Interventions for treatment of herpes labialis (cold sores on the lips)

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of interventions for treating herpes labialis among immunocompetent people.

Background

A glossary of terms can be found in Table 1.

1. Glossary.

Clinical term	Explanation
Autoinoculation	An infective agent spreading from one part to other parts in the same body
Buccally	From the point of view of the cheek or the mouth
Crust	The drying bodily exudate or secretion (contains dried sebum, pus, or blood) mixed with epithelial tissue forming an outer layer
Encephalitis	An inflammation of the brain
Endogenous	Produced or causing within an organism or cell
Erythema	Redness over the skin or mucous membranes
Erythema multiforme	A skin reaction involving the mucous membrane usually triggered by an infection or medicine
Exogenous	The material present and active in an individual organism or cell but its origin is outside of the organism
Ganglion	A structure in the peripheral nervous system containing nerve cell bodies, glia, and connective tissue
Immunocompetent	The ability to develop a normal immune response to recognise antigens and act against them
Immunocompromised	A weakened immune system reduces the ability to prevent infections and other diseases
Keratitis	An inflammation of the eye’s cornea
Latency	The inactivity status of a carcinogen, toxin, or disease‐causing organism in a living individual
Nephrotoxicity	Rapid deterioration in kidney function due to toxic effect of medications and chemicals
Nucleoside	A structural subunit of nucleic acids that function as signalling molecules and as precursors for DNA and RNA synthesis
Photosensitiser	A chemical entity, which upon absorption of light, causes a sensitivity reaction in organisms
Polymerase	Enzymes which catalyse the formation of a particular polymer (as DNA or RNA)
Prodrome	An early sign or symptom indicating the onset of a disease
Pruritus	Itchy skin; an uncomfortable, irritating feeling that makes people want to scratch
Sensory ganglia	Enlargements along the peripheral nerve consisting of sensory nerve cell bodies
Seroprevalence	The percentage of individuals in a population who have antibodies to a specific disease based on serology

Description of the condition

Herpes labialis (cold sores on the lips) is a common and recurrent  viral infection. The lifetime prevalence of recurrent herpes labialis in the United States is estimated to be between 20% and 45% of the adult population, and the prevalence of recurrent herpes labialis varies from 0.72% to 5.2% in studies in other populations (Ahluwalia 2019; Celik 2013; Higgins 1993). The prognosis of herpes labialis is characterised by recurrences of variable frequency, ranging from sporadic episodes to monthly or even more frequent outbreaks per year (Spruance 1997). There are six stages in a classic case of herpes labialis: prodrome (tingling, pain, itching, or burning over the infected site), erythema, papule or oedema, ulcer, crust, and healing. The recurrence and manifestations of herpes labialis are influenced by many factors, such as emotional stress, lifestyle (e.g. sexual experience, alcohol intake), as well as endogenous (e.g. immunodeficiency) and exogenous influences (e.g. ultraviolet (UV) radiation) (Logan 1998; Stock 2001).

Herpes simplex virus type 1 (HSV‐1) is the main causative pathogen of herpes labialis, though HSV type 2 (HSV‐2) has been reported to cause recurrent herpes labialis (Spruance 2002). The most common route of infection is via oral mucosa contact with the virus from the sores, saliva, or the lips surfaces of the mouth, which establishes lifelong latency in a sensory ganglion following initial acquisition. The infected ganglion subsequently provides a HSV reservoir for transmission to susceptible individuals (Whitley 2001). Amongst the HSV family, HSV‐1 infection is mostly characterised by oral or facial lesions, with some exceptional cases of first‐episode genital herpes reported in some high‐income countries (Brugha 1997). The seroprevalence of HSV‐1 in different age and risk groups varies by continent, country, and study year. However, HSV‐1 infection is generally high in most geographic areas, even in low‐risk populations, and it is more prevalent than HSV‐2 infection. HSV‐1 infection mostly occurs in childhood and adolescence and presents with a roughly linear trend with increasing age. The limited data indicate that HSV‐1 was less prevalent worldwide in 2015 than in 2002 (Looker 2015; Smith 2002).

In addition to embarrassment due to conspicuous facial lesions, herpes labialis may cause burns and pain. The cosmetically undesirable lesions often cause psychological distress, considerable physical discomfort, and pose a risk of autoinoculation and transmission (Dréno 2012). Therapy is indicated when there are frequent recurrences, or if the patient is immunocompromised (Cunningham 2012; Spruance 2002). In immunocompromised individuals, the lesions may persist for a longer duration and may spread to cause major morbidity. Erythema multiforme may be triggered by HSV‐1 infections and can be temporarily disabling (Huff 1992; Orgaz‐Molina 2013). Herpetic keratitis and herpes encephalitis are infrequent but life‐threatening complications of orofacial HSV‐1 infection (Stanberry 2000).

Description of the intervention

Approximately 50% of people with herpes labialis seek medical care specifically for recurrent HSV‐1 lesions, and attempt treatment because of the discomfort and visibility of recurrent lesions (Dréno 2012). Many prescription medications and over‐the‐counter products have been tried as therapy. For those who have severe infection and who are immunocompromised, the symptoms might be more extensive and aggressive than those of the immunocompetent; in these cases, systemic use of antiviral agents may be considered (Arduino 2006).

Antiviral agents

Both topical and peroral episodic nucleoside antiviral drugs (NADs) are used to treat cold sores. Regimens shown to be effective in reducing the duration of herpes labialis symptoms include aciclovir 400 mg orally three times daily for five to 10 days, aciclovir 5% cream topically five times per day for four days, aciclovir 50 mg tablet buccally in upper gum above incisor tooth (canine fossa) for 30 seconds, penciclovir 1% cream topically every two hours while awake for four days (Boon 2000), famciclovir 1500 mg orally as a single dose initiating at the earliest sign or symptom of a cold sore, and valaciclovir 2 g orally twice daily for one day separating doses by 12 hours (Chen 2017; Whitley 2002). No major drug‐drug interactions of topical NADs such as penciclovir are known. However, nitisinone, leflunomide, and teriflunomide combined with systemic NADs may increase the levels of NADs in a person’s bloodstream (Huledal 2019; Liao 2020). This in turn may result in a range of adverse effects, including nausea, abdominal pain, and delirium. Finally, foscarnet combined with systemic NADs may result in nephrotoxicity (Becker 1996).

Oral NADs have been given as prophylactic drugs for people with at least six recurrences per year (Chi 2015). As long‐term oral NADs may not be feasible for most people, effective therapeutic interventions at the onset of the episode would be preferable (Spruance 1997).

Two other topical antiviral agents, tromantadine and docosanol, have also been used in treating herpes labialis (Diezel 1993; Sacks 2001). 

Anti‐inflammatory agents

Anti‐inflammatory agents, such as 90% kanuka honey:10% glycerine cream applied topically five times per day, have been used in herpes labialis treatment with limited benefit (Semprini 2019).

Photo and photodynamic therapy

Photodynamic therapy (photosensitiser: 5‐aminolevulinic acid or methylene blue; light source: red light or laser) or laser phototherapy (diode laser, wavelength 870 nm, energy density 4.5 J/cm², frequency 600 Hz, and maximum pulse radiation power 80 W for a minute per day) represent other therapeutic options for herpes labialis (Al‐Maweri 2018; Honarmand 2017; Lotufo 2020). In their systematic review, Lotufo and colleagues found that local pain and hyperpigmentation were possible adverse events of photodynamic therapy (Al‐Maweri 2018; Honarmand 2017; Lotufo 2020). 

Other agents

One study reported that a zinc sulphate 0.5% suspension applied topically three times per day for four days was effective in healing lesions without causing any adverse events (Altaei 2005).

How the intervention might work

After the initial infection, the virus remains in our sensory ganglia and is incurable. The mechanisms of the interventions for shortening the recurrent lesions or relieving the symptoms are summarised below:

Antiviral agents

Nucleoside antiviral drugs (NADs) include acyclic guanosine analogues, acyclic nucleotide analogues, and pyrophosphate analogues that interfere with viral nucleic acid replication with resultant DNA chain termination or mutagenesis and suppression of virus activity (Furman 1979; Jiang 2016). Tromantadine may inhibit a late event in HSV‐1 replication (Ickes 1990). Docosanol may inhibit the fusion between herpes virus envelopes and target cell membranes, preventing the virus from entering the cells and repressing viral replication (Pham 2001). 

Anti‐inflammatory agents

Decreasing the local inflammation could relieve the symptoms and sign of herpes labialis. Honey has been reported as a natural agent with multiple functions, including antioxidative, antiproliferative, and anti‐inflammatory effects (Ranneh 2021).

Photo and photodynamic therapy

Photodynamic therapy involves a light source and photosensitiser. After the light is beamed, the photosensitiser induces oxygen production to interfere with viral replication and damage the target cells (Lotufo 2020; Schnipper 1980). Laser phototherapy is posited to have potential analgesic, anti‐inflammatory, and bio‐stimulating effects (including neovascularisation, tissue regeneration, and immune response) that could relieve the symptoms of herpes labialis (Al‐Maweri 2018; Pandeshwar 2016).

Other agents

Zinc could play an anti‐HSV role in multiple ways, including interfering with viral polymerase and protein production, free virus inactivation, and reduction in HSV replication (Read 2019).

Why it is important to do this review

Over the past decade, there have been many new interventions and clinical trials for herpes labialis treatment. Some systematic reviews have evaluated NADs, photodynamic therapy, or phototherapy for treating HSV infection (Al‐Maweri 2018; Chen 2017; Lotufo 2020). However, these reviews did not include other interventions such as zinc, docosanol, or honey (Altaei 2005; Ranneh 2021; Sacks 2001). Therefore, this review aims to examine the best evidence concerning the benefits and harms of all types of available interventions in treating herpes labialis. 

Cochrane has updated its methods for assessing the certainty of evidence. Therefore, we decided to update the previous protocol to accommodate these developments (see Other published versions of this review). 

Objectives

To assess the effects of interventions for treating herpes labialis among immunocompetent people.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), including parallel, cluster‐randomised, and cross‐over within‐participant RCTs. We will exclude quasi‐randomised studies.

Types of participants

We will include immunocompetent participants with herpes labialis diagnosed by a healthcare professional or a trained researcher based on clinical presentation. We will exclude participants with HIV infection or those receiving immunosuppressive agents, including chemotherapy or radiotherapy. We will include participants in any setting, with no restrictions on demographic factors such as age and sex.

When a study includes participants with herpes simplex involving various sites, or includes immunocompetent and immunocompromised individuals, we will include the study only if the authors report separate data for herpes labialis. If the publication does not provide separate data, we will contact the study authors and request separate data for herpes labialis.

Types of interventions

We will include any intervention specifically used for the treatment of herpes labialis. 

• Photodynamic therapy

• Antiviral agents (NADs, tromantadine, and docosanol)

• Anti‐inflammatory agents

• Phototherapy

• Photodynamic therapy

Participants may receive a single intervention or a combination of interventions. We will include all interventions with no limitations on the dose, frequency, and duration. 

We will include the following comparators.

• Another active intervention (a different type of non‐placebo intervention, another kind of medication, or an extra dose or different duration of the same intervention)

• Placebo

• No treatment

Types of outcome measures

Primary outcomes

• Duration of the clinical episode (time to healing, measured in days; defined as loss of crusts or loss of all symptoms), participant‐ or investigator‐rated

• Any adverse event severe enough to lead to cessation of treatment

Secondary outcomes

• Participant‐rated global degree of improvement of the signs and symptoms (such as global rate of change (GRC) scales (Jaeschke 1989)) at each time point the studies recorded

• Change from baseline in the participant‐ or investigator‐rated severity of clinical episode (for example, lesion size) at each time point the studies recorded

• Change from baseline in the severity of pain (as global pain score) at each time point the studies recorded

• Any mild or moderate adverse event not leading to cessation of treatment

If a study measures these outcomes at multiple time points, we will report each separately. If a study uses more than one scale for a given outcome, we will report the result of each scale separately with no hierarchy of scales. We will not exclude studies that do not report relevant outcome data. 

Search methods for identification of studies

We aim to identify all relevant RCTs regardless of publication language or status (published, unpublished, in press, or in progress).

Electronic searches

Yu‐Shiun Tsai will search the following databases for relevant trials with no restriction by date:

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

• MEDLINE via Ovid (from 1946 onwards); and

• Embase via Ovid (from 1974 onwards).

The Information Specialist has devised draft search strategies for these databases, which are displayed in Appendix 1, Appendix 2, and Appendix 3. The draft MEDLINE strategy will be peer‐reviewed by another Cochrane information specialist prior to execution using the Search methods and strategy peer review assessment form for Cochrane intervention protocols. We will use this strategy as the basis for search strategies for the other databases listed. 

A medical librarian (YST) will search the following databases using terms based on those in lines 1 to 17 of the MEDLINE search strategy in Appendix 2:

• The US National Institutes of Health ongoing trials register on www.clinicaltrials.gov;

• The World Health Organization International Clinical Trials Registry platform on www.who.int/trialsearch/.

Searching other resources

Errata and retractions 

The Cochrane Skin Information Specialist will run a specific search to identify errata or retractions related to our included studies. We will examine any relevant retraction statements and errata retrieved.

Searching reference lists

We will check the bibliographies of included RCTs and relevant systematic reviews for further references to relevant trials.  

Correspondence with trialists

We will contact the authors of relevant RCTs published within the past three years to ask if they are aware of other relevant unpublished data. We will contact study investigators for clarification and further data if trial reports are unclear. 

Adverse events

We will not perform a separate search for adverse events of these interventions for treating herpes labialis. We will analyse only adverse events reported in included RCTs.

Data collection and analysis

Some parts of this section use text originally published in another Cochrane protocol (Lin 2018), and some parts of 'Assessment of risk of bias' in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022b), hereafter referred to as the Cochrane Handbook.

Selection of studies

Two review authors (HL and PL) will independently check titles and abstracts identified from the searches. We will not blind the names of trialists or their institutions. We will exclude the studies that do not relate to an RCT on interventions for treating herpes labialis, judging from the title and abstract. The same two review authors will independently examine the full text of each remaining study and judge whether it meets our inclusion criteria. If we disagree on whether to include a study, we will achieve unanimity through discussion with a third review author (CC). We will list the studies we exclude after examining the full text and provide reasons for exclusion in the 'Characteristics of excluded studies' tables. We will use Covidence for study selection.

Data extraction and management

Two review authors (HL and PL) will independently extract data from the included RCTs using a pre‐piloted data extraction form. We will collect the following information: study methods, participants, interventions, outcomes, country, setting, and funding source (see Appendix 4). We will use WebPlotDigitizer 2017 to extract data from figures and graphs. We will use extracted data to create the 'Characteristics of included studies’ tables. If we encounter disagreement about some data, we will consult with a third review author (CC) to achieve unanimity. One review author (HL) will enter the data into Review Manager 5.4 (Review Manager 2014) and another (PL) will recheck the entered data.

Assessment of risk of bias in included studies

Two authors (HL and PL) will independently assess the risk of bias for each included RCT by using risk of bias 2 (RoB 2) described in Chapter 8 of the Cochrane Handbook (Higgins 2022b). If our judgements diverge, we will consult with a third review author (CC) to achieve unanimity. We will analyse the effect of assignment to the interventions at baseline, regardless of whether the interventions are received as intended (the ‘intention‐to‐treat effect’). If the ITT data are not available, we will include the results of the modified intention‐to‐treat (mITT) analysis or per‐protocol analysis and use RoB 2 to account for any situations when the ideal ITT data are not available.

We will assess the risk of bias for all primary and secondary outcomes.

The domains considered in RoB 2 are as follows.

• Bias arising from the randomisation process (whether the allocation sequence is random; or the allocation sequence is adequately concealed; or do baseline differences between intervention groups suggest a problem with the randomisation process?)

• Bias due to deviations from the intended interventions (whether participants are aware of their assigned intervention during the trial; or carers and people delivering the interventions are aware of participants’ assigned intervention during the trial; or deviations from the intended intervention arise because of the experimental context; or an appropriate analysis is used to estimate the effect of assignment to intervention).

• Bias due to missing outcome data (whether data for this outcome are available for all, or nearly all, participants randomised; (if applicable) there is evidence that the results are not biased by missing outcome data; (if applicable) missingness in the outcome is likely to depend on its true value).

• Bias in measurement of the outcome (whether the method of measuring the outcome is inappropriate; or measurement or ascertainment of the outcome differs between intervention groups; or outcome assessors are aware of the intervention received by study participants; or (if applicable) assessment of the outcome is likely to be influenced by knowledge of intervention received).

• Bias in selection of the reported result (whether the trial is analysed by a prespecified plan that is finalised before unblinded outcome data are available for analysis; or the numerical result being assessed is likely to be selected based on the results from multiple outcome measurements within the outcome domain; or the numerical result being assessed is likely to be selected based on the results from multiple analyses of the data).

We will assess these RoB 2 domains with the recommended signalling questions. The response options are as follows.

• Yes

• Probably yes

• Probably no

• No

• No information

The RoB 2 tool includes algorithms that map responses to signalling questions to a proposed risk‐of‐bias judgement for each domain (Higgins 2022b). These are as follows.

• Low risk of bias: when all domains are assessed as low risk.

• Some concerns: when the trial result is judged to raise some concerns in at least one domain for this result, but not at high risk of bias for any domain.

• High risk of bias: the trial is judged at high risk of bias in at least one domain for this result or when it is judged to have some concerns for multiple domains that lowers confidence in the result.

We will implement the data for RoB 2 with the RoB 2 Excel tool (available from www.riskofbias.info/welcome/rob-2-0-tool/) and store the data in an online repository.

We will assess risk of bias for cross‐over RCTs using the standard version of RoB 2, and cluster‐randomised trials using the variant RoB 2 described in Chapter 23 of the Cochrane Handbook (Higgins 2022c).

Measures of treatment effect

Dichotomous data

We will present dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs) for these outcomes: 'any adverse event severe enough leading to cessation of the treatment' and 'any mild or moderate adverse event not leading to cessation of the treatment'. We will calculate the risk difference with its 95% CI as direction, magnitude, and certainty of effect.

Continuous data

We will present continuous data as mean differences (MDs) with 95% CIs for the following outcomes: duration of the clinical episode (time to healing); participant‐rated global degree of improvement of the signs and symptoms; change from baseline in the participant‐ or investigator‐rated severity of clinical episode; and change from baseline in the severity of pain. If the outcome scales are different, we will use standardised mean differences (SMDs) with 95% CIs to express these continuous data.

Time‐to‐event data

We will present time‐to‐event data as hazard ratios (HRs) with 95% CIs. We will pool the HRs in the included study report. When HRs are not reported, we will estimate the HRs by the methods described in Tierney 2007.

Unit of analysis issues

Randomised participants of included studies are the unit of analysis. If there are multiple episodes within the same participant, we will try to obtain the original data from study authors and analyse the first episode in the studies. If the original data are unavailable, we will analyse each episode for outcomes. We will use appropriate techniques described in the Cochrane Handbook to analyse studies of the following types of design (Higgins 2022a).

Cluster‐randomised trials

When the cluster analysis in a cluster‐randomised trial is not adjusted, we will contact the authors to obtain estimates of intracluster correlation (ICC) or impute this using estimates from other included trials or similar external trials. We will use the Rao methods described in Chapter 23 of the Cochrane Handbook to estimate the intervention effect (Higgins 2022c; Rao 1992). If these data are unavailable, we will assume an ICC coefficient of 0.05 to estimate the intervention affect.

We will conduct a sensitivity analysis where we have imputed ICCs to examine the impact on estimates.

Cross‐over trials

We will only analyse the data from the first period of cross‐over trials. When the data of the first period are not available, we will use data adjusted for the 'paired' design of the trial (either extracted from the paper if an appropriate analysis is conducted, or it may be possible to adjust data reported in the paper using an estimate of within‐participant correlation), according to the statistical methods described in Section 23.2.7 of the Cochrane Handbook (Higgins 2022c).

Trials with multiple treatment groups

For trials with multiple intervention groups, we will make separate pairwise comparisons. That is, in an RCT with three intervention groups – Group A, Group B, and Group C (placebo or the most frequently used intervention) – we will pair the comparisons of group A versus group C and group B versus group C.

Dealing with missing data

We will conduct an intention‐to‐treat (ITT) analysis by including all randomised participants regardless of their compliance and data missingness. We will contact the authors of included studies reported within the last 10 years to request missing data.

When we are unable to obtain missing data, for dichotomous outcomes, we will assume that participants with missing outcome data developed undesirable events that led to cessation of treatment. For continuous outcomes, we will use the imputation method described in Section 10.12 of the Cochrane Handbook (Higgins 2022a).

Assessment of heterogeneity

We will assess the heterogeneity across the included trials using the I² statistic (Deeks 2022). The I² statistic depends on the effects of direction and magnitude, and the strength of evidence for heterogeneity (as P value from the Chi² test, CI for I² statistic; Deeks 2022). We will interpret the CI for the I² statistic as follows:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity; and

• 75% to 100%: may show considerable heterogeneity.

We will also assess statistical heterogeneity via inspection of a forest plot. If there is a high I² statistic with the estimates all on the same side of the forest plot, we will conduct a subgroup analysis for different dosages of the intervention to examine the dose response or minimum therapeutic dose.

Assessment of reporting biases

We will look for funnel plot asymmetry to assess publication bias for the primary outcomes where we have included 10 or more trials in a meta‐analysis (Page 2022).

Data synthesis

We will describe all outcomes with available data. We will only pool trials with similar participant groups, interventions, and outcomes by performing a random‐effects model meta‐analysis. Where it is inappropriate or impossible to perform a meta‐analysis, we will summarise the data narratively for each trial. 

In this review, we are interested in the efficacy of each intervention versus the other interventions listed in the Description of the intervention section, or versus placebo or no treatment. We will perform separate meta‐analysis for different antiviral agents; for example, acyclovir and famciclovir. We will not pool various antiviral agents of the same class together in a meta‐analysis.

Subgroup analysis and investigation of heterogeneity

We will conduct the following subgroup analyses.

• Different regimens of an intervention (for example, oral famciclovir (1500 mg) as a single dose versus famciclovir 750 mg twice in the first day; laser therapy with 172 narrow waveband light (NWBL) three minutes twice a day for two days versus 172 NWBL three minutes three times a day for two days) when relevant data are available.

• Age: children (aged < 18 years) versus adults (aged ≥ 18 years).

We will employ a random‐effects model meta‐analysis and use the methods developed by Borenstein 2008, which have been implemented in the Review Manager software (Review Manager 2014), as a formal test for subgroup differences.

Sensitivity analysis

When appropriate, we will conduct a sensitivity analysis for intervention effects by: (a) excluding trials with a high risk of bias in one or more domains; (b) excluding cluster‐RCTs; and (c) excluding studies that handle missing data by imputation or assumption.

Summary of findings and assessment of the certainty of the evidence

We will create summary of findings (SOF) tables for our main comparisons to summarise data on our outcomes. 

We have selected the following comparisons because we believe these to be the most relevant and important comparisons, from both clinician and patient perspectives.

• Topical aciclovir versus placebo

• Topical penciclovir versus placebo

• Topical penciclovir versus topical aciclovir

• Oral aciclovir versus placebo

• Topical aciclovir versus oral aciclovir

We will include the following outcomes in each SOF table. 

• Duration of the clinical episode (time to healing (days); defined as loss of crusts or loss of all symptoms), participant‐ or investigator‐rated.

• Any adverse event severe enough to lead to cessation of treatment.

• Participant‐rated global degree of improvement of the signs and symptoms.

• Change from baseline in the participant‐ or investigator‐rated severity of clinical episode (for example, lesion size).

• Change from baseline in the severity of pain.

• Any mild or moderate adverse event not leading to cessation of treatment.

We will analyse the data during the period in these studies for duration of the clinical episode (time to healing, measured in days) and adverse event (mild to moderate or severe). We will analyse the data at the closest time point to one week for: participant‐rated global degree of improvement of the signs and symptoms; change from baseline in the participant‐ or investigator‐rated severity of clinical episode (for example lesional size) after interventions; and change from baseline in the severity of pain (as global pain score) after interventions.

We will apply the overall RoB 2 judgement for the 'Grading of Recommendations, Assessment, Development and Evaluation' (GRADE) assessment. We will use the GRADE approach to assess the certainty of evidence for each outcome listed above for our main comparisons. GRADE includes the assessment of five factors: study limitations (risk of bias), inconsistency of results, indirectness of evidence, imprecision, and publication bias (Schünemann 2013). Each outcome can be downgraded by one or two levels for each domain, and the overall certainty will be classed as either high, moderate, low or very low.

Two review authors (HL and PL) will perform the GRADE assessments independently, and any disagreement will be resolved via discussion or input from a third review author (CC). We will use GRADEpro to create our summary of findings tables and undertake our GRADE assessments (GRADEpro GDT).

We will interpret the results in the summary of findings tables using the methods described in Chapter 15 of the Cochrane Handbook (Schünemann 2022).

Appendices

Appendix 1. CENTRAL (Cochrane Library) draft search strategy

Search Name: Rev#40 Cold sores on the lips update 2022
Last Saved: 24/03/2022 14:21:16
Comment: 24 March 2022 with QA edits

ID Search
#1 MeSH descriptor: [Herpes Labialis] explode all trees
#2  herpes near/2 labial*:ti,ab
#3 ((cold next sore*) or (fever next blister*)):ti,ab
#4 {or #1‐#3}
#5 MeSH descriptor: [Herpes Simplex] explode all trees
#6 MeSH descriptor: [Herpesvirus 1, Human] explode all trees
#7 MeSH descriptor: [Simplexvirus] explode all trees
#8 MeSH descriptor: [Stomatitis, Herpetic] this term only
#9 (herpes or simplexvirus or herpetic or herpesvir* or herpetiform* or "hsv‐1"):ti,ab
#10 {or #5‐#9}
#11 MeSH descriptor: [Lip] explode all trees
#12 MeSH descriptor: [Lip Diseases] explode all trees
#13 (lip or lips):ti,ab
#14 (labial or orolabial or oro‐labial):ti,ab
#15 {or #11‐#14}
#16 #10 and #15
#17 #4 or #16
 

Appendix 2. MEDLINE (Ovid) draft search strategy

Ovid MEDLINE(R) ALL <1946 to March 22, 2022>

1 Herpes Labialis/ 1212
2 (herpes adj2 labial$).ti,ab. 875
3 cold sore$.ti,ab. 307
4 fever blister$.ti,ab. 40
5 or/1‐4 1767
6 Stomatitis, Herpetic/ 927
7 (herpetic and (stomatiti$ or gingivostomatiti$)).ti,ab. 405
8 Herpes Simplex/ 14945
9 simplexvirus/ or herpesvirus 1, human/ 28532
10 (herpes or herpetic or herpesvir$ or herpetiform$).ti,ab. 92007
11 simplexvirus.ti,ab. 40
12 "hsv‐1".ti,ab. 12958
13 or/6‐12 98416
14 Lip/ 11780
15 Lip Diseases/ 1988
16 lip$1.ti,ab. 52243
17 (orolabial or oro‐labial or labial).ti,ab. 9265
18 14 or 15 or 16 or 17 64200
19 13 and 18 693
20 5 or 19 2209
21 randomized controlled trial.pt. 562194
22 controlled clinical trial.pt. 94756
23 randomized.ab. 554670
24 placebo.ab. 226604
25 clinical trials as topic.sh. 199571
26 randomly.ab. 378397
27 trial.ti. 258823
28 21 or 22 or 23 or 24 or 25 or 26 or 27 1434415
29 exp animals/ not humans.sh. 4976850
30 28 not 29 1319316
31 20 and 30 265

[Lines 21‐30: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision); Ovid format, from section 3.6.1 in Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M‐I, et al. Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston MS, Li T, Page MJ, Welch VA (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 6. Cochrane, 2019. Available from: www.training.cochrane.org/handbook]

Appendix 3.  Embase (Ovid) draft search strategy

Embase <1974 to 2022 Week 11>

1 herpes labialis/ 2294
2 (herpes adj2 labial$).ti,ab. 1092
3 cold sore$.ti,ab. 445
4 fever blister$.ti,ab. 55
5 or/1‐4 2847
6 herpetic stomatitis/ 716
7 herpes simplex/ 20266
8 simplexvirus/ 981
9 human alphaherpesvirus 1/ 4063
10 (herpes or herpetic or herpesvir$ or herpetiform$).ti,ab. 106664
11 simplexvirus.ti,ab. 53
12 "hsv‐1".ti,ab. 15252
13 or/6‐12 117901
14 lip disease/ 2944
15 exp lip/ 18140
16 lip$1.ti,ab. 63211
17 (labial or orolabial or oro‐labial).ti,ab. 10377
18 or/14‐17 77713
19 13 and 18 1111
20 5 or 19 3613
21 Randomized controlled trial/ 699845
22 Controlled clinical study/ 465245
23 random$.ti,ab. 1765836
24 randomization/ 93235
25 intermethod comparison/ 281028
26 placebo.ti,ab. 337993
27 (open adj label).ti,ab. 95281
28 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab. 254384
29 double blind procedure/ 193232
30 parallel group$1.ti,ab. 29058
31 (crossover or cross over).ti,ab. 115239
32 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab. 375058
33 (controlled adj7 (study or design or trial)).ti,ab. 402267
34 trial.ti. 353232
35 or/21‐34 2829890
36 exp animal/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ 30258074
37 human/ or normal human/ 23378226
38 36 and 37 23378226
39 36 not 38 6879848
40 35 not 39 2531745
41 20 and 40 496

[Lines 21‐40: Based on terms suggested for identifying RCTs in Embase (section 3.6.2) in Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M‐I, Noel‐Storr A, Rader T, Shokraneh F, Thomas J, Wieland LS. Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston MS, Li T, Page MJ, Welch VA (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 6. Cochrane, 2019. Available from: www.training.cochrane.org/handbook] 

Appendix 4. Data extraction form

Study characteristics	Data to be extracted	Instruction for data extraction
Study ID	(Surname of first author and publication year of first full report of study)
Study information	Study title	Enter the title of the study
Methods	Randomisation methods	How is the randomisation sequence generated?
	Blinding	Are participants, outcome assessors, or providers blinded to which treatment is given?
	Numbers of recruitment locations	At how many study sites are participants recruited for the trial?
Participants	Inclusion criteria	Enter the characteristics that the participants must have in this trial
	Exclusion criteria	Enter the characteristics that the participants cannot have if enrolled in this trial
	Numbers of participants randomised	How many participants were randomised in this trial?
	Mean age (years)	Enter the mean age ± SD of participants assigned to each group
	Sex (% male)	Enter the percentage of male participants assigned to each group
	Numbers of participants analysed	Data from how many participants are analysed in this trial?
	Numbers of dropouts	How many randomised participants are lost to follow‐up during the study period?
	Dropout reasons	What are the reasons for participant dropouts?
Interventions	Types of interventions	Enter the types and methods of interventions, for example, topical antibiotics, antiseptic agents, systemic antibiotics, phototherapy, or surgical interventions.
	Names of medications or methods	Enter the names of the interventions, such as the generic name of drugs
	Dosage	Enter the dose and frequency for drugs. Enter the duration and frequency for phototherapy. For surgical intervention, enter 'N/A'.
	Duration	How long do participants receive therapy?
	Time point	When are the outcomes measured?
Outcomes	Primary outcomes	Enter data on primary outcomes
	Secondary outcomes	Enter data on secondary outcomes

 

Contributions of authors

CC was the contact person with the editorial base while the protocol was being developed.
HL coordinated the contributions from the co‐authors and wrote the final draft of the protocol.
HL worked on the methods sections.
HL drafted the clinical sections of the background and responded to the clinical comments of the referees.
CC responded to the methodology and statistics comments of the referees.
PL, YT, and CC contributed to writing the protocol.
CC is the guarantor of the final review.

Disclaimer

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Skin. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the Department of Health.

Sources of support

Internal sources

• No sources of support provided, Other

External sources

• The National Institute for Health Research (NIHR), UK

  The NIHR, UK, is the largest single funder of Cochrane Skin

Declarations of interest

Huang‐Shen Lin, Pei‐Tzu Lin, Yu‐Shiun Tsai, and Ching‐Chi Chi have declared that they have no conflicts of interest.

Ching‐Chi Chi is an editor with Cochrane Skin but has had no involvement in the editorial process for this protocol.

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