Clinical Topic A-Z Clinical Speciality

Herpes simplex - oral

Herpes simplex - oral
D006561Herpes Simplex
D003945Diagnosis, Oral
D013283Stomatitis, Herpetic
D006560Herpes Labialis
Infections and infestationsOral health
2012-09-01Last revised in September 2012

Herpes simplex - oral - Summary

Herpes simplex virus type 1 (HSV-1) is usually the cause of oral herpes (rarely, herpes simplex virus type 2).

Primary HSV-1 infection may be asymptomatic, but may present as gingivostomatitis and pharyngitis, usually in children under 5 years of age.

Recurrent oral disease is usually caused by HSV-1 infection.

Many primary infections are asymptomatic. Symptomatic primary infection usually presents as gingivostomatitis in children, and as pharyngotonsillitis or a mononucleosis (glandular fever) -type illness in adults. Prodromal symptoms include fever, nausea, malaise, headache, and irritability.

Symptoms of active infection include a painful mouth and throat, salivation, and drooling.

Signs include:

Vesicles which can affect the border of the lip with the skin, and the pharyngeal and oral mucosa (soft palate, buccal mucosa, tongue, and floor of the mouth).

Breaking down of the vesicles into small, red lesions. These enlarge and develop central ulcerations covered by yellow/grey membranes.

Halitosis.

Cervical and submandibular lymphadenopathy.

Fever.

Dehydration.

In people who are immunocompromised, infection can be severe, with large, necrotizing lesions which cover large areas.

Tests are not usually necessary in immunocompetent people, as history and examination will usually confirm the diagnosis.

Recurrent herpes simplex type 1 (HSV-1) infections can be triggered by a number of factors, including fatigue, bright sunlight, trauma, and menstruation.

Recurrences of HSV-1 infection usually present as cold sores at the border between the lip and skin of the face.

Recurrent HSV infection in people who are immunocompromised is often atypical and may present as single or multiple ulcers anywhere in the oral cavity, which may be large, progressive, and persistent.

Management of cold sores involves:

Reassuring the person that the condition is self limiting and that lesions will heal without scarring usually within 7–10 days.

Advising paracetamol or ibuprofen to relieve pain if required.

Offering advice to minimize transmission.

Advising that the benefits of topical antivirals (aciclovir or penciclovir) are small and require treatment to be initiated at the onset of symptoms (erythema or prodromal stage) before vesicles appear.

Seeking specialist advice is recommended:

For people who are immunocompromised (including people with HIV).

If neonatal herpes simplex infection is suspected.

Specialist advice should be considered in the management of pregnant women (particularly near term).

To prevent cold sores recurring:

The impact of trigger factors should be minimized.

For people with frequent or severe episodes, or for immunocompromised individuals, prophylactic oral antiviral treatment may be helpful.

Management of gingivostomatitis involves:

Reassurance that gingivostomatitis is self limiting.

Offering paracetamol or ibuprofen to relieve pain and fever.

Encouraging adequate fluid intake to avoid dehydration.

Considering the use of topical benzydamine for additional pain relief.

Offering chlorhexidine mouthwash to help control secondary infections and to control plaque accumulation if brushing of teeth is painful.

Considering prescribing oral antivirals for immunocompetent individuals with severe gingivostomatitis.

Admitting the person if they are at risk of becoming dehydrated.

Have I got the right topic?

0months3060monthsBoth

This CKS topic covers the management of oral herpes simplex including gingivostomatitis and cold sores (oral herpes labialis).

This CKS topic does not cover herpetic whitlow, eczema herpeticum, or other herpes infections such as herpes zoster.

There are separate CKS topics on Aphthous ulcer, Chickenpox, Herpes simplex - genital, Herpes simplex - ocular, Palliative cancer care - oral, Post-herpetic neuralgia, Shingles, and Trigeminal neuralgia.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in September 2012

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

August 2012 — reviewed. A literature search was conducted in August 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made.

Previous changes

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the Medicines and Healthcare products Regulatory Agency [MHRA, 2011]. Prescriptions have been updated to reflect the revised dosing. Issued in July 2011.

March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

April 2009 — minor update. Topical products containing choline salicylate (e.g. Bonjela®) are no longer licensed for use in children under 16 years of age because of the theoretical risk of Reye's syndrome if they are overused. The prescriptions have been updated accordingly. Issued in May 2009.

April 2008 — minor update to text following late comments from an external reviewer.

September to December 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

October 2006 — minor update. Analgesia prescriptions updated because new doses of ibuprofen for children are recommend by the British National Formulary. Issued in October 2006.

October 2005 — minor technical update. Issued in November 2005.

July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Clinical Excellence. Issued in July 2005.

June 2004 — reviewed. Validated in September 2004 and issued in November 2004.

January 2002 — rewritten. Validated in March 2002 and issued in April 2002.

August 1998 — written, replacing guidance called Herpes simplex gingivostomatitis.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 August 2012.

HTAs (Health Technology Assessments)

No new HTAs since 1 August 2012.

Economic appraisals

No new economic appraisals relevant to England since 1 August 2012.

Systematic reviews and meta-analyses

No new systematic reviews and meta-analyses since 1 August 2012.

Primary evidence

No new randomized controlled trials in the major journals since 1 August 2012.

New policies

No new national policies or guidelines since 1 August 2012.

New safety alerts

No new safety alerts since 1 August 2012.

Changes in product availability

No changes in product availability since 1 August 2012.

Goals and outcome measures

Goals

To minimize the symptoms of oral herpes simplex

To avoid development of complications

QIPP - options for local implementation

QIPP - options for local implementation

Non-steroidal anti-inflammatory drugs (NSAIDs)

Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of both gastrointestinal (GI) and cardiovascular (CV) morbidity and mortality (e.g. older patients).

If initiating an NSAID is obligatory, use ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review patients currently prescribed NSAIDs. If continued use is necessary, consider changing to ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review and, where appropriate, revise prescribing of etoricoxib to ensure it is in line with MHRA advice and the NICE clinical guideline on osteoarthritis [CSM, 2005; NICE, 2008].

Co-prescribe a proton pump inhibitor (PPI) with NSAIDs for people with osteoarthritis, rheumatoid arthritis, or low back pain (for people over 45 years) in accordance with NICE guidance [NICE, 2008; NICE, 2009a; NICE, 2009b].

Take account of drug interactions when co-prescribing NSAIDs with other medicines (see Summaries of Product Characteristics). For example, co-prescribing NSAIDs with ACE inhibitors or angiotensin receptor blockers (ARBs) may pose particular risks to renal function; this combination should be especially carefully considered and regularly monitored if continued.

[NICE, 2013]

Background information

Definition

What is it?

Herpes simplex virus type 1 (HSV-1) is usually the cause of oral herpes [Esmann, 2001; Fatahzadeh and Schwartz, 2007; Usatine and Tinitigan, 2010].

Primary HSV-1 infection may be asymptomatic, but may present as gingivostomatitis (inflammation of the gums and mucous membranes of the mouth) and pharyngitis, usually in children under 5 years of age [Fatahzadeh and Schwartz, 2007; Usatine and Tinitigan, 2010].

Recurrent oral disease is usually caused by HSV-1 infection. This occurs when the herpes simplex virus persists in a latent state in the trigeminal ganglion and reactivates later as 'cold sores' [Hirsch, 1995; Bentley et al, 2003; Gonsalves et al, 2007; Eastern, 2011].

Rarely, herpes simplex virus type 2 (HSV-2) may cause primary infection of the oral cavity, typically in association with orogenital sex, but recurrent disease in this location is rare [Esmann, 2001; Tovaru et al, 2009].

Transmission

How is it transmitted?

A person is susceptible to herpes simplex virus type 1 (HSV-1) if they do not have antibodies to the virus [Leflore et al, 2000].

For HSV-1 infection to occur, there must be intimate contact between a person without antibodies to the virus and someone who is actively shedding the virus or secreting body fluids containing the virus [Torres, 2007; Eastern, 2011].

HSV-1 viral shedding has a median duration of 4–60 hours from the onset of symptoms [Torres, 2007]. Transmission between a person who has been infected with HSV-1 and someone who has not can still happen even when there are no lesions present [Bentley et al, 2003].

Lesions are most contagious at the time of vesicular rupture and continue to be contagious until healed [Bentley et al, 2003].

The incubation period is 2–12 days [Hirsch, 1995].

Prevalence

How common is it?

Around 1% of primary care consultations are for cold sores [Worrall, 2009].

Between 20% and 40% of young adults who are seropositive for herpes simplex virus type 1 (HSV-1) have recurrent cold sores [Esmann, 2001]. Recurrences typically occur two to three times a year [Bentley et al, 2003], but may occur up to 6 times a year [Jensen et al, 2004; Kolokotronis and Doumas, 2006].

By early adulthood, 56–85% of people have serologic evidence of HSV-1 infection, depending on the country they live in [Torres, 2007].

Complications and prognosis

Complications

In most people, oral herpes simplex virus (HSV) infection is a mild, self-limiting illness, but it can cause serious illness in immunocompromised people [Fatahzadeh and Schwartz, 2007; Worrall, 2009]. The spectrum of potential complications of oral HSV infection includes:

Dehydration from poor fluid intake and fever (especially common in young children).

Herpetic whitlow (from autoinoculation) [Usatine and Tinitigan, 2010].

Eczema herpeticum (atopic dermatitis with HSV infection).

Recurrent erythema multiforme (associated with recurrences of orolabial HSV-1 infection).

Eye involvement (herpetic keratoconjunctivitis) from autoinoculation from herpetic gingivostomatitis or oral HSV.

Tracheobronchitis, pneumonia, and oesophagitis (from direct extension of oropharyngeal infection).

Encephalitis.

[Hirsch, 1995; Kolokotronis and Doumas, 2006; Eastern, 2011]

Prognosis

The lesions of oral herpes simplex virus infection (cold sores) usually heal within 7–10 days without scarring [Bentley et al, 2003; Kolokotronis and Doumas, 2006; Torres, 2007; Worrall, 2009].

Gingivostomatitis may take longer to heal; the vesicular lesions ulcerate and will usually heal within 2–3 weeks [Kolokotronis and Doumas, 2006; Torres, 2007].

Most people with recurrent cold sores experience two or more episodes per year [Bentley et al, 2003], but a minority have six or more episodes per year [Jensen et al, 2004; Kolokotronis and Doumas, 2006].

Diagnosis

Diagnosis of oral herpes simplex

Diagnosis of primary infection

How do I know my patient has primary infection?

Primary infection refers to first-time exposure to herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2).

Many primary infections do not cause symptoms or signs, and therefore will not present to a healthcare professional.

Symptomatic primary infection usually presents as gingivostomatitis in children, and as pharyngotonsillitis or a mononucleosis (glandular fever)-type illness in adults.

Prodromal symptoms include fever, nausea, malaise, headache, and irritability.

Symptoms of active infection include a painful mouth and throat, salivation, and drooling.

Signs include:

Vesicles which can affect the border of the lip with the skin, and the pharyngeal and oral mucosa (soft palate, buccal mucosa, tongue, and floor of the mouth).

Breaking down of the vesicles into small, red lesions. These enlarge and develop central ulcerations covered by yellow/grey membranes.

Halitosis.

Cervical and submandibular lymphadenopathy.

Fever.

Dehydration.

In people who are immunocompromised, infection can be severe, with necrotizing lesions which cover large areas.

Tests are not usually necessary in immunocompetent people, as history and examination will usually confirm the diagnosis.

Herpes simplex virus can be detected, and the type determined, using viral culture from skin vesicles. Early in the infection, 80–90% of viral cultures from untreated lesions are positive, but the false-negative rate increases 2 days after the lesions have appeared.

Polymerase chain reaction (PCR) is an alternative diagnostic test which in general detects HSV 3–4 times more often than cultures.

The availability of tests may vary in primary care, therefore check with the local laboratory.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion in review articles [Leflore et al, 2000; Esmann, 2001; Jensen et al, 2004; Kolokotronis and Doumas, 2006; Gonsalves et al, 2007; Woo and Challacombe, 2007; Usatine and Tinitigan, 2010; Eastern, 2011] and expert opinion in a textbook [Hirsch, 1995].

Diagnosis of recurrent disease

How do I know my patient has recurrent disease?

Recurrent herpes simplex type 1 (HSV-1) infections can be triggered by a number of factors, including fatigue, bright sunlight, trauma, and menstruation.

Recurrences of HSV-1 infection are often shorter and less severe than the initial attack and usually present as cold sores at the border between the lip and skin of the face. It is rare for recurrent episodes of gingivostomatitis to occur; this usually only happens if the person has reduced immunity.

Diagnosis of recurrent cold sores is usually clinical, based on the lesions and lack of systemic symptoms.

Prodromal symptoms last between 6 and 48 hours and include pain, burning, tingling, itching, and paraesthesia.

Pain is usually most severe up to 24 hours after the lesions appear, but resolves over 4–5 days.

Signs:

Vesicles appear at the border of the outer lip between the lip and the skin (more commonly the lower lip) and may occur at the same site for each recurrence.

Ulceration and crusting of vesicles usually occurs within 48 hours.

Usually lesions are less than 100 mm2 in area.

Systemic complications are not usually associated with recurrent oral infections, but local lymphadenopathy may be seen.

Recurrent HSV infection in people who are immunocompromised is often atypical and may present as single or multiple ulcers anywhere in the oral cavity, which may be large, progressive, and persistent.

Tests are not usually necessary in immunocompetent people, as history and examination will usually confirm the diagnosis.

Herpes simplex virus can be detected, and the type determined, using viral culture from skin vesicles. Early in the infection, 80–90% of viral cultures from untreated lesions are positive, but the false-negative rate increases 2 days after the lesions have appeared.

Polymerase chain reaction (PCR) is an alternative diagnostic test, which in general detects HSV 3–4 times more often than cultures.

The availability of tests may vary in primary care, therefore check with the local laboratory.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion in review articles [Esmann, 2001; Bentley et al, 2003; Kolokotronis and Doumas, 2006; Gonsalves et al, 2007; Woo and Challacombe, 2007; Worrall, 2009; Usatine and Tinitigan, 2010; Eastern, 2011] and expert opinion in a textbook [Hirsch, 1995].

Differential diagnosis

What else might it be?

Differential diagnosis of cold sores:

Impetigo

Aphthous ulcers (on inside of the lips)

Chickenpox (lesions occur rarely at mucocutaneous junction)

Stevens-Johnson syndrome

Syphilis

Behçet syndrome

Differential diagnosis of herpes simplex gingivostomatitis:

Aphthous ulcers

Infectious mononucleosis (glandular fever)

Erythema multiforme

Hand, foot, and mouth disease

Herpes zoster

Streptococcal or diphtheritic pharyngitis

Mucositis from chemotherapy or radiation

Basis for recommendation

Basis for recommendation

This information is based on expert opinion in a text book and review articles [Hirsch, 1995; Usatine and Tinitigan, 2010; Eastern, 2011].

Red flags

What concerning features should I look for?

The National Institute for Health and Care Excellence (NICE) guidance on referral for suspected cancer recommends urgent referral for a person with:

Unexplained red and white patches (including suspected lichen planus) of the oral mucosa that are painful, or swollen, or bleeding.

Unexplained ulceration of the oral mucosa, or mass persisting for more than 3 weeks.

NICE also recommends that any person with persistent symptoms or signs related to the oral cavity in whom a definitive diagnosis of a benign lesion cannot be made should be referred or followed up until the symptoms and signs disappear. If the symptoms and signs have not disappeared after 6 weeks, an urgent referral should be made.

Basis for recommendation

Basis for recommendation

This recommendation is based on guidance from the National Institute for Health and Care Excellence: Referral for suspected cancer [NICE, 2005].

Management

Management

Scenario: Cold sores : covers the management of herpes simplex cold sores, including self-care advice and advice on preventing further episodes.

Scenario: Gingivostomatitis : covers the management of gingivostomatitis caused by herpes simplex infection.

Scenario: Cold sores

Scenario: Cold sores

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Specialist advice for cold sores

When should I seek specialist advice for cold sores?

Seek specialist advice for managing immunocompromised individuals with cold sores.

Consider seeking specialist advice for pregnant women (particularly near term).

Neonatal herpes simplex infection is rare and may present with skin, eye and/or mouth symptoms. Seek specialist advice if this is suspected.

Basis for recommendation

Basis for recommendation

CKS recommends seeking specialist advice on the management of immunocompromised people with cold sores and neonates with oral herpes simplex infection because of the increased risk of severe disease and complications in these groups [Arduino and Porter, 2006; Kimberlin, 2007; RCOG, 2007; Woo and Challacombe, 2007; BNF 63, 2012].

In immunocompromised individuals, recurrent herpes simplex virus (HSV) type 1 infection may be 'atypical', usually more extensive and aggressive than that of immunocompetent individuals, slow healing, and extremely painful [Arduino and Porter, 2006]. Oral recrudescent HSV may lead to HSV viraemia and life-threatening disseminated disease [Woo and Challacombe, 2007].

In neonates, HSV infection is rare with a high morbidity (particularly if the central nervous system or multiple organs are affected) [RCOG, 2007]. Most cases occur as a result of direct contact with infected maternal secretions. Neonatal herpes can be localized to the skin, eye and/or mouth (SEM) which can progress to more severe disseminated disease. Treatment with intravenous aciclovir may be required for SEM infection [Kimberlin, 2007].

Pregnant women

There is a risk of HSV transmission to the neonate, particularly at childbirth if the mother with cold sores is actively shedding the herpes simplex virus [RCOG, 2007].

It is well documented that genital HSV infections in pregnancy can lead to potentially severe consequences to the fetus or neonate (such as long-term disabilities or death). However, evidence and literature on the effect of oral HSV infections in pregnancy is very limited [Straface et al, 2012].

Expert opinion from reviewers of this CKS topic is divided as to whether specialist advice should be sought. Expert opinion in a review article states that HSV-1 gingivostomatitis and recurrent labialis in pregnancy are not associated with adverse fetal outcomes. However, the authors advise that care should be taken when managing pregnant women with oral HSV infection [Ficarra and Birek, 2009].

Self care advice

What self care advice can I give to someone with cold sores?

Reassure the person that the condition is self limiting and that lesions will heal without scarring.

Advise paracetamol or ibuprofen to relieve pain if required.

Topical anaesthetics or analgesics may relieve symptoms but there is little evidence to support their use and some are not licensed for use in children.

Give advice to minimize transmission:

Avoid touching the lesions, other than when applying medication.

Wash hands with soap and water immediately after touching lesions.

Topical medications should be dabbed on rather than rubbed in to minimize mechanical trauma to the lesions. They should not be shared with others.

Avoid kissing until the lesions have completely healed.

Do not share items that come into contact with lesion area (for example lipstick or lip gloss).

Avoid oral sex until all lesions are completely healed.

There is a risk of transmission to the eye if contact lenses become contaminated.

Inform parents or carers that children with cold sores do not need to be excluded from nurseries and schools.

Advise the person to seek medical advice if their condition deteriorates (for example the lesion spreads, new lesions develop after the initial outbreak, persistent fever, inability to eat) or no significant improvement is seen after 7 days.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion and advice issued by the Health Protection Agency (HPA) as most episodes of cold sores are generally mild and self limiting with spontaneous healing occurring over 7–10 days [Worrall, 2009] without scarring. Treatment is primarily symptomatic [Birek, 2000; Barbarash, 2001; Siegel, 2002; Spruance and Kriesel, 2002; Gonsalves et al, 2007; Woo and Challacombe, 2007; HPA, 2010; HPA North West, 2011].

Cold sore lesions are generally self-limiting, starting to resolve within 7 days. Extensive or persistent lesions should raise the suspicion of immunosuppression [Birek, 2000; Spruance and Kriesel, 2002]. Expert opinion from reviewers of this CKS topic suggests reviewing the person if their condition deteriorates or no significant improvement is seen after 7 days.

Topical preparations for symptomatic relief

A variety of these preparations are widely available to buy. However, CKS could find very little evidence from randomized controlled trials (RCTs) supporting their use.

Topical anaesthetics: evidence from a small double-blind placebo-controlled RCT (n = 72) found that topical tetracaine offers short term subjective relief (mainly for itch but not for pain) when initiated within 48 hours of cold sore lesions appearing [Kaminester et al, 1999]. No adverse reactions were reported for both groups. Lidocaine 5% ointment may be considered to relieve pain in oral lesions [BNF 63, 2012].

Topical analgesics: CKS found no double-blind RCTs supporting their use. Choline salicylate gel (Bonjela®) is licensed for use in adults and children over 16 years of age to relieve cold sore symptoms and may be sufficient for mildly painful lesions.

However, they may be considered by patients if they have found them useful. They might help to relieve cold sore symptoms such as dryness, itching and pain [Barbarash, 2001].

Indirect evidence from double-blind RCTs has found even inert preparations can relieve symptoms by a direct or placebo effect [Shaw et al, 1985; Bodsworth et al, 2003].

Topical antivirals for cold sores

Should I advise use of a topical antiviral to treat cold sores?

Advise that the benefits of topical antivirals (aciclovir or penciclovir) are small and require treatment to be initiated at the onset of symptoms (erythema or prodromal stage) before vesicles appear.

Reassure the individual that the cold sores will usually resolve within 7–10 days even without treatment.

If topical antiviral therapy is desired, remind the individual that:

Topical antivirals only affect the course of the current episode. They do not provide a cure or prevent future episodes of cold sores.

Treatment needs to be initiated at the onset of symptoms before vesicles appear.

Compliance with treatment is important, as topical antivirals need to be applied frequently for a minimum of 4–5 days.

Topical antivirals are widely available (without prescription) to treat future recurrences, if the individual finds them helpful. This can help to minimize the delay before starting treatment.

For further information, see:

Topical antiviral preparations ;

How to apply topical antiviral preps ;

Oral antivirals to treat cold sores .

Seek specialist advice when managing neonates and people who are immunocompromised (including people with HIV) with cold sores. For more information on when to seek specialist advice, see Specialist advice for cold sores.

Basis for recommendation

Basis for recommendation

These recommendations are pragmatic advice, based on expert opinion in review articles and evidence from randomized controlled trials (RCTs).

Most episodes of cold sores are generally mild and self limiting and can be treated symptomatically [Fatahzadeh and Schwartz, 2007]. For further information, see Self care advice.

Use of topical antivirals

Aciclovir and penciclovir do not cure herpes simplex viral (HSV) infections. They work by inhibiting viral replication and thus affect the course of HSV disease [Leflore et al, 2000; Woo and Challacombe, 2007].

Evidence from double-blind placebo-controlled RCTs involving topical antiviral creams (aciclovir 1% cream or penciclovir 1% cream) indicate that the benefits of topical treatment are small:

Although an earlier RCT found no benefit [Shaw et al, 1985], aciclovir 5% cream has been shown in a larger study to reduce the mean duration of an episode and pain by approximately 0.5 days [Spruance et al, 2002]. For penciclovir 1% cream, a reduction of about 0.6–1 day was found in 2 RCTs [Raborn, 1996; Spruance et al, 1997; Raborn et al, 2002].

However, treatments with topical aciclovir or penciclovir do not appear to have an impact on the development of lesions, the number of participants developing lesion pain, or the proportion of people with aborted lesions [Raborn, 1996; Spruance et al, 1997; Raborn et al, 2002; Spruance et al, 2002].

A literature review of RCTs studying cold sores cautioned that 'significant' results should be interpreted in the context of statistical (not clinical) significance [Woo and Challacombe, 2007].

The effects of aciclovir cream were investigated in 10 studies (number of participants varied from 30 to 673). In each study group, treatment with aciclovir was started as soon as the first prodromal symptoms appeared [Opstelten et al, 2008].

None of the trials reported a decrease in severity or duration of pain. However, there was a reduction in the time to recovery in 8 of the studies (varying from 0.5 to 2.5 days).

Two other studies of penciclovir showed similar effects, and one of the studies reported a reduction in the duration of pain. However, the 2 hourly application of penciclovir makes it less practical than aciclovir which is applied 5 times daily.

Timing of treatment

In double-blind placebo-controlled RCTs, treatment with topical aciclovir or penciclovir was initiated within 1 hour of onset of signs or symptoms of a cold sore episode (erythema or prodromal stage) [Raborn, 1996; Spruance et al, 1997; Raborn et al, 2002; Spruance et al, 2002].

It is expected that the maximum clinical benefit from antiviral therapy is gained when treatment is started early because most viral replication occurs within the first 48 hours. Early initiation of antiviral therapy terminates virus replication and hence limits the subsequent epithelial damage responsible for the development of visible lesions [Esmann, 2001].

Oral antivirals to treat cold sores

Should I consider prescribing an oral antiviral to treat cold sores?

For immunocompetent individuals, oral antivirals are not routinely indicated for the treatment of cold sores but may be indicated in severe episodes. However, the optimum timing and dose of oral antiviral treatment are uncertain. Consider seeking specialist advice (particularly for pregnant women — off-label use).

Seek specialist advice for people who are immunocompromised (including people with HIV). For more information on when to seek specialist advice, see Specialist advice for cold sores.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in review articles, evidence from randomized controlled trials (RCTs) and feedback from expert reviewers.

Use of oral antivirals

CKS does not recommend that oral antivirals should be used in immunocompetent individuals for mild-to-moderate episodes given the self-limiting nature of the disease, the limited benefits of oral antivirals, and that treatment needs to be initiated at the onset of prodromal symptoms (before the appearance of lesions).

Most episodes of cold sores are generally mild and self limiting and can be treated symptomatically. For further information, see Self care advice.

Evidence from double-blind placebo-controlled RCTs involving immunocompetent individuals indicates that [Raborn et al, 1987; Spruance et al, 1990b; Spruance et al, 2003; Spruance et al, 2006]:

Treatment with oral antivirals (aciclovir, valaciclovir, and famciclovir) does not appear to have an impact on the development of lesions, number of participants developing lesion pain, or the proportion of people with aborted lesions.

Oral antivirals can reduce the duration of a cold sore episode by 1.0–1.5 days when taken very early (typically within 1 hour of the onset of prodromal symptoms and before the appearance of any signs of cold sore lesions). Aciclovir taken at the papular lesion stage was found to have no effect on the duration of the episode and pain.

A reduction of 1.0–1.5 days in the duration of pain and lesion healing was only seen with higher dosage regimens of oral antivirals.

However, oral antivirals may be of most use in severe cases or in immunocompromised individuals at risk of developing further complications [Spruance et al, 1990b; Arduino and Porter, 2006; Woo and Challacombe, 2007; BNF 63, 2012].

Specialist advice should be sought for systemic treatment of herpes simplex infection in pregnancy [BNF 63, 2012] because oral antivirals are not licensed for use in pregnancy.

Data on the use of oral aciclovir, valaciclovir, and famciclovir in early pregnancy are limited. However, a large cohort study reported that exposure to oral aciclovir, valaciclovir, and famciclovir in early pregnancy was not associated with an increased risk of major birth defects [Pasternak and Hviid, 2010].

Seek specialist advice when considering oral antiviral therapy in children because there are no trials involving oral antivirals in those under 18 years of age for the treatment of cold sores [Woo and Challacombe, 2007].

Timing of treatment

As for topical antivirals, it is expected that the maximum clinical benefit from antiviral therapy is gained when treatment is started early because most viral replication occurs within the first 48 hours. Early initiation of antiviral therapy terminates virus replication and hence limits the subsequent epithelial damage responsible for the development of visible lesions [Esmann, 2001]. However, the optimal timing and dose of treatment are uncertain [Arduino and Porter, 2006].

Treating further episodes of cold sores

What advice should I give about treating further episodes of cold sores?

Offer self care advice on how to manage future episodes symptomatically.

If treatment with a topical antiviral is desired, advise the individual that these should be applied at the onset of symptoms (erythema or prodromal stage) before vesicles appear. Inform the individual that the benefits might be small.

Seek specialist advice for immunocompromised individuals (including people with HIV). For more information, see Specialist advice for cold sores.

Basis for recommendation

Basis for recommendation

This recommendation is based on what CKS consider to be good clinical practice.

For more detailed information on the basis for the recommendations, see:

Self care advice ;

Topical antivirals for cold sores ;

Specialist advice for cold sores .

Advice about preventing cold sores

What advice should I give about preventing cold sores recurring?

Advise the person to minimize the impact of trigger factors.

They should consider the use of sunblock lip balm (SPF 15 or greater) to help reduce outbreaks if sunlight is a potential trigger.

Inform the individual that prophylactic use of topical antivirals is ineffective.

Advise that, for immunocompetent people, the benefits of suppressive (continuous) therapy with oral antivirals are small and do not justify the routine use of long-term treatment. Episodic treatment might be preferred and more convenient (for example for those with 1–2 mild episodes per year).

For people with frequent or severe episodes, or for immunocompromised individuals (for example people with HIV), prophylactic oral antiviral treatment may be helpful. Specialist advice should be sought.

Basis for recommendation

Basis for recommendation

Minimizing the impact of trigger factors

In practice, trigger factors for cold sores are difficult to avoid or to modify (for example fatigue, psychological stress, trauma, and menstruation).

However, randomized controlled trials (RCTs) involving ultraviolet (UV) light-induced cold sores indicate that sunblock may reduce recurrences if sunlight is a potential trigger factor [Worrall, 2009].

One small crossover RCT (n = 38) found sunblock (SPF 15) prevented lesions developing after UV exposure, while 71% of the placebo group developed lesions [Rooney et al, 1991]. Another small crossover RCT (n = 19) found a lower incidence of recurrence in the sunscreen group (5% recurrence) than placebo (58% recurrence) (p < 0.01) [Duteil et al, 1998].

Prophylactic use of oral antivirals

There is limited evidence to support long-term prophylactic therapy in immunocompetent individuals. Treatment can increase the risk of systemic adverse effects. Compliance with therapy is important.

A small, double-blind placebo-controlled RCT indicated that aciclovir may delay the onset of cold sores. However, the study was small (n = 22 healthy adults) and 18% of the aciclovir group dropped out due to adverse effects [Rooney et al, 1993].

The combined results of 2 double-blind RCTs (n = 98 healthy adults) found that prophylactic oral valaciclovir therapy delays recurrence of cold sores compared with placebo [Baker and Eisen, 2003]. However, it is uncertain if the populations of the two separate trials were matched. The study did not provide any details on the randomization procedure, severity of recurrences and symptoms, and treatment compliance, nor any period effect.

There is little evidence to favour long-term suppressive (continuous) therapy over episodic (as required) treatment with oral antivirals:

CKS found one open-label, crossover RCT (76 adults enrolled but only 55 completed study) which found modest benefits with suppressive therapy (valaciclovir 1 g daily) compared with episodic treatment (valaciclovir 2 g twice daily, during attack) when treatments were taken for 6 months (mean number of cold sore episodes per 120 days of follow up: 0.49 episode for suppressive therapy vs. 1.1 for episodic therapy) [Gilbert, 2007]. However, the authors cautioned that results should be interpreted in the context of a significant period effect, which was not explained by the time of the year.

Prophylaxis regimens for patients who experience mild outbreaks 1 to 2 times a year are not recommended [Woo and Challacombe, 2007].

However, prophylactic therapy may be of use for those with frequent, severe episodes, or immunocompromised individuals who are at risk of developing severe complications [Arduino and Porter, 2006; Woo and Challacombe, 2007]. Specialist advice should be sought as the optimal timing and dose of treatment are uncertain and can vary in different situations [Arduino and Porter, 2006].

Prophylactic use of topical antivirals

There is no good evidence to suggest that topical antivirals (aciclovir or penciclovir) can prevent or delay recurring cold sores.

Two small trials (n = 18 and n = 23) found no, or a modest, benefit with aciclovir compared with placebo [Fawcett et al, 1983; Gibson et al, 1986; Esmann, 2001].

One larger randomized, double-blind trial (undertaken in seven ski resorts, n = 191 treated) found no significant difference between topical aciclovir 5% cream and placebo in the number of people who experienced lesions during the treatment period [Raborn et al, 1997].

Given that frequent daily application is required, long-term continuous suppression with a topical antiviral preparation might be impractical [Esmann, 2001].

Scenario: Gingivostomatitis

Scenario: Gingivostomatitis

0months3060monthsBoth

Managing gingivostomatitis

How should I manage someone with gingivostomatitis?

Reassure the individual or parent that gingivostomatitis (inflammation of the gums and mucous membranes of the mouth) is self limiting.

Treat symptomatically:

Offer paracetamol or ibuprofen to relieve pain and fever.

Encourage adequate fluid intake to avoid dehydration.

Consider offering topical benzydamine for additional pain relief.

Offer chlorhexidine mouthwash to help control secondary infections and to control plaque accumulation if brushing of teeth is painful.

Advise that the use of a lip barrier preparation (for example Vaseline®, Lypsyl®) may be useful to prevent lip adhesion.

Provide advice to minimize transmission:

Avoid touching the lesions, other than when applying medication.

Wash hands with soap and water immediately after touching lesions.

Avoid kissing until the lesions have completely healed.

Do not share items that come into contact with lesion area (for example lipstick or lip gloss).

Avoid oral sex until all lesions are completely healed.

Children with gingivostomatitis who are generally well do not need to be excluded from nurseries and schools.

Consider oral antivirals for immunocompetent individuals with severe gingivostomatitis. The optimum timing and dose of oral antiviral treatment are uncertain. Consider seeking specialist advice before prescribing.

Seek specialist advice if:

Symptoms are not improving after 5 days.

The affected person is pregnant, a neonate, or is immunocompromised.

Admit the person if they have difficulty drinking and are at risk of becoming dehydrated. Intravenous fluids may be required.

Basis for recommendation

Basis for recommendation

These recommendations are pragmatic advice, given that herpetic gingivostomatitis is a self-limiting disease (lasting from 7–14 days, and up to 3 weeks for severe lesions to heal) [Birek, 2000; Amir, 2001; Esmann, 2001; Sladden and Johnston, 2005; Arduino and Porter, 2006; Kolokotronis and Doumas, 2006; BNF 63, 2012].

It is generally managed by changes to diet and with analgesics [Scully and Felix, 2006; BNF 63, 2012].

Benzydamine, a topical analgesic, may provide additional relief [BNF for Children, 2012].

Chlorhexidine, an antiseptic, can help to reduce secondary infection and maintain dental hygiene if brushing of teeth is painful [BNF 63, 2012; BNF for Children, 2012].

Prevention of dehydration:

Drinking plenty of fluids should be encouraged, particularly in young children as they tend to avoid eating or drinking because of the pain.

The most common cause of morbidity following gingivostomatitis is dehydration, and in severe cases this may require hospital admission [Amir et al, 1997; Amir, 2001; Esmann, 2001; Kolokotronis and Doumas, 2006].

At risk groups:

CKS recommends seeking specialist advice on the management of oral herpes simplex virus (HSV) infection in those who are immunocompromised or in neonates, because of the increased risk of severe disease and complications in these groups [Leflore et al, 2000; Scully and Felix, 2006; Kimberlin, 2007; BNF 63, 2012].

It is well documented that genital HSV infections in pregnancy can lead to potentially severe consequences to the fetus or neonate (such as long-term disabilities or death). However, evidence and literature on the effect of oral HSV infections in pregnancy is very limited [Straface et al, 2012].

Expert opinion from reviewers of this CKS topic is divided as to whether specialist advice should be sought. Expert opinion in a review article states that HSV-1 gingivostomatitis and recurrent herpes labialis in pregnancy are not associated with adverse fetal outcomes. However, the authors advise that care should be taken when managing pregnant women with oral HSV infection [Ficarra and Birek, 2009].

Herpetic gingivostomatitis generally runs its course within one to two weeks with mild lesions usually healing within 5–7 days [Birek, 2000; Kolokotronis and Doumas, 2006]. Expert feedback suggests that specialist advice should be sought if no improvement in symptoms is seen after 5 days.

The Health Protection Agency (HPA) does not recommend children with gingivostomatitis to be excluded from schools and nurseries [HPA North West, 2011].

Antiviral drugs:

Oral antiviral therapy might be of value, especially in severe infection, neonates, or immunocompromised people [Scully and Felix, 2006; BNF 63, 2012]. However, there is uncertainty regarding the optimal timing and dosage.

CKS found only three randomized controlled trials investigating the use of antiviral drugs in those with gingivostomatitis. All studies involved children.

The results suggested that aciclovir suspension may be effective in reducing the duration of symptoms of herpetic gingivostomatitis in young children, but the optimal timing and dose of antiviral therapy are uncertain [Amir, 2001; Esmann, 2001; Arduino and Porter, 2006].

It is expected that the maximum clinical benefit from antiviral therapy is gained when treatment is started early because most viral replication occurs within the first 48 hours. Early initiation of antiviral therapy terminates virus replication and hence limits the subsequent epithelial damage responsible for the development of visible lesions [Esmann, 2001].

Specialist advice should be sought for systemic treatment of herpes simplex infection in pregnancy [BNF 63, 2012].

Use of lip barrier cream:

Based on a case report, the use of lip barrier preparations is recommended as a simple measure to prevent adherence of the lips (labial adhesions). This is a rare and serious complication of gingivostomatitis which might require surgical intervention in severe cases [Thomas, 2007].

Doxycycline mouthwash:

Although recommended by the British National Formulary for the treatment of herpes infection in the mouth [BNF 63, 2012], CKS could not find any evidence to support this use.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Analgesics / antipyretics

Prescribing paracetamol or ibuprofen

What are the general issues when prescribing paracetamol or ibuprofen?

Paracetamol and ibuprofen are well tolerated when used for short periods [BNF 63, 2012].

Both paracetamol and ibuprofen are licensed for the relief of pain and fever from 3 months of age:

Both drugs are recommended for the management of feverish illnesses in children younger than 5 years of age [NICE, 2007].

For use in pregnancy or when breastfeeding, see Treatment in pregnancy/breastfeeding.

Seek specialist advice before prescribing to neonates younger than 4 weeks of age given the high risk of complications in this age group.

People with known hypersensitivity to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), people with renal complications, or people with a known risk of gastrointestinal bleeding, should avoid ibuprofen.

Paracetamol is often a safer option in older people.

Paracetamol and ibuprofen rarely cause adverse effects when used in the short term [BNF 63, 2012].

Paracetamol has no notable adverse effects when used at the correct dosage.

Ibuprofen may occasionally cause gastrointestinal adverse effects, such as discomfort, nausea, and diarrhoea.

For more information on prescribing paracetamol and ibuprofen, see the CKS topics on Analgesia - mild-to-moderate pain and NSAIDs - prescribing issues.

Treatment in pregnancy/breastfeeding

Which analgesic and antipyretic treatment is suitable for use during pregnancy or when breastfeeding?

Paracetamol is the analgesic and antipyretic of choice because it can be used at the usual dosage and at any stage of pregnancy and during breastfeeding.

Ibuprofen may be considered for use in breastfeeding and pregnant women, but it should not be used beyond 27 weeks of gestation because of the increased risk of constriction of the ductus arteriosus:

Constriction is related to gestational age; it is rare before week 27, but its incidence increases with advancing gestational age to 50–70% at 32 weeks and up to 100% with exposure from week 34 onwards.

The effect appears not to be dose dependent.

If the use of ibuprofen is unavoidable, fetal circulation should be monitored regularly (once or twice weekly) with Doppler sonography, and medication use should be stopped as soon as signs of ductal constriction appear.

[Schaefer et al, 2007]

Topical antiviral drugs

Topical antiviral preparations

Which topical antiviral preparation is recommended for cold sores?

Recommend aciclovir 5% cream as a suitable topical antiviral for the treatment of cold sores.

Two topical antiviral preparations are available on prescription and over the counter without prescription:

Aciclovir 5% cream is available to buy in pharmacies, supermarkets, and other stores as it is classed under the General Sale List (GSL).

Penciclovir 1% cream is only available through pharmacies.

For further information on the use of topical antiviral preparations, see How to apply topical antiviral preps

Basis for recommendation

Aciclovir 5% cream is preferred over penciclovir 1% cream because:

It requires less frequent application (five times a day for 5 days) than penciclovir 1% cream (every 2 hours during waking hours for 4 days).

It is licensed for use under 12 years of age.

It is less expensive than penciclovir 1% cream.

CKS found no good evidence to indicate that either aciclovir 5% cream or penciclovir 1% cream is superior to the other. Consequently, the choice of topical antiviral will be influenced by the ease of application, its licensed uses, and cost.

One Chinese double-blind RCT (n = 248) found no significant differences in terms of efficacy endpoint, clinical cure rate, and safety, between those treated with aciclovir 3% cream (unavailable in UK) and penciclovir 1% cream [Lin et al, 2002].

Another published study (n = 40) found that penciclovir 1% cream reduced healing time and duration of pain more than aciclovir 5% cream [Femiano et al, 2001]. However, the sample size was small (n = 10 in each of four treatment arms). No information was given as to whether the trial was double blinded or randomized.

Topical antivirals not recommended:

Topical idoxuridine: one double-blind RCT found idoxuridine (15%, in 80% dimethyl sulfoxide) to be effective in reducing the mean duration of pain and healing time by approximately 1–2 days compared to control [Spruance et al, 1990a]. However, treatment was associated with a higher level of skin irritations. The 15% solution is not available in the UK. Only the 5% solution (Herpid®) is available commercially in the UK.

How to apply topical antiviral preparations

How should topical antiviral preparations be applied?

Recommended regimen:

Topical aciclovir 5% cream: apply five times a day at approximately 4-hourly intervals, omitting the night-time application, for 5 days.

The manufacturer advises that, if healing is not complete, treatment may be continued for up to an additional 5 days [ABPI Medicines Compendium, 2011]. However, CKS could not find any evidence to support this use.

Topical penciclovir 1% cream: apply to lesions every 2 hours during waking hours, for 4 days.

Topical antivirals should be used at the first sign of an attack (at erythema or prodromal stage — before vesicles appear).

For further information, see Topical antivirals for cold sores.

Application of topical antiviral preparations:

Topical antivirals should be dabbed on rather than rubbed in to minimize mechanical trauma to the lesions.

Hands should be washed after application.

Topical antiviral preparations should not be shared with other people as this may spread infection.

Topical antiviral preparations rarely cause adverse effects when used in the short term.

The most common adverse effects are transient burning or stinging following application and allergic reactions to excipients (for example propylene glycol).

[Barbarash, 2001; BNF 63, 2012]

Evidence

Evidence

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of herpes simplex - oral.

Search dates

2007 - August 2012.

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Herpes Simplex/, herpes simplex.tw., exp Herpes Labialis/, herpes labialis.tw., cold sore$.tw., exp Stomatitis, Herpetic/, gingivostomatitis.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - The patient's journey

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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