapy in primary herpetic
gingivostomatitis. Paediatric Drugs 2001;3(8):593–7.
Amir 2002 {published data only}
Amir J. Primary herpetic gingivostomatitis--clinical aspects and
anti-viral treatment. Harefuah 2002;141(1):81–4.
Jacobs 1998 {published data only}
Jacobs RF. Neonatal herpes simplex virus infections. Seminars in
Perinatology 1998;22(1):64–71.
Madigosky 2004 {published data only}
Madigosky WS, Meadows S, McCormack O. Clinical inquiries.
Does acyclovir help herpes simplex virus cold sores if treatment is
delayed?. The Journal of Family Practice 2004;53(11):923–4.
Chauvin 2002
Chauvin PJ, Ajar AH. Acute herpetic gingivostomatitis in adults: a
review of 13 cases, including diagnosis and management. Journal of
the Canadian Dental Association 2002;68(4):247–51.
Egger 1997
Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315(7109):
629–34.
Faden 2006
Faden H. Management of primary herpetic gingivostomatitis in
young children. Pediatric Emergency Care 2006;22(4):268–9.
Higgins 2008
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions version 5.0.0 (updated
February 2008). The Cochrane Collaboration 2008. Available
from www.cochrane–handbook.org.
13
Kolokotronis 2006
Kolokotronis A, Doumas S. Herpes simplex virus infection, with
particular reference to the progression and complications of
primary herpetic gingivostomatitis. Clinical Microbiology and
Infection 2006;12(3):202–11.
Neville 2002
Neville BW, Damm DD, Allen CM, Bouqout JE. Viral infections.
Oral and maxillofacial pathology. 2nd Edition. Philadelphia: WB
Saunders Co, 2002:213–20.
RevMan 2008
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). 5.0. Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2008.
Siegel 2002
Siegel MA. Diagnosis and management of recurrent herpes simplex
infections. Journal of the American Dental Association 2002;133(9):
1245–9.
∗
Indicates the major publication for the study
14
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Amir 1997b
Methods
Double blind, randomised controlled trial.
Participants
72 patients aged 1-6 years (gender unspecified)diagnosed with clinical gingivostomatitis. The parents of
1 child from the control group refused to attend follow up after 2 days.
From the remaining 71 children, 10 (5 acyclovir group, 5 control group) had a negative viral culture for
herpes simplex and a negative serological result during convalescence. The results of these 10 patients plus
the 1 previous drop out were reported but the trialists considered them as excluded.
Eligibility criteria: clinical manifestation of gingivostomatitis lasting less than 72 hours identified by
primary paediatrician and referred to the paediatric day care unit of Hasharon Hospital.
Group 1 (n = 36) (from the 31 with cultures positive for herpes simplex virus (14 male, 17 female)),
mean age 33.1 months, 11 with mild lesions, 16 with moderate and 4 severe. Group 2 (n = 35) (from the
30 with cultures positive for herpes simplex virus (16 male, 14 female)), mean age 35.9 months with 7
patients with mild lesions, 17 moderate and 6 severe. All of the patients had problems in eating and most
of them also in drinking.
Interventions
Group 1 (n = 31): Acyclovir was given in a dose of 15 mg/kg (0.375 ml/kg), 5 times a day (up to a
maximum of 200 mg per dose) for a period of 7 days.
Group 2 (n = 30): Placebo was given in the same volume, 5 times a day, the suspension was exactly similar
to acyclovir.
14 patients equally distributed between the 2 groups received also Collu Hextril as an adjuvant treatment.
Outcomes
Difference in median (95% CI) duration (in days) of clinical variables: oral lesions, fever, extraoral lesions.
Along with this, other outcomes were considered like hospital admission (before and after inclusion in
the study), drooling, eating difficulties, drinking difficulties, viral shedding along with the compliance of
the participants to the treatment and the side effects of it.
Notes
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Ducoulombier 1988
Methods
Double blind, randomised controlled trial.
Participants
n = 20 (11 boys, 9 girls), mean age 2 years, mean weight 12 kg.
Eligibility criteria: clinical symptoms of primary herpetic infection less than 4 days, HSV-1 isolated from
human diploid cells culture.
The majority of the children were in good health except 2 patients from the treatment group and 1 from
the placebo who were reported to have drowsiness.
15
(Continued)
Ducoulombier 1988
The patients have also shown other symptoms like pain (18 cases), loss of appetite (18 cases) and hypersialorrhea (excessive drooling of saliva) (17 cases).
The most common physical lesions were labial, gingival, lingual and buccal lesions, there were also some
less common symptoms like peribuccal lesions (13 cases), palatine lesions (12 cases), pharyngeal lesions
(10 cases), cutaneous lesions (10 cases).
The 2 groups were stated to be homogeneous in terms of pathological and physical characteristics and signs
and symptoms of the infection. Fever was the only symptom which was more prevalent in the acyclovir
group (9 cases) compared with the placebo group (4 cases).
Interventions
Group 1 (n = 10): Acyclovir 5 tablets per day for 5 days.
Group 2 (n = 10): Placebo a similar dose. The characteristics of the placebo were not specified.
Outcomes
Time to resolution of pain, time to resolution of hypersialorrhea, anorexia (loss of appetite), general physical
health, body temperature (time period to get to the normal temperature < 37 C), physical symptoms (
including labial lesions, lingual lesions, palatal lesions, gingival lesions, buccal lesions, pharyngeal lesions,
peribuccal lesions), cervical adenopathy and the trialists have also taken viral cultures from the lesions.
Notes
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
CI = confidence interval
Characteristics of excluded studies [ordered by study ID]
Amir 1997a
The study refers to Amir 1997b.
Amir 2001
Literature review with no relevant new randomised controlled trials.
Amir 2002
Jacobs 1998
The study compared acyclovir with intravenous vidarabine which did not match our inclusion criteria.
Madigosky 2004
Literature review with no relevant randomised controlled trials.
Mennemeyer 1997
Literature review with no relevant randomised controlled trials.
Yarom 2006
16
(Continued)
Zhilina 1976
This is a cohort study not a randomised controlled trial.
17
DATA AND ANALYSES
Comparison 1. Acyclovir versus placebo
Outcome or subgroup title
No. of
studies
No. of
participants
1
72
Risk Ratio (M-H, Fixed, 95% CI)
0.10 [0.02, 0.38]
1
72
0.04 [0.00, 0.65]
1
72
0.14 [0.03, 0.58]
1
72
0.11 [0.01, 0.83]
1
72
0.14 [0.01, 2.67]
1 The number of individuals
with oral lesions (8 days after
the administration of the
intervention)
2 The number of individuals who
developed new extraoral lesions
after the administration of the
intervention
with eating difficulties (8 days
intervention)
4 The number of individuals with
drinking difficulties (8 days
intervention)
admitted to hospital after
the administration of the
intervention
Statistical method
Effect size
Analysis 1.1. Comparison 1 Acyclovir versus placebo, Outcome 1 The number of individuals with oral
lesions (8 days after the administration of the intervention).
Review:
Comparison: 1 Acyclovir versus placebo
Outcome: 1 The number of individuals with oral lesions (8 days after the administration of the intervention)
Study or subgroup
Amir 1997b
Total (95% CI)
Treatment
Control
n/N
n/N
Risk Ratio
Weight
2/36
21/36
100.0 %
0.10 [ 0.02, 0.38 ]
36
36
100.0 %
0.10 [ 0.02, 0.38 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 2 (Treatment), 21 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 3.35 (P = 0.00080)
0.1 0.2
0.5
Favours treatment
1
2
5
10
Favours control
18
Analysis 1.2. Comparison 1 Acyclovir versus placebo, Outcome 2 The number of individuals who developed
new extraoral lesions after the administration of the intervention.
Review:
Outcome: 2 The number of individuals who developed new extraoral lesions after the administration of the intervention
Study or subgroup
Amir 1997b
Total (95% CI)
Treatment
Control
n/N
n/N
Risk Ratio
Weight
0/36
12/36
100.0 %
0.04 [ 0.00, 0.65 ]
36
36
100.0 %
0.04 [ 0.00, 0.65 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.1 0.2
0.5
1
Favours treatment
2
5
10
Favours control
Analysis 1.3. Comparison 1 Acyclovir versus placebo, Outcome 3 The number of individuals with eating
difficulties (8 days after the administration of the intervention).
Review:
Outcome: 3 The number of individuals with eating difficulties (8 days after the administration of the intervention)
Study or subgroup
Amir 1997b
Total (95% CI)
Treatment
Control
n/N
n/N
Risk Ratio
Weight
2/36
14/36
100.0 %
0.14 [ 0.03, 0.58 ]
36
36
100.0 %
0.14 [ 0.03, 0.58 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.1 0.2
0.5
Favours treatment
1
2
5
10
Favours control
19
Analysis 1.4. Comparison 1 Acyclovir versus placebo, Outcome 4 The number of individuals with drinking
difficulties (8 days after the administration of the intervention).
Review:
Outcome: 4 The number of individuals with drinking difficulties (8 days after the administration of the intervention)
Study or subgroup
Amir 1997b
Total (95% CI)
Treatment
Control
n/N
n/N
Risk Ratio
Weight
1/36
9/36
100.0 %
0.11 [ 0.01, 0.83 ]
36
36
100.0 %
0.11 [ 0.01, 0.83 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.1 0.2
0.5
1
Favours treatment
2
5
10
Favours control
Analysis 1.5. Comparison 1 Acyclovir versus placebo, Outcome 5 The number of individuals admitted to
hospital after the administration of the intervention.
Review:
Outcome: 5 The number of individuals admitted to hospital after the administration of the intervention
Study or subgroup
Amir 1997b
Total (95% CI)
Treatment
Control
n/N
n/N
Risk Ratio
Weight
0/36
3/36
100.0 %
0.14 [ 0.01, 2.67 ]
36
36
100.0 %
0.14 [ 0.01, 2.67 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.1 0.2
0.5
Favours treatment
1
2
5
10
Favours control
20
APPENDICES
Appendix 1. Cochrane Oral Health Group’s Trials Register search strategy
((“stomatitis herpetic” or “herpetic stomatitis” or “herpetic gingivostomatitis” or (“herpes simplex” AND mouth) or “herpetic lesion”
or “cold sore*” or “herpes labialis” or “herpes orofacialis” or “herpes infection” or (ulcer and (mouth or oral)) or “canker sore*” or
“stomatitis herpetica”) AND (acyclovir or aciclovir or ganciclovir or valacyclovir or “anti-retroviral agents” or “antviral agent*”))
Appendix 2. CENTRAL search strategy
#1 STOMATITIS HERPETIC (Single term MeSH)
#2 ((herpetic near gingivostomatitis) OR (herpetic stomatitis))
#3 herpes next simplex NEAR mouth
#4 ((herpes next simplex) AND oral mucosa*)
#5 ((herpetic next lesion*) AND (mouth or oral cavity))
#6 ((herpetic next lesion*) near (oral next cavity))
#7 (cold next sore*)
#8 ((herpes next labialis) and mouth)
#9 (herpes next orofacialis)
#10 ((herpes or herpetic) and infection* and mouth)
#11 ((oral next ulcer*) or (canker next sore*))
#12 ORAL ULCER (Single term MeSH)
#13 (stomatitis next herpetica)
#14 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12
or #13)
#15 ACYCLOVIR (Explode all trees MeSH)
#16 ANTI-RETROVIRAL AGENTS (Explode all trees MeSH)
#17 (acyclovir or aciclovir)
#18 (antiviral next agent*)
#19 ganciclovir or valacyclovir
#20 Abduce or Acerpes or acic or aciclin or aciclo or aciclobeta or acicloftal or aciclor or aciclobene or aciclodan or aciclomed or
aciclosina or aciclovan or aciclostad or aciclotyrol or aciclovivax or acifur or acihexal or acilax or aci-sanorania or acitop or aciveral or
acivir or aciviran or acivirax or activir or acurax or acyclo-v or aclovir or aclovirax or acyclostad or acyclo-v or acyclox or acyl or acyrax
or acyvir or akivir or aklovir or alovir or amodivyr or anclomax or antix or antivirax or apofarm or apo-vir or asiviral or avir or aviral or
avirax or avirase or avirex-T or avirox or avix or avorax or avyclor or avyplus or avysal or bearax or “bel labial” or biozirox or cargosil or
cevinolon or cevirin or ciclavix or ciclocris or cicloferon or ciclor or cicloviral or citivir or clearsore or clinovir or clociver or clonorax
or clover or cloven or clovira or clovirax or clovirex or clovix or colsor or cusiviral or cyclivex or cyclomed or cyclorax or cyclovax or
cyclovir or cycloviran or danovir or declovir or dioxis or divicil or dravyr or ductovirax or dynexan or efriviral or entir or epsin or erlvirax
or erpaclovir or erpizon or erser or esavir or etasisen or eurovir or exaliver or exavir or exviral or ezopen or farocid or faulviral or fibril
or filivir or firex or fuviron or geavir or hagevir or heclivir or helposol or helvevir or hepirax or hermocil or hermixsofex or hernovir or
herpeks or herpesil or herpesnil or herpavir or herpenon or herpescreme or herpetad or herpesin or herpex or herpilem or herpisin or
herpofug or herpolips or herpomed or herpotern or herpoviric or hervirax or herzkur or iliaclor or immunovir or ipaviran or ipsovir or
isavir or jersin or juviral or kendix or kerastil or klovir or klovireks-L or aoekruidvat koortslipcremea or laciken or lermex or lesaclor or
lisovyr or lovir or lovire or lovrak
#21 maclov or mapox or marvir or medovir or maynar or milavir or neclovir or neldim or neviran or norum or nycovir or oftavir or
orivir or oviral or pharcilex or previum or provir or provirsan or pulibex or ranvir or rexan or riduvir or sanavir or seracic or sifiviral
or silovir or solovir or simplex-fieberblasen or sinarden or soothelip or sophivir or soviclor or stadovir or supra-vir or supraviran or
synclovir or telviran or uniplex or “uni vir” or uniplex or vacrax or vermis or verpir or vicloran or viclovir or vidaclovir or vilerm or
vipral or viraban or virabelte or viralief or virasorb or virax or viraxy or virazone or virest or virestat or virherpes or virless or virmen or
viro or viroclear or virogon or virolan or virokill or virolex or viromed or vironida or viropox or virosil or virovir or viroxil or viroxy
or virucalm or virucid or viruderm or virupos or virusteril or virupos or viruseen or virzin or vivax or vivir or voraclor or vyrohexal
or wariviron or xiclovir or xorox or zeramil or zetavir or zevin or ziclovir or zidovimm or zirconia or ziverone or zocovin or zolaten or
zoliparin or zoral or zorax or zoraxin or zoviplus or zovir or zovirax or zov800 or zoylex or zyclir
21
#22#15 or #16 or #17 or #18 or #19 or #20 or #21
#23#14 AND #22
Appendix 3. MEDLINE (OVID) search strategy
1. Stomatitis, Herpetic/
2. ((herpetic adj3 gingivostomatitis) or (herpetic adj3 stomatitis)).mp. [mp=title, original title, abstract, name of substance word, subject
heading word]
3. (“herpetic lesion$” and (mouth or oral cavity)).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
4. (“herpes simplex” and (“oral mucosa$” or mouth)).mp. [mp=title, original title, abstract, name of substance word, subject heading
word]
5. “cold sore$”.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
6. (herpes labialis and mouth).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
7. herpes orofacialis.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
8. ((herpes or herpetic) and infection$ and mouth).mp. [mp=title, original title, abstract, name of substance word, subject heading
word]
9. (oral ulcer$ or canker sore$).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
10. Oral Ulcer/
11. stomatitis herpetica.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
12. or/1-11
13. acyclovir/or ganciclovir/
14. Anti-Retroviral Agents/
15. (acyclovir or aciclovir).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
16. antiviral agent$.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
17. (ganciclovir or valacyclovir).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
18. (Abduce or Acerpes or acic or aciclin or aciclo or aciclobeta or acicloftal or aciclor or aciclobene or aciclodan or aciclomed or
avirax or avirase or avirex-T or avirox or avix or avorax or avyclor or avyplus or avysal or bearax or bel labial or biozirox or cargosil or
isavir or jersin or juviral or kendix or kerastil or klovir or klovireks-L or aoekruidvat koortslipcremea or laciken or lermex or lesaclor or
lisovyr or lovir or lovire or lovrak).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
19. (maclov or mapox or marvir or medovir or maynar or milavir or neclovir or neldim or neviran or norum or nycovir or oftavir or
synclovir or telviran or uniplex or uni vir or uniplex or vacrax or vermis or verpir or vicloran or viclovir or vidaclovir or vilerm or vipral
or viraban or virabelte or viralief or virasorb or virax or viraxy or virazone or virest or virestat or virherpes or virless or virmen or viro or
viroclear or virogon or virolan or virokill or virolex or viromed or vironida or viropox or virosil or virovir or viroxil or viroxy or virucalm
or virucid or viruderm or virupos or virusteril or virupos or viruseen or virzin or vivax or vivir or voraclor or vyrohexal or wariviron
or xiclovir or xorox or zeramil or zetavir or zevin or ziclovir or zidovimm or zirconia or ziverone or zocovin or zolaten or zoliparin or
zoral or zorax or zoraxin or zoviplus or zovir or zovirax or zov800 or zoylex or zyclir).mp. [mp=title, original title, abstract, name of
substance word, subject heading word]
20. or/13-19
21. 12 and 20
Cochrane/Oral Health Group search filter for MEDLINE (OVID)
22
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1-8
10. human.sh.
11. 9 and 10
Appendix 4. EMBASE (OVID) search strategy
1. (Stomatitis and Herpetic).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
2. ((herpetic adj3 gingivostomatitis) or (herpetic adj3 stomatitis)).mp. [mp=title, abstract, subject headings, heading word, drug trade
name, original title, device manufacturer, drug manufacturer name]
3. (“herpetic lesion$” and (mouth or oral cavity)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
title, device manufacturer, drug manufacturer name]
4. (“herpes simplex” and (“oral mucosa$” or mouth)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
5. “cold sore$”.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
6. (herpes labialis and mouth).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
7. herpes orofacialis.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
8. ((herpes or herpetic) and infection$ and mouth).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
9. (oral ulcer$ or canker sore$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
10. Mouth Ulcer/
11. stomatitis herpetica.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,
drug manufacturer name]
12. or/1-11
13. acyclovir/or ganciclovir/
14. Antiretrovirus Agent/
15. (acyclovir or aciclovir).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,
drug manufacturer name]
16. antiviral agent$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
17. (ganciclovir or valacyclovir).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
18. (Abduce or Acerpes or acic or aciclin or aciclo or aciclobeta or acicloftal or aciclor or aciclobene or aciclodan or aciclomed or
avirax or avirase or avirex-T or avirox or avix or avorax or avyclor or avyplus or avysal or bearax or bel labial or biozirox or cargosil or
23
isavir or jersin or juviral or kendix or kerastil or klovir or klovireks-L or aoekruidvat koortslipcremea or laciken or lermex or lesaclor
or lisovyr or lovir or lovire or lovrak).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
19. (maclov or mapox or marvir or medovir or maynar or milavir or neclovir or neldim or neviran or norum or nycovir or oftavir or
synclovir or telviran or uniplex or uni vir or uniplex or vacrax or vermis or verpir or vicloran or viclovir or vidaclovir or vilerm or vipral
or viraban or virabelte or viralief or virasorb or virax or viraxy or virazone or virest or virestat or virherpes or virless or virmen or viro or
viroclear or virogon or virolan or virokill or virolex or viromed or vironida or viropox or virosil or virovir or viroxil or viroxy or virucalm
or virucid or viruderm or virupos or virusteril or virupos or viruseen or virzin or vivax or vivir or voraclor or vyrohexal or wariviron
or xiclovir or xorox or zeramil or zetavir or zevin or ziclovir or zidovimm or zirconia or ziverone or zocovin or zolaten or zoliparin or
zoral or zorax or zoraxin or zoviplus or zovir or zovirax or zov800 or zoylex or zyclir).mp. [mp=title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer name]
20. or/13-19
21. 12 and 20
Filter for EMBASE (OVID)
1. random$.ti,ab.
2. factorial$.ti,ab.
3. (crossover$ or cross over$ or cross-over$).ti,ab.
4. placebo$.ti,ab.
5. (doubl$ adj blind$).ti,ab.
6. (singl$ adj blind$).ti,ab.
7. assign$.ti,ab.
8. allocat$.ti,ab.
9. volunteer$.ti,ab.
10. CROSSOVER PROCEDURE.sh.
11. DOUBLE-BLIND PROCEDURE.sh.
12. RANDOMIZED CONTROLLED TRIAL.sh.
13. SINGLE BLIND PROCEDURE.sh.
14. or/1-13
15. ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/
16. HUMAN/
17. 16 and 15
18. 15 not 17
19. 14 not 18
WHAT’S NEW
Last assessed as up-to-date: 25 June 2008.
26 June 2008
Amended
Converted to new review format.
24
HISTORY
Protocol first published: Issue 3, 2007
Review first published: Issue 4, 2008
CONTRIBUTIONS OF AUTHORS
Mona Nasser (MN) was responsible for co-ordinating the review.
MN and Maryam Shahiri (MS) were responsible for screening of the search results, and the retrieved papers against inclusion criteria.
MN and MS were responsible for appraising the quality of papers.
MN was responsible for organising the retrieval of papers and writing to authors of papers for additional information.
Zbys Fedorowicz (ZF) and MN were responsible for data management of the review including extracting data from papers and entering
data into RevMan.
MN and MS were responsible for obtaining and screening data on unpublished studies.
MN and ZF were responsible for the interpretation and analysis of data.
MN, ZF, Mohammad Khoshnevisan (MK) and MS were responsible for writing the protocol and the review.
MN will be the guarantor for the review.
DECLARATIONS OF INTEREST
There are no financial conflicts of interest and the review authors declare that they do not have any associations with any parties who
may have vested interests in the results of this review.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Changes were made to the outcomes. These changes include: adding the number of individuals with persistent or new oral lesions
after the treatment, with difficulties in eating and drinking or the number of individuals who were admitted to hospital during the
treatment.
INDEX TERMS
Medical Subject Headings (MeSH)
Acyclovir [∗ therapeutic use]; Antiviral Agents [∗ therapeutic use]; Gingivitis [∗ drug therapy; virology]; Randomized Controlled Trials
as Topic; Stomatitis, Herpetic [∗ drug therapy]
25
MeSH check words
Child; Child, Preschool; Female; Humans; Infant; Male
26

Acyclovir for treating primary herpetic gingivostomatitis (Review) The Cochrane Library

Transcription

Similar documents

Issue No. 4 - Cucamonga Valley | Medical Group

How To Get Comfortable With Prescription Oral Medications How To

Acute Herpetic Gingivostomatitis in Adults: and Management

Hidradenitis Suppurativa(HS) Acne Inversa Conflicts of interest

GLES CASE STUDY

Print/View PDF - veterinaryteambrief.com

randomized clinical study comparing compeed® cold sore patch