Herpes labialis

Herpes labialis 

Updated 2011 May 27 07:32:00 AM: correction (N Engl J Med 2011 May 26) view updateShow more updates

Related Summaries: 

Herpes genitalis

General Information Description:    

contagious viral infection primarily caused by herpes simplex virus type 1 (HSV-1) resulting in rash of skin and mucous membranes (usually lips)(1) often characterized by prodrome of tingling, itching and burning, followed by oral and perioral lesions(1, 3) self-limiting illness in immunocompetent persons (usually heals spontaneously within 1-2 weeks), but associated with lifelong latency(1, 3) contagious to persons not previously infected by virus and immunosuppressed patients(1)

Also called:      

cold sore fever blister herpes simplex labialis (HSL) herpetic gingivostomatitis herpetic stomatitis "canker sores" on inner lip areas

Types: 

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primary infection(1, 2) o can affect all of oral mucosa o more severe and lasts longer than recurrence recurrent disease(1, 2) o also called nonprimary disease or relapsing disease o usually affects vermillion border of lips or mucosa of hard palate o usually less severe than primary infection o may be precipitated by stress, sun, illness

Organs involved:   

junction of lips (vermillion border) or nose oral cavity (buccal mucosa, gums, sometimes hard palate and tongue) can also infect eye, skin, and rarely central nervous system

Who is most affected: 

primary infection usually before age 20 years(1)

Incidence/Prevalence:   

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most common cause of gingivostomatitis in children most common oral lesion in patients with HIV infection incidence of herpes simplex on skin and lips in children 1.8 per 1,000 person-years, based on study of 88,307 children seen in 104 Dutch general practices in 2001 (BMC Dermatol 2006 Mar 21;6:4 ) seroprevalence data o age-adjusted seroprevalence of herpes simplex virus (HSV)-1 in persons aged 14-49 years in United States decreased from 62% in 1988-1994 (based on 9,167 persons) to 57.7% in 1999-2004 (based on 11,508 persons) (JAMA 2006 Aug 23;296(8):964 ) o 80% overall seroprevalence rates for HSV-1 and 19.3% for HSV-2 in sera collected from 3,120 adults aged 35-64 years in Switzerland 1992-1993 (BMC Infect Dis 2004 Mar 17;4:10 ) o 72% seroprevalence of HSV among 626 pregnant women in United States 1999-2002, with 63% seroprevalence of HSV-1 and 22% seroprevalence of HSV-2 (Am J Obstet Gynecol 2007 Jan;196(1):43e1)

Causes and Risk Factors Causes: 

herpes simplex virus (HSV) type 1, also HSV type 2(1, 2, 3)

Pathogenesis:      

transmitted via saliva or direct contact attaches to fibroblast growth factor receptor spread by contiguity, budding from nuclear membrane, cytolytic latency in nerve root (sensory ganglion such as trigeminal ganglion), carrier state for life asymptomatic viral shedding contributes to spread of infection, but risk of transmission highest during symptomatic periods(3) risk of transmission based on systematic literature review o high risk of transmission (> 75%)

o

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incubation period 1-6 days (mean 3.5 days) based on moderate evidence (well-designed study with 5-50 patients) o duration of shedding 1-8 weeks (median 3 weeks) and intermittently thereafter, based on moderate evidence (well-designed study with 5-50 patients) o period of infectiousness not known (no evidence found) o serial interval (interval between onset of clinical disease in index case and secondary case) 2-12 days (mean 6 days), based on good evidence o Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184 herpes simplex virus can survive on dry inanimate surfaces for 4.5 hours to 8 weeks, based on 4 citations in systematic review (BMC Infect Dis 2006 Aug 16;6:130 )

Likely risk factors:  

immunosuppressed patients prone to chronic, severe herpes simplex virus infections(3) stimuli that may cause reactivation of virus(1, 3) o sunlight or ultraviolet (UV) light exposure o upper respiratory tract infection o fever o trauma o menstruation o immunosuppression o corticosteroid use o surgery o stress

Complications and Associated Conditions Complications:   

genital herpes through orogenital contact with infected person(1, 3) gingival recession in case report (J Periodontol 2002 Jan;73(1):110) hepatitis and acute liver failure (rare) (Liver Transpl 2007 Oct;13(10):1428 ), commentary can be found in Nat Clin Pract Gastroenterol Hepatol 2008 Jun;5(6):298

Associated conditions:     

keratoconjunctivitis encephalitis herpetic whitlow radiculitis disseminated visceral infections in immunocompromised patients - esophagitis, pneumonitis, hepatitis, eczema

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Bell's palsy - polymerase chain reaction assay was used to amplify viral genomic sequences from endoneurial fluid from facial nerve or tissue of posterior auricular muscle in 14 patients with Bell's palsy and 9 patients with Ramsay-Hunt syndrome during decompressive surgery, and control specimens during similar surgeries on patients with temporal bone fractures or bacterial infection; herpes simplex virus type 1 genomic material was present in 11 of 14 patients with Bell's palsy but in no other patients; varicella-zoster virus was likewise found in 8 of 9 patients with Ramsay-Hunt syndrome but in no others (Ann Intern Med 1996 Jan 1;124(1 Pt 1):27 )

History and Physical History: Chief concern (CC):  

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oral and perioral lesions or ulcerations(1, 2, 3) primary infection(1, 2, 3) o can affect any part of oral mucosa o may be asymptomatic o systemic symptoms can include  fever  chills  fatigue  muscle aches  sore throat  dysphagia  cervical lymph node swelling relapsing infection(1) o usually affects lips (in older children and adults) and mucosa of hard palate o burning skin rash on lips and around mouth

History of present illness (HPI): 

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prodromal symptoms accompany most cases and may include (2, 3) o tingling o itching o burning o swelling primary infection usually resolves within 1-2 weeks(2, 3) lesions generally self-limiting in immunocompetent persons(3) clinical progression of lesions(1, 2, 3) o initially groups of papules on erythematous base o progression from papules to vesicles o progression through ulceration, crusting, and healing stages

Past medical history (PMH):

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ask about history of oral lesions

Social history (SH): 

obtain sexual history

Physical: General physical: 

fever may be present with primary infection(2, 3)

Skin: 

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primary infection(1, 2, 3) o can affect any part of oral mucosa o small blisters (vesicles) in front of and around mouth, on tongue and lips relapsing infection(1, 2, 3) o usually affects lips (in older children and adults) and mucosa of hard palate o burning skin rash on lips and around mouth clinical progression of lesions(1, 2, 3) o initially groups of papules on erythematous base o progression from papules to vesicles o progression through ulceration, crusting, and healing stages

HEENT: 

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gingivitis (3) o generalized, marginal o features include diffuse, purple, boggy swelling of gingivae, especially anteriorly (J Oral Pathol Med 2008 Feb;37(2):107) mouth ulcers in primary infection

Neck: 

lymphadenopathy may be present in primary infection(1, 3)

Diagnosis Making the diagnosis:  

diagnosis usually made clinically based on history and appearance of typical perioral lesions(1, 3) testing usually reserved for atypical cases or immunosuppressed patients (3)

Rule out:

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other viruses including (1) o infectious mononucleosis (2) o herpes zoster mucositis from chemotherapy or radiation aphthous stomatitis(3) trauma impetigo skin cancer necrotizing stomatitis (case presentation in Am Fam Physician 2009 Oct 15;80(8):875)

Testing overview:  

testing usually not necessary for typical cases(3) tests that may confirm diagnosis include (2, 3) o viral culture o Tzanck smear o immunofluorescence antibody staining o biopsy o polymerase chain reaction (PCR)

Biopsy and pathology: 

Tzanck test o allows for rapid diagnosis o staining of specimen from early viral vesicle (not pustule or ulcer) o presence of multinucleated epithelial giant cells on microscopic exam consistent with herpes simplex virus (HSV) infection o usually detects about 60% of HSV infections o test cannot differentiate between HSV-1, HSV-2 and varicella-zoster virus o smears taken from lesions developing later in infection usually negative o Reference - J Can Dent Assoc 2002 Apr;68(4):247 PDF o 85% sensitivity of multinucleated giant cells and acantholytic cells in herpes infection on Tzanck smear in study of 400 patients with moist skin lesions (J Am Acad Dermatol 2008 Dec;59(6):958), editorial can be found in J Am Acad Dermatol 2008 Dec;59(6):965, commentary can be found in J Am Acad Dermatol 2009 Jul;61(1):152

Other diagnostic testing: 

viral culture o considered gold standard for diagnosis but requires appropriate equipment and facilities to store and examine culture o culture intact vesicle and keep in medium suitable for viral growth and free from bacterial or fungal contamination o cytopathic effects on cell culture usually develop 24-48 hours after inoculation

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Reference - Lancet 2001 May 12;357(9267):1513, J Can Dent Assoc 2002 Apr;68(4):247 PDF vesicles yielded 100% positive viral culture and 67% positive Tzanck smear in series of 32 lesions in 30 patients (JAMA 1984 Feb 3;251(5):633) review of tests for detecting herpes simplex viruses can be found in Dermatol Clin 1994 Jan;12(1):51

Treatment Treatment overview:  

provide education on contagious nature of virus and modes of transmission antiviral medications o indicated for immunocompromised patients and healthy persons with frequent outbreaks o may be recommended for moderate and severe cases of primary infection in healthy persons o antiviral medications may improve symptoms and prevent recurrences but cannot cure infection (lifelong latency) o episodic dosing for primary or recurrent herpes labialis  acyclovir  adults - 400 mg orally 5 times daily for 5 days (400 mg 3 times daily for 7-14 days if HIV infection)  children  immunocompetent children - 15 mg/kg (up to 200 mg) orally 5 times daily for 7 days has been used  HIV infection with mild, symptomatic gingivostomatitis - 20 mg/kg (up to 400 mg) orally 3 times daily for 7-14 days  HIV infection with moderate-to-severe gingivostomatitis - 5-10 mg/kg IV 3 times daily for 714 days  valacyclovir  2 g orally every 12 hours for 1 day (2 doses) in adults and adolescents  alternative regimen - 1 g orally twice daily for 7 days  famciclovir  1,500 mg single dose in adults and adolescents  for recurrent mucocutaneous infections in adults and adolescents with HIV infection - 500 mg every 12 hours for 7 days (some experts recommend 7-14 days)  alternative regimen - 500 mg orally twice daily for 7 days o intermittent episodic therapy for recurrent herpes labialis (start at earliest sign or symptom)  acyclovir 5% cream topically 5 times daily for 4 days  penciclovir 1% cream topically every 2 hours while awake for 4 days

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Diet:

docosanol 10% cream topically 5 times daily until healed (maximum 10 days), available over-the-counter o chronic suppressive therapy (secondary prophylaxis)  acyclovir  adults and adolescents - 200 mg orally 3 times daily or 400 mg orally twice daily  infants and children with HIV infection - 80 mg/kg/day orally (up to 1 g/day) in 3-4 divided doses  valacyclovir  500 mg orally twice daily  alternative regimens - 500 mg orally once daily or 1 g orally once daily  famciclovir  250 mg orally twice daily  alternative regimen - 500 mg orally twice daily o IV antivirals (foscarnet, cidofovir) are highly nephrotoxic and reserved for treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients efficacy of antiviral medications o antiviral drugs reduce duration by about 1 day (0.5-2 days) o oral medications  oral acyclovir may reduce duration of pain and lesions, and may reduce eating and drinking difficulties in children with herpes labialis (level 2 [mid-level] evidence)  oral valacyclovir (1 or 2 day course) may reduce duration of episode in patients with ≥ 3 herpes labialis episodes per year (level 2 [midlevel] evidence)  oral famciclovir 1,500 mg in 1 or 2 doses may reduce time to healing of recurrent herpes labialis by about 2 days (level 2 [mid-level] evidence) o topical medications  acyclovir 5% cream reduces duration of herpes labialis by about half a day (level 1 [likely reliable] evidence)  docosanol 10% cream may reduce time to healing of recurrent herpes labialis lesions  penciclovir 1% cream reduces duration of recurrent herpes labialis lesions by 1 day (level 1 [likely reliable] evidence) topical treatments which may reduce symptom severity or duration based on single trials include (level 2 [mid-level] evidence) o undecylenic acid cream o zinc oxide/glycine cream o tetracaine 1.8% cream (Cepacol Viractin) o fluocinonide 0.05% gel o balm mint cream o rhubarb-sage cream

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anecdotal evidence that certain dietary changes may prevent recurrences o decreasing dietary sources of arginine (such as nuts, chocolate and seeds) o increasing dietary sources of lysine (such as legumes, animal proteins) o restricting refined dietary carbohydrates o Reference - Altern Med Rev 2006 Jun;11(2):93

Counseling: 

provide patient education including(3) o advice on handwashing, especially after application of topical medications o avoidance of kissing children or partners o avoidance of shared utensils o education on contagious nature of virus and modes of transmission o education on potential triggers of viral reactivation o appropriate use of sunscreen

Medications: Antiviral medications:    

indicated for immunocompromised patients and healthy persons with frequent outbreaks(3) may be recommended for moderate and severe cases of primary infection in healthy persons(2) antiviral medications may improve symptoms and prevent recurrences but cannot cure infection (lifelong latency) (3) all antiviral drugs reduce duration by about 1 day, except docosanol which reduces duration by about 18 hours (Med Lett Drugs Ther 2002 Nov 11;44(1143):95 TOC)

Oral antivirals: Acyclovir: 

prescribing information for acyclovir (Zovirax) o indications  treatment of orolabial herpes simplex virus (HSV) infections in immunocompetent adults and children  treatment of initial and recurrent mucocutaneous HSV-1 and HSV-2 labial infections in immunocompromised adults, adolescents, and children, including persons with HIV infection  chronic suppressive or maintenance therapy (secondary prophylaxis) of recurrent HSV infections in immunocompromised adults, adolescents, and children, including persons with HIV infection who have frequent or severe recurrences  generally ineffective or minimally effective for prevention of recurrence of herpes labialis in immunocompetent persons o adult dosing

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treatment of orolabial HSV infections - 400 mg orally 5 times daily for 5 days  if HIV infection - Centers for Disease Control and Prevention (CDC) and others recommend 400 mg orally 3 times daily for 7-14 days  chronic suppressive or maintenance therapy (secondary prophylaxis) of HSV infections in adults with HIV infection - 200 mg orally 3 times daily or 400 mg orally twice daily o pediatric dosing  immunocompetent children - 15 mg/kg (up to 200 mg) orally 5 times daily for 7 days has been used in some children aged 1-6 years  if HIV infection and  mild, symptomatic gingivostomatitis - CDC and others recommend 20 mg/kg (up to 400 mg) orally 3 times daily for 7-14 days  moderate to severe gingivostomatitis - CDC and others recommend 5-10 mg/kg IV 3 times daily for 7-14 days  consider chronic oral suppressive or maintenance therapy (secondary prophylaxis) for frequent or severe recurrences of gingivostomatitis  infants and children with HIV infection - 80 mg/kg/day orally (up to 1 g/day) in 3-4 divided doses  adolescents with HIV infection - 200 mg orally 3 times daily or 400 mg orally twice daily o see Acyclovir (Systemic) for details efficacy o acyclovir 400 mg orally 5 times daily for 5 days associated with shorter duration of pain and shorter healing time if started during prodrome or erythema lesion stages  based on randomized trial  174 patients with recurrent herpes labialis randomized to patientinitiated acyclovir 400 mg vs. placebo orally 5 times daily for 5 days  patients instructed to start treatment within 1 hour of symptoms and skip treatment if awakening with symptoms or first realization of vesicle or ulcer stage  comparing acyclovir vs. placebo  mean duration of pain 2.5 days vs. 3.8 days (p = 0.01) with no significant effect on lesion progression, size, or time to healing  in subgroup of 90 patients with lesions in prodrome or erythema stage at start of treatment  mean pain duration 2.5 days vs. 3.9 days (p = 0.02)  mean healing time to loss of crust 5.8 days vs. 7.9 days (p = 0.03)  in subgroup of 84 patients with lesions in papule or vesicle stage at start of treatment  mean pain duration 2.5 days vs. 3.6 days (not significant)

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mean healing time to loss of crust 8 days vs. 7.2 days (not significant)  Reference - J Infect Dis 1990 Feb;161(2):185 in J Fam Pract 2004 Nov;53(11):923 acyclovir may reduce lesions and eating and drinking difficulties in children with herpetic gingivostomatitis (level 2 [mid-level] evidence)  based on Cochrane review of limited evidence  systematic review of 2 randomized placebo-controlled trials evaluating acyclovir in 92 children and adults < 25 years old with primary herpetic gingivostomatitis (with or without herpes labialis)  meta-analysis not feasible due to clinical heterogeneity between trials  1 trial with 72 children aged 1-6 years had unclear blinding of outcome assessors  children randomized within 72 hours of onset to acyclovir suspension 15 mg/kg (maximum 200 mg/dose) vs. placebo 5 times daily for 7 days  10 children (13.9%) with viral cultures negative for HSV excluded from clinical evaluation but were included in intention-to-treat analysis  comparing acyclovir vs. placebo  oral lesions 8 days after treatment in 5.6% vs. 58.3% (p = 0.0008, NNT 2)  new extraoral lesions in 0 vs. 33.3% (p = 0.024, NNT 3)  eating difficulties 8 days after treatment in 5.6% vs.

38.9% (p = 0.0067, NNT 3)  drinking difficulties 8 days after treatment in 2.8% vs.

25% (p = 0.032, NNT 5)  no significant differences in hospital admissions after treatment  median duration of difficulties comparing acyclovir vs. placebo  oral lesions 4 vs. 10 days  perioral lesions 0 vs. 5.5 days  fever 1 vs. 3 days  eating difficulties 4 vs. 7 days  drinking difficulties 3 vs. 6 days  viral shedding 1 vs. 5 days  Reference - BMJ 1997 Jun 21;314(7097):1800 , commentary can be found in BMJ 1997 Nov 1;315(7116):1162  1 trial with 20 children (mean age 2 years) had unclear allocation concealment and blinding  18 children (90%) included in analysis  outcomes not used due to inconsistent reporting  no trials found in adults  Reference - Cochrane Database Syst Rev 2008 Oct 8;(4):CD006700

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acyclovir may be effective for treatment of HSV infections in patients being treated for cancer (level 2 [mid-level] evidence)  based on Cochrane review of trials with unclear risk of bias for primary outcome  systematic review of 17 randomized trials evaluating interventions for prevention and/or treatment of HSV infection in patients being treated for cancer  2 trials evaluated acyclovir for treatment of HSV infections  both trials had unclear allocation concealment and uncertain risk of bias for primary outcome in within study summary assessment  no data available for recurrence of lesions, amount of analgesia, duration of hospital stay, cost of oral care or patient quality of life  comparing acyclovir vs. placebo  median time to 50% healing 6 days vs. 11 days in 1 trial (p = 0.01)  acyclovir associated with shorter median time to healing, shorter duration of viral shedding and shorter time to pain relief compared to placebo in each trial  Reference - Cochrane Database Syst Rev 2009 Jan 21;(1):CD006706 "stat" acyclovir 800 mg single dose at earliest sensory sign of recurrent oral or genital herpes simplex reported to prevent lesions in 26 of 32 adults (level 3 [lacking direct] evidence) in case series (Cutis 1996 Jun;57(6):453)

Valacyclovir: 

prescribing information for valacyclovir (Valtrex) o indications  treatment of herpes labialis in immunocompetent adults and adolescents  treatment of recurrent mucocutaneous herpes simplex virus (HSV) infections in adults with HIV infection  chronic suppressive or maintenance therapy (secondary prophylaxis) in persons with HIV infection who have frequent or severe recurrences o dosing  immunocompetent adults and adolescents - 2 g every 12 hours for 1 day (2 doses)  alternative regimen for episodic dosing - 1 g orally twice daily for 7 days  chronic suppressive or maintenance therapy (secondary prophylaxis) in persons with HIV infection who have frequent or severe recurrences - 500 mg twice daily  alternative regimens for chronic suppressive therapy (secondary prophylaxis) - 500 mg orally once daily or 1 g orally once daily

o

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start at earliest symptom of cold sore (tingling, itching, burning), efficacy not established if started after development of clinical signs (papule, vesicle, ulcer) o safety and efficacy not established in immunocompromised patients o see Valacyclovir for details valacyclovir (1 or 2 day course) may reduce duration of episode in patients with ≥ 3 herpes labialis episodes per year (level 2 [mid-level] evidence) o based on 2 randomized trials published together with allocation concealment not stated o 1,856 patients ≥ 12 years old with history of ≥ 3 cold sores within previous year were randomized to valacyclovir 2 g orally every 12 hours (2 doses) vs. valacyclovir 2-day course (2 g orally twice daily on day 1, 1 g orally twice daily on day 2) vs. placebo o most patients started treatment within 2 hours of prodrome o both valacyclovir doses reduced duration of episodes by about 1 day o no significant differences between dosing regimens o Reference - Antimicrob Agents Chemother 2003 Mar;47(3):1072

Famciclovir: 

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prescribing information for famciclovir (Famvir) o indications  episodic treatment of herpes labialis in immunocompetent or adults and adolescents with HIV infection  treatment of recurrent mucocutaneous herpes simplex virus (HSV) infections in adults and adolescents with HIV infection  chronic suppressive or maintenance therapy (secondary prophylaxis) against recurrence in adults and adolescents with HIV infection who have frequent or severe recurrences o dosing  start treatment at first prodromal symptom (tingling, itching, burning)  immunocompetent or adults and adolescents with HIV infection 1,500 mg single dose  recurrent mucocutaneous HSV infections in adults and adolescents with HIV infection - 500 mg every 12 hours for 7 days, some experts recommend 7-14 days  alternative regimen for episodic dosing - 500 mg orally twice daily for 7 days  chronic suppressive or maintenance therapy (secondary prophylaxis) against recurrence in adults and adolescents with HIV infection who have frequent or severe recurrences - 250 mg twice daily  alternative regimen for chronic suppressive therapy (secondary prophylaxis) - 500 mg orally twice daily o see Famciclovir for details efficacy

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famciclovir 1,500 mg in 1 or 2 doses may reduce time to healing of recurrent herpes labialis by about 2 days (level 2 [mid-level] evidence)  based on randomized trial with inadequate reporting of blinding  701 immunocompetent adults with recurrent herpes labialis were randomized to famciclovir 1,500 mg single dose vs. famciclovir 750 mg twice daily vs. placebo self-initiated within 1 hour of prodromal symptoms of herpes labialis  median healing times of first vesicular lesion  6.2 days with placebo  4.4 days with single dose (p < 0.001 vs. placebo)  4 days with split dose (p < 0.001 vs. placebo)  no significant difference between famciclovir regimens in time to healing  Reference - J Am Acad Dermatol 2006 Jul;55(1):47 famciclovir 500 mg orally 3 times daily for 5 days started within 48 hours of ultraviolet (UV) exposure associated with shorter duration of herpes labialis lesions (level 2 [mid-level] evidence)  based on randomized trial with unclear allocation concealment  243 adults with history of sunlight-induced herpes labialis were randomized to famciclovir 125 mg vs. 250 mg vs. 500 mg vs. placebo orally 3 times daily for 5 days starting 48 hours after UV radiation exposure (to induce recurrence)  among 102 patients who had recurrence of lesions between 48 hours and 7 days of UV exposure  famciclovir 500 mg dose associated with reduced mean maximum area of lesions (p = 0.009 vs. placebo)  famciclovir 500 mg reduced duration of lesions by 2 days (p = 0.01 vs. placebo)  no significant differences between other doses of famciclovir and placebo  Reference - J Infect Dis 1999 Feb;179(2):303

Topical antivirals: 

acyclovir 5% cream (Zovirax) o prescribing information  indications  treatment of recurrent herpes labialis in immunocompetent patients ≥ 12 years old  has been used for treatment of non-life-threatening, nongenital, mucocutaneous herpes simplex virus (HSV) infections in immunocompromised adults, efficacy not established in immunocompetent patients  should not be used for prevention of recurrent HSV infections  dosing  patients ≥ 12 years old - apply 5% cream to affected area times 5 times daily for 4 days

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start at earliest sign or symptom use enough to adequately cover lesion and symptomatic area  for external use only, do not apply in or near eyes or inside mouth or nose  see Acyclovir (Topical) for details o topical acyclovir 5% cream reduces duration of herpes labialis by about half a day (level 1 [likely reliable] evidence)  based on 2 randomized trials  2 trials of adults with history of frequent herpes labialis were randomized to 5% acyclovir cream vs. placebo  patients told to self-initiate treatment 5 times daily for 4 days, starting within 1 hour of recurrent episode  comparing acyclovir cream vs. placebo  in trial with 686 patients initiating treatment, mean duration of episodes 4.3 vs. 4.8 days (p = 0.007)  in trial with 699 patients initiating treatment, mean duration of episodes 4.6 vs. 5.2 days (p = 0.006)  efficacy found when treatment initiated "early" (prodrome or erythema lesion stage) or "late" (papule or vesicle stage)  Reference - Antimicrob Agents Chemother 2002 Jul;46(7):2238 docosanol 10% cream (Abreva) o prescribing information  indications and general information  topical treatment of recurrent herpes labialis  available over-the-counter  safety and efficacy not established in immunocompromised patients  dosing  patients ≥ 12 years old - apply to affected areas 5 times daily until healed (maximum 10 days)  start at earliest sign or symptom (tingling, pruritus, redness, presence of bump)  use enough to adequately cover lesions and symptomatic area  for external use only, do not apply in or near eyes or inside mouth  see Docosanol for details o docosanol 10% cream may reduce time to healing of recurrent herpes labialis lesions by about 18 hours  based on randomized trial  737 adults with history of recurrent herpes simplex labialis were randomized to docosanol 10% cream vs. polyethylene glycol placebo topically 5 times daily within 12 hours of prodrome or erythema and continuing until resolution of active lesion  docosanol 10% cream associated with decreased  median time to complete healing by 18 hours (p = 0.008)  median time to complete cessation of discomfort (pain, itching, burning, tingling) (p = 0.002)  time to complete healing of classic lesions (p = 0.023)

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time to cessation of ulcer or soft crust stage of classic lesions (p < .001)  Reference - J Am Acad Dermatol 2001 Aug;45(2):222, commentary can be found in J Am Acad Dermatol 2002 Sep;47(3):457 penciclovir 1% cream (Denavir) o prescribing information  indications and general information  treatment of recurrent herpes labialis in adults  efficacy not established in immunocompromised patients or children  dosing  apply every 2 hours while awake for 4 days  start at earliest sign or symptom (within 1 hour of prodrome or appearance of first lesion)  use enough to adequately cover all lesions on lips and surrounding skin  do not apply in or near eyes, application to mucous membranes not recommended  see Penciclovir for details o efficacy  penciclovir 1% cream reduces duration of recurrent herpes labialis lesions by 1 day (level 1 [likely reliable] evidence)  based on 2 randomized trials  3,057 immunocompetent patients with history of ≥ 3 episodes of recurrent herpes labialis per year were randomized to penciclovir 1% cream vs. placebo within 1 hour of first sign or symptom of recurrence  patients self-initiated treatment 6 times daily for 1 day and every 2 hours while awake for next 4 days  comparing penciclovir vs. placebo  resolution of classical lesions by 5 days vs. 6 days on investigator assessment (p = 0.0001)  resolution of pain by 3.5 days vs. 4.2 days on patient assessment (p = 0.0001)  benefits of penciclovir achieved both when treatment was started in early (prodrome and erythema) and late (vesicle or pustule) stages  Reference - J Am Dent Assoc 2002 Mar;133(3):303  penciclovir 1% cream may reduce duration of recurrent herpes labialis lesions by 0.7 day  based on randomized trial  1,573 immunocompetent patients with ≥ 3 outbreaks of herpes labialis per year and prodromal symptoms were randomized to topical 1% penciclovir cream vs. placebo within 1 hour of first sign or symptom of recurrence  patients instructed to apply cream every 2 hours while awake for 4 days

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comparing penciclovir vs. placebo  median duration of lesions 4.8 days vs. 5.5 days (p < 0.001)  median time to pain resolution 3.5 days vs. 4.1 days (p < 0.001)  benefits of penciclovir achieved both when treatment was started in early (prodrome and erythema) and late (vesicle or pustule) stages  Reference - JAMA 1997 May 7;277(17):1374  similar results in randomized trial of 541 patients (Clin Ther 2000 Jan;22(1):76)  penciclovir not effective for acyclovir-resistant thymidine kinasemutant of HSV (Med Lett Drugs Ther 1997 Jun 20;39(1003):57 TOC) cidofovir gel may improve healing and reduce pain in patients with Acquired Immune Deficiency Syndrome (AIDS) and mucocutaneous HSV infection refractory to acyclovir (level 2 [mid-level] evidence) o based on small randomized trial o 30 patients with AIDS and acyclovir-unresponsive mucocutaneous HSV infections were randomized to cidofovir gel (0.3% or 1%) vs. placebo gel once daily for 5 days o comparing cidofovir vs. placebo  complete healing in 30% vs. 0 (p = 0.031, NNT 4)  cessation of viral shedding in 87% vs. 0% (p = 0.00004, NNT 2)  decrease in median lesion area by 58% vs. 0 (p = 0.005)  change in mean pain score -1.84 vs. -0.34 (p = 0.042)  application site reactions in 25% vs. 20% (not significant), none required dose reduction or discontinuation o Reference - J Infect Dis 1997 Oct;176(4):892 topical idoxuridine 15% solution may reduce pain and healing time associated with herpes labialis o based on randomized trial o 301 immunocompetent patients with recurrence of herpes labialis were randomized to topical 15% idoxuridine in dimethyl sulfoxide (DMSO) vs.

80% DMSO control vs. 2% DMSO control o compared to combined control groups, idoxuridine associated with  decrease in mean duration of pain by 1.3 days (p = 0.01)  decrease in mean healing time to loss of crust by 1.7 days (p = 0.004) o treatment with idoxuridine most effective when started in prodrome or erythema lesion stage o Reference - J Infect Dis 1990 Feb;161(2):191

IV antivirals: 

IV foscarnet (Foscavir) and cidofovir (Vistide)(3) o given IV, highly nephrotoxic

o

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reserved for treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients treatment of foscarnet-resistant herpes simplex stomatitis with IV cidofovir in case report of child with leukemia following bone marrow transplant (Pediatr Infect Dis J 2001 Nov;20(11):1083)

Other topical medications: 

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topical undecylenic acid cream may be effective if applied during prodrome (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 573 patients with recurrent herpes labialis treated with undecylenic acid 15% cream vs. placebo applied 5-6 times daily until crusting and then 3 times daily until healing o undecylenic acid associated with  significant reduction in incidence and duration of viral shedding  significant reduction in duration and severity of itching  no increase in abortive episodes  no significant reduction in time to healing, crusting, or progression of lesion size o undecylenic acid associated with reduced time to crusting only in patients starting treatment during prodrome o Reference - J Infect Dis 1997 Jul;176(1):78 topical zinc oxide/glycine cream may reduce duration of lesions and severity of symptoms in patients with facial herpes infection (level 2 [mid-level] evidence) o based on small randomized trial o 59 immunocompetent patients aged 18-65 years with facial or circumoral herpes infections within 24 hours of recurrent facial herpes infection were randomized to zinc oxide/glycine (ionic zinc 0.3%) cream vs. placebo cream every 2 hours while awake for 21 days or until cold sore resolution o 46 patients (78%) were analyzed o comparing zinc oxide/glycine vs. placebo  mean duration of cold sore lesions 5 days vs. 6.5 days (until resolution or only crusting, p = 0.018)  adverse reaction of burning in 22% vs. 7% (not significant), 1 patient in zinc oxide group discontinued treatment due to burning sensation  adverse reaction of itching in 9% vs. 4% (not significant) o zinc oxide/glycine cream associated with reduced overall severity of signs and symptoms o Reference - Altern Ther Health Med 2001 May-Jun;7(3):49 topical tetracaine 1.8% cream (Cepacol Viractin) applied frequently may significantly reduce healing time of recurrent herpes labialis lesions (level 2 [mid-level] evidence) o based on randomized trial with method of randomization not stated o topical tetracaine available over-the-counter

o

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72 immunocompetent adults with recurrent herpes labialis were randomized to tetracaine 1.8% vs. placebo cream applied up to 6 times daily until lesions healed (scab loss) or maximum 12 days o comparing tetracaine vs. placebo  mean time to scab formation 2.3 vs. 2.4 days  mean time to healing (scab loss) 5.1 vs. 7.2 days (p = 0.0002) o tetracaine associated with significantly greater relief from itching 2 and 3 days after starting treatment o Reference - J Am Acad Dermatol 1999 Dec;41(6):996 addition of topical fluocinonide 0.05% gel to oral famciclovir may be associated with smaller lesions and reduced pain compared to famciclovir alone (level 2 [mid-level] evidence) o based on small randomized pilot trial o 49 patients with history of sunlight-induced herpes labialis were treated with famciclovir 500 mg orally 3 times daily for 5 days and randomized to topical fluocinonide 0.05% (Lidex) vs. placebo gel 3 times daily for 5 days o patients were exposed to ultraviolet (UV) radiation and instructed to start medications within 1 hour of symptoms o 29 (60%) patients developed lesions in 7 days following UV radiation o comparing fluocinonide vs. placebo 2 2  median maximum lesion size 48 mm vs. 162 mm (p = 0.02)  median healing time to normal skin 5.3 days vs. 8.9 days (p = 0.06)  median healing time to loss of crust 6.6 days vs. 10.3 days (not significant)  pain reported in 59% vs. 100% (p = 0.02, NNT 3) o Reference - J Infect Dis 2000 Jun;181(6):1906, commentary can be found in Am Fam Physician 2000 Dec 15;62(12):2672 balm mint cream (1% extract from Melissa officinalis L. leaves) may improve symptoms in patients with recurrent herpes labialis o based on randomized trial o 66 patients with history of recurrent herpes labialis (≥ 4 episodes per year) were randomized to topical balm mint cream vs. placebo 4 times daily for 5 days o balm mint extract associated with significant improvement in median combined symptom score (including patient complaints, size of affected area and blisters at day 2 of treatment) o Reference - Phytomedicine 1999 Oct;6(4):225 topical rhubarb-sage cream may be as effective as acyclovir cream in mean time to healing of herpes labialis lesions o based on randomized trial o 149 patients with herpes labialis were randomized to rhubarb-sage cream vs. sage cream vs. acyclovir (Zovirax) cream o mean time to healing 6.7 days with rhubarb-sage cream vs. 7.6 days with sage cream vs. 6.5 days with acyclovir cream o Reference - Forsch Komplementarmed Klass Naturheilkd 2001 Dec;8(6):373

Prognosis     

no cure, life-long latency in infected host(3) lesions usually self-limiting in healthy persons, resolving over 1-2 weeks(1, 3) virus may reactivate upon stimulation(3) number of relapses decreases after age 35 years(1, 3) death in patient with fulminant hepatic failure contracting herpes simplex virus in case report (N Engl J Med 2009 Jun 11;360(24):2564), correction can be found in N Engl J Med 2011 May 26;364(21):2078

Prevention and Screening Prevention: 

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oral acyclovir for patients with frequent outbreaks may reduce recurrence rate (level 2 [mid-level] evidence) o based on small randomized crossover trial o 56 otherwise healthy adults with recurrent herpes labialis (≥ 6 times/year) were observed for 4 months o 22 patients with ≥ 2 episodes were randomized to acyclovir 400 mg orally twice daily vs. placebo for 4 months then crossed over to alternate regimen o 20 patients (91%) completed study and were observed for posttreatment recurrence o comparing acyclovir vs. placebo  median time to first clinically documented recurrence 118 days vs.

46 days (p = 0.05)  mean number of recurrences per patient per 4-month treatment period 0.85 vs. 1.8 (p = 0.009) o Reference - Ann Intern Med 1993 Feb 15;118(4):268 for recurrent light-induced herpes labialis o acyclovir 5% cream may reduce number of lesions in patients with history of recurrent sun-induced herpes labialis  based on randomized trial  191 patients with > 3 episodes of sun-induced herpes labialis during previous year were randomized to acyclovir 5% cream vs. placebo at 7 ski sites in United States and Canada  comparing acyclovir vs. placebo  adverse events in 15 patients vs. 13 patients (not significant)  lesions developed during 4-day follow-up in 21% vs. 40% (p < 0.01, NNT 6)  no significant difference between groups in adverse events  Reference - Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 Dec;84(6):641 o sunscreen may reduce rate of recurrent ultraviolet (UV) light-induced herpes labialis lesions  based on crossover trial

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38 adults with recurrent herpes labialis were exposed to UV light at area of previous herpes labialis recurrence on 2 separate occasions  solution containing sunscreen applied to lips before 1 exposure  placebo solution applied to lips before other exposure  herpes labialis lesions developed in 71% of patients who received placebo vs. 0% of patients who received sunscreen  mean time to recurrence of lesions 2.9 days  Reference - Lancet 1991 Dec 7;338(8780):1419, commentary can be found in Lancet 1992 Jan 11;339(8785):133  similar results in crossover trial of 19 healthy volunteers with herpes labialis and ≥ 2 recurrences per year (J Dermatol Treat 1998;9:11 in Fam Pract 1999 Nov;24(8):16) acyclovir may be effective for prevention and treatment of herpes simplex virus (HSV) infections in patients being treated for cancer (level 2 [mid-level] evidence) o based on Cochrane review of trials with unclear risk of bias for primary outcome o systematic review of 17 randomized trials evaluating interventions for prevention and/or treatment of HSV infection in patients being treated for cancer o for prevention of HSV infections  11 trials had uncertain risk of bias and 2 trials had high-risk of bias for primary outcome in within study summary assessment  comparing prophylactic acyclovir vs. placebo  HSV incidence measured by oral lesions 5% vs. 46.7% in analysis of 9 trials with 398 patients (p < 0.00001, NNT 3)  HSV incidence measured by viral isolates 7.5% vs. 46.3% in analysis of 9 trials with 511 patients (p = 0.000013, NNT 3), results only significant for oral acyclovir (7 trials with 442 patients)  no evidence that valacyclovir more effective for preventing HSV oral lesions than acyclovir in analysis of 2 trials with 181 patients  comparing oral valacyclovir lower dose vs. higher dose  HSV incidence measured by oral lesions 2.2% vs. 9% in analysis of 2 trials with 181 patients (p = 0.055)  no cases of HSV measured by viral isolates identified comparing valacyclovir 500 mg every 8 hours vs. 1,000 mg every 8 hours in 1 trial with 81 patients  prostaglandin E not beneficial for prevention of viral isolates compared to placebo in 1 trial with 60 patients (HSV incidence measured by viral isolates 71% with prostaglandin E vs. 37.9% with placebo, p = 0.018, NNH 3) o Reference - Cochrane Database Syst Rev 2009 Jan 21;(1):CD006706 other proposed natural remedies with limited evidence for treatment of prevention of recurrences o lysine supplementation

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limited evidence that lysine may reduce recurrence rate of herpes simplex infections in several small studies  optimal dose unknown, but have ranged from 500-3,000 mg/day o vitamin C supplementation o oral zinc supplementation o topical vitamin E o intramuscular adenosine monophosphate injections o oral or topical lithium o Reference - Altern Med Rev 2006 Jun;11(2):93 no recommended exclusion period from school o exclusion not required as illness generally mild in childhood o exclusion will not be fully effective because asymptomatic infections occur and may be involved in transmission o prolonged excretion makes exclusion impractical o Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184 Centers for Disease Control and Prevention (CDC) guidelines for infection control in hospital personnel can be found in Infect Control Hosp Epidemiol 1998 Jun;19(6):407 PDF

Guidelines and Resources Guidelines: 

no relevant guideline for "herpes labialis" or "herpetic gingivostomatitis" found 2012 Nov 30 on systematic search of MEDLINE (using guidelines limiter) and National Guideline Clearinghouse

Review articles:          

review can be found in J Oral Pathol Med 2008 Feb;37(2):107 review can be found in J Fam Pract 2007 Jul;56(7):576 review can be found in Oral Dis 2006 May;12(3):254 review can be found in Quintessence Int 2003 Jun;34(6):453 review of nongenital herpes simplex virus can be found in Am Fam Physician 2010 Nov 1;82(9):1075 review of recurrent herpes infection can be found in Postgrad Med 2000 May 15;107(6):139 review of treatment of common cutaneous herpes simplex virus infections can be found in Am Fam Physician 2000 Mar 15;61(6):1697 review of drugs for non-HIV viral infections can be found in Treat Guidel Med Lett 2010 Oct;8(98):71 review of management of herpes simplex virus infections can be found in West J Med 1997 Mar;166(3):211 PDF review of management of acyclovir-resistant herpes simplex virus can be found in Dermatol Clin 2003 Apr;21(2):311

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review of common oral lesions (superficial mucosal lesions) can be found in Am Fam Physician 2007 Feb 15;75(4):501 , editorial can be found in Am Fam Physician 2007 Feb 15;75(4):475 , commentary can be found in Am Fam Physician 2007 Nov 1;76(9):1280 review of common skin infections in children can be found in BMJ 2005 May 21;330(7501):1194 , commentary can be found in BMJ 2005 Jun 25;330(7506):1510 review of antiviral drugs can be found in Am Fam Physician 2003 Feb 15;67(4):757