Herpes simplex orofacial infection

Herpesviral vesicular dermatitis
Herpes lesion on upper lip and face

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Anahita Deylamsalehi, M.D.[2] ; Cafer Zorkun, M.D., Ph.D. [3]

Overview

Infection by HSV-1 is the most common cause of herpes that affects the face and mouth (orofacial herpes), although within the recent years an increase in oral HSV-2 infections has been reported. Studies demonstrated different rate of herpes simplex orofacial infection prevalence in different populations, nevertheless lifetime prevalences of herpes simplex orofacial infection has been estimated 42.1% and 32.4%, in women and men, respectively. There are some evidences that report higher rate of herpes simplex orofacial infection in low socioeconomic status. A majority of primary HSV-1 infections occur during childhood. Early HSV infection could be asymptomatic without any obvious skin lesions. Transmission commonly occurs when infection source comes in contact with the mucosa or abraded skin. However there are other rout of transmission such as infants born to infected mothers who are also at risk of catching the HSV-1 during the delivery. The estimated duration of primary HSV infection has been estimated between 2-20 days after contact with the source of infection. Skin involvement usually appear as grouped ulcers or vesicles on an erythematous base. Subsequently skin vesicles may ulcerate and then become crusted. Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing. Once a primary oral HSV-1 infection has resolved, the HSV enters the nerves surrounding the primary lesion, migrates to the cell body of the neuron, and becomes latent in the trigeminal ganglion. In some patients, the virus reactivates to cause recurrent infection, which is more common with HSV-1 than HSV-2 oral infection. Even though trigeminal ganglion is the most common location for HSV-1 infection, inferior and superior cervical ganglia could also become infected with this serotype of herpes simplex. Prodromal symptoms often precede a recurrence, which typically begins with reddening of the skin around the infected site. Pain, itching and paresthesia are some of the other prodromal symptoms in herpes simplex infection. Duration of the prodromal symptoms can range between few hours to several days before lesions develop. Some factors such as concurrent viral infection, trauma, menstural period, fatigue, stress and sun exposure could trigger recurrent herpes simplex lesions. It has been estimated that patients with HSV-1 orofacial infection could experience recurrent infections 1-6 times in a year. Each episode of orofacial infection is less sever and shorter, compared to previous episodes of orofacial infections. There are numerous differential diagnosis such as oral candidiasis, aphthous ulcers, squamous cell carcinoma, leukoplakia, behcet's disease, crohn's disease and burning mouth syndrome. Some conditions such as leukemia, bell's palsy, chronic atopic dermatitis and Human immunodeficiency virus infection have been known as associated conditions in orofacial herpes. Orofacial herpes simplex infection is usually diagnosed clinically, nevertheless PCR test, immunodot glycoprotein G-specific (IgG) test, skin biopsy, virus culture and direct fluorescent anti body (DFA) studies are some of the available laboratory investigations to better diagnose orofacial infection due to herpes simplex. Unfortunately there is no approved treatment to completely eradicate the herpes simplex virus from body. Nevertheless antiviral treatments have been successful in lowering the severity and duration of skin lesions. The available antiviral drugs that can be used for herpes simplex infection include acyclovir, valaciclovir, famciclovir and penciclovir. Acyclovir is effective in decreasing the viral shedding period in infected patients (median of 2.5 days when patients received acyclovir, compared to 17 days). It also has been reported to be efficient in augmenting pain resolution and healing of the skin lesions.

Epidemiology

• Based on a study, lifetime prevalences of herpes simplex orofacial infection are 42.1% and 32.4%, in women and men, respectively. Moreover HSV1 prevalence was estimated 50.3%.
• Another study reported herpes simplex infection rate approximately 70-80% in low socioeconomic status and 40%-60% in high socioeconomic status individuals.
• Prevalence of HSV-1 estimated as 57.7% in US population.
• Based on a study done on college students demonstrated that 25.6 % of first year college students had history of recurrent orofacial HSV-1 infection compared to 28 % in fourth-year students.
• A study done in France estimated annual prevalence of orofacial herpes simplex infection as 14.8% (only 23% of these population were aware of their infection). Based on this study female population has higher chance of infection, compared to male populations.

Clinical Presentations

• Early HSV infection could be asymptomatic without any obvious symptoms (Also called asymptomatic seroconversion).
• A majority of primary HSV-1 infections occur during childhood and if the virus comes into contact with the mucosa or abraded skin, it can cause acute herpetic gingivostomatitis (inflammation of the cheek's mucosa and gums) within 5–10 days. Some other symptoms may also develop, including fever and sore throat, refuse to eat or drink and painful ulcers may appear.
• Prodromal symptoms often precede a recurrence, which typically begins with reddening of the skin around the infected site, with eventual ulceration to form fluid-filled blisters that affect the lip (labial) tissue and the area between the lip and skin (vermillion border).
• The following list includes some of the prodromal symptoms in herpes simplex infection:
  • Itching
  • Pain
  • Paresthesia (may be described as tingling)
• Duration of the prodromal symptoms can range between few hours to several days before lesions develop.
• Most of the time orofacial infection just involves lips and oral mucosa and is often called herpes simplex labialis.
• Skin involvement usually appear as grouped ulcers or vesicles on an erythematous base. Subsequently skin vesicles may ulcerate (severely painful at this stage) and then become crusted.
• Presence of cervical or submandibular lymphadenopathy is possible during the orofacial HSV-1 infection.
• The estimated duration of primary HSV infection has been estimated between 2-20 days after contact with the source of infection.
• Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes (lymphadenopathy).
• Primary HSV infections in adults often presents as pharyngitis similar to that observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely. The symptoms of primary HSV infection generally resolve within two weeks.
• Immunodeficient patients can develop sever and atypical manifestations such as linear erosions in skin creases which has a similar appearance to knife cuts (Knife-Cut Sign).

HSV-1 infection of external ear and adjacent periauricular area in an immunodeficient patient which resembles knife cuts.

• Ocular infection due to HSV-2 can present as acute retinal necrosis syndrome.

Disease Progression And Recurrence

• Transmission of HSV-1 usually occurs via direct contact with skin lesions or body fluids of the involved patient (aerosol and fomite spread are rare). In orofacial infection the virus get inoculated onto oropharynx and conjunctiva or through small cracks in the skin.
• Some occupations such as dentists, hospital, nursery or respiratory care unit personnel are at risk of HSV-1 spread via patient's oral secretion. The aforementioned occupations are also at risk of herpes simplex infection due to hospital outbreaks.
• Outbreaks are also reported in some athletes, such as wrestlers.
• Infants born to infected mothers are also at risk of catching the HSV-1 during the delivery.
• HSV-1 infection can be transmitted through sexual activity especially in men who have sex with men.
• Incubation period of primary infection is very short, approximately 5 days.
• Based on reports, viral shedding last for 60 hours (when measured by PCR) and 48 hours (when measured by culture).
• Once a primary oral HSV-1 infection has resolved, the HSV enters the nerves surrounding the primary lesion, migrates to the cell body of the neuron, and becomes latent in the trigeminal ganglion. In some patients, the virus reactivates to cause recurrent infection; which is more common with HSV-1 than HSV-2 oral infection.
• Even though trigeminal ganglion is the most common location for HSV-1 infection, inferior and superior cervical ganglia could also become infected with this serotype of herpes simplex.
• After initial infection with one type of herpes simplex virus antibody development occurs which prevent another form of infection with the same type. Based on this, a patient with history of orofacial HSV-1 infection is immune against herpetic whitlow, ocular infection or genital herpes simplex caused by HSV-1. Antibody production occurs 6 months after the initial infection with HSV-1.
• Even though infection with HSV-1 will not protect patients from HSV-2 infection, it will decrease the severity of HSV-2 infection.
• Most of the time recurrent episodes of HSV-1 orofacial infection just involves lips and oral mucosa which is called herpes simplex labialis. Rare occasions of reinfections occur inside the mouth (intraoral HSV stomatitis), affecting the gums, alveolar ridge, hard palate, and the back of the tongue. This may be accompanied by herpes labialis.
• It seems that some factors are responsible for recurrent herpes simplex infection due to decreasing the cell mediated immunity (either antigen dependent or no antigen dependent). the following list contains some of these factors:
  • Other viral infections with fever
  • Fatigue
  • Menstural period
  • Stress
  • Local trauma
  • Ultraviolet light
  • Local injury due to high temprature or frostbite
  • Sun exposure
• A study reported a protein named protein VP16 as an involved factor in infection recurrency.
• It has been estimated that patients with HSV-1 orofacial infection could experience recurrent infections 1-6 times in a year. Each episode of orofacial infection is less sever and shorter, compared to previous episodes of orofacial infections.
• Chance of recurrent orofacial involvement has been estimated 0.12 monthly.
• Oral herpes is spread by direct contact with an active sore in an infected person, for instance, by kissing. However, the virus can be transmitted through the skin in the absence of a lesion.
• Oral herpes and cold sores can sometimes be confused with canker sores.
• Healing time has been estimated 10 to 14 days, based on a study done on herpes simplex infections.

Differential diagnosis

Herpes simplex orofacial infection must be differentiated from other diseases causing oral lesions such as leukoplakia and herpes simplex virus infection.

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Diseases predominantly affecting the oral cavity
Oral Candidiasis	Dysphagia or odynophagia White patches on the mouth and tongue	Newborn babies Dentures users Poor controlled diabetes Medication's adverse effect, most commonly due to antibiotics and inhaled corticosteroids (treatment of lung conditions such as asthma or COPD) can result in oral candidiasis. (It may be reduced by regularly rinsing the mouth with water after taking the medication) Patients with poor nutrition, especifically vitamin A, iron and folate deficiencies. Patient with Immunodeficiency (such as AIDS/HIV or chemotherapy treatment). Women undergoing hormonal changes, like pregnancy or those on birth control pills. Organ transplantation patients	Clinical diagnosis Confirmatory tests rarely needed	Localized candidiasis Oral and esophageal candidasis Candida vulvovaginitis Chronic mucocutaneous candidiasis Invasive candidasis Candidaemia Candida endocarditis Candida osteoarticular disease	Oral candidiaisis is a benign self limiting disease unless accompanied by immunosuppression.	Tongue infected with oral candidiasis - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=11717223.jpg
Herpes simplex oral lesions	Fever Sore throat Painful ulcers	Stress Recent URTI Female gender	Physical examination Viral culture Tzanck smear	Orofacial infection Anogenital infection Ocular infection Herpes encephalitis Neonatal herpes Herpetic whitlow Herpes gladiatorum	The symptoms of primary HSV infection generally resolve within two weeks	Oral herpes simplex infection - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=19051042.jpg
Aphthous ulcers	Painful, red spot or bump that develops into an open ulcer	Female gender Between the ages of 10-40 Family history of aphthous ulcers	Physical examination Diagnosis of exclusion	Oral cavity	It is elf-limiting and pain usually decreases in 7 to 10 days, with complete healing in 1 to 3 weeks	By Ebarruda - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=7903358
Squamous cell carcinoma	Non healing ulcer, nodule, indurated plaque or mass May involve skin, lips, inside the mouth, throat or esophagus	Chronic sun or UV exposure Fair skin Elderly age (>45 yrs) Male sex Smoking	Physical exam Biopsy	Oral Cavity Floor of mouth Lateral tongue Throat Esophagus	Malignant Can spread to TMJ Some times associated with leukoplakia	Squamous cell carcinoma - By Luca Pastore, Maria Luisa Fiorella, Raffaele Fiorella, Lorenzo Lo Muzio - http://www.plosmedicine.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.pmed.0050212.g001, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=15252632
Leukoplakia	White leathery spots on the mucous membranes of the tongue and inside of the mouth Lateral borders of tongue	Tobacco use Chronic irritation Immunodeficiency Bloodroot (sanguinaria)	Physical exam Diagnosis of exclusion Biopsy	Vulvar lesions occur independent of oral lesions	Associated with HIV Persistant white spots Benign but can progress to carcinoma after almost 10 years Oral proliferative verrucous leukoplakia is an aggressive subtype with multiple lesions and higher conversion to warts or carcinoma	Leukoplakia - By Aitor III - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9873087
Melanoma	A lesion with ABCD: Asymmetry Border irregularity Color variation Diameter changes (or diameter more than 6 mm) Bleeding from the lesion	UV radiations Genetic predisposition Old age Male gender Family or personal history of melanoma Multiple benign or atypical nevi	Presence of ABCD characteristics Bleeding or ulceration may be related to malignancy Serum LDH may be elevated in case of malignancy Biopsy	Can metastasize All UV radiation or sun exposed areas can be effected independently 1-2 to hundreds of granules	Neural crest cell derivative Development begins with disruption of nevus growth control Progression involves MAPK/ERK pathway N-RAS or BRAF oncogene also involved	Oral melanoma - By Emmanouil K Symvoulakis, Dionysios E Kyrmizakis, Emmanouil I Drivas, Anastassios V Koutsopoulos, Stylianos G Malandrakis, Charalambos E Skoulakis and John G Bizakis - Symvoulakis et al. Head & Face Medicine 2006 2:7 doi:10.1186/1746-160X-2-7 (Open Access), [1], CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=9839811
Fordyce spots	Rice-like granules or spots Small, painless, raised, pale, red or white 1 to 3 mm in diameter	Greasy skin types Some rheumatic disorders Hereditary nonpolyposis colorectal cancer Lower gingiva (gums) Vestibular mucosa	Physical exam Small keratin-filled pseudocysts May be seen on incidental mucosal biopsy Biopsy not done for patients primarily	Oral cavity Vermilion border of the lips Oral mucosa of the upper lip Buccal mucosa in the commissural region often bilaterally Genitals	Benign neoplasms with sebaceous features Visible sebaceous glands No surrounding mucosal change Several adjacent glands may coalesce into a larger cauliflower-like cluster	Fordyce spots - Por Perene - Obra do próprio, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19772899
Burning mouth syndrome	Burning or tingling on the lips, tongue, or entire mouth	Nutritional deficiencies Chronic anxiety or depression Diabetes type 2 Menopause Oral thrush or dry mouth, or damaged nerves transmitting taste Female gender Menopause	Presentation Physical exam	Oral cavity	Pain typically is mild in the morning and builds up over the day Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may be effective
Torus palatinus	Bony growth on midline of the hard palate Nodular mass covered with normal mucosa	Genetic predisposition Autosomal dominant	Physical examination Types: Flat tori Spindle tori Nodular tori Lobular tori	Hard palate	More common in Asian and Inuit populations Twice more common in females Repeated trauma can cause bleeding Surgery may be required in symptomatic patients	Torus palatinus - By Photo taken by dozenist, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=846591
Diseases involving oral cavity and other organ systems
Behcet's disease	Painful mouth sores Acne like skin lesions Headache, fever, poor balance and disorientation Abdominal pain, diarrhea or bleeding Uveitis Joint swelling and joint pain Genital sores wit pain and scaring Aneurysms	Overactive immune system	Physical examination	Mouth Genitals Gastrointestinal tract Eye Joints Skin Vascular system Brain	Outbreaks of exaggerated inflammation Affects smaller blood vessels	Behcet's disease - By Ahmet Altiner MD, Rajni Mandal MD - http://dermatology.cdlib.org/1611/articles/18_2009-10-20/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17863021
Crohn's disease	Chronic, episodic diarrhea or constipation Abdominal pain Vomiting Weight loss or weight gain	Smoking Whites and European Jews Hormonal contraception Diets high in microparticles, sweet, fatty or refined foods Industrialized country	Typical history and symptoms Skip lesions on biopsy Anti-Saccharomyces cerevisiae antibodies (ASCA) Anti-neutrophil cytoplasmic antibody (ANCA)	Eyes Joints Skin	May lead to Obstructions Abscesses Free perforation Hemorrhage
Agranulocytosis	Fever or chills Frequent infections Unusual redness, pain, or swelling around a wound Mouth ulcers Abdominal pain Burning sensation when urinating Sore throat	Medications Cytotoxic chemotherapy Hematologic malignancies Autoimmune disorders	Neutropenia <100 cells per micro liter Eosinopenia Basopenia	Oral cavity Skin GIT Urinary system Conjunctiva	Immunocompromization Types: Drug-induced Malignant Autoimmune
Syphilis	Chancre Regional lymphadenopathy	Multiple sexual partners Illicit drug use Unprotected sex Homosexual men Residence in highly prevalent areas HIV infection Presence of other Sexually transmitted diseases Previous history of Sexually transmitted diseases Intravenous drug use	Dark field microscopy Non treponemal tests like VDRL and RPR test) Treponemal tests, such as FTA-ABS tests, TPPA assay, enzyme immunoassays, and chemiluminescence immunoassays)	Oral cavity Penis Cervix Labia Anal canal Rectum CNS CVS	Primary syphilis Chancre Secondary syphilis Condylomata lata Latent syphilis Asymptomatic Tertiary syphilis Gummas Neurosyphilis	oral syphilis - By CDC/Susan Lindsley - http://phil.cdc.gov/phil_images/20021114/34/PHIL_2385_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2134349
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy Immunodeficiency	History and physical examination Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh equal to 1000 grams Immunocompromised	History and physical examination PCR to detect VZV in skin lesions (such as vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated	Chickenpox - By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=52872565
Measles	Fever Rash Cough Rhinorrhea (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and physical examination PCR for measles-specific IgM antibody PCR for measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles	Koplick spots (Measles) - By CDC - http://phil.cdc.gov/PHIL_Images/20040908/4f54ee8f0e5f49f58aaa30c1bc6413ba/6111_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=824483

Associated Conditions

• Leukemia:
  • Herpes simplex orofacial infection has been reported in 40% of patients with acute leukemia.
• Chronic atopic dermatitis:
  • Chronic atopic dermatitis is associated with a form of herpes simplex infection in the eczematous areas (eczema herpeticum).
  • It seems that atopic dermatitis in this patients further augments the herpes simplex infection spread within the eczematous skin.
• Bell's palsy:
  • Although the explicit cause of bell's palsy is not fully understood, but it could be related to reactivation of HSV-1 infection.
• Human immunodeficiency virus (HIV) infection
  • HSV-1 active infection elevates risk of contracting HIV virus.

Prognosis

• Many patients with herpes simplex infection experience recurrent lesions within the first year after infection.
• Symptoms in recurrent infection can range from minor burning or just an itch to painful facial lesions that may cause debilitation.
• Based on some reports genetical factors may play a role in prognosis of orofacial herpes simplex infection.

Diagnosis

• Orofacial herpes simplex infection is usually diagnosed clinically. Skin and oral involvement usually present as multiple superficial round ulcers on face or mouth with or without acute gingivitis.
• Although most orofacial infections of herpes simplex is due to HSV-1, nevertheless HSV-2 could be also responsible in some cases. Hence differentiating the two serotypes could be necessary in some occasions.
• PCR test which detects herpes simplex antibodies and immunodot glycoprotein G-specific (IgG) test are two specific tests (more than 98%) to differentiate these two different serotypes.
• Beside PCR test there are some other laboratory tests include skin biopsy, virus culture and direct fluorescent anti body (DFA) studies.
• If it is possible tissue culture for diagnosis should be taken from vesicles. Highest measure of herpes simplex virus has been found in the first 24 to 48 hours of vesicles appearance.
• Compared to tissue culture, direct fluorescent antibody testing is capable of detecting 80 % of HSV infections.
• Tzanck test require expert personnel to perform the test. It is reported positive if multinucleated giant cells are seen. Tzanck test could not be used to differente HSV-1 from HSV-2, nevertheless it's sensitivity has been estimated 40-77 % for herpetic gingivostomatitis.

Treatment

Unfortunately, there is no approved treatment to completely eradicate the herpes simplex virus from the body. Nevertheless, antiviral treatments have been successful in lowering the severity and duration of skin lesions. Soft, smooth, and cold foods are helpful in lowering the symptoms severity during meals.

Antiviral drugs

• The available antiviral drugs that can be used for herpes simplex infection include acyclovir, valaciclovir, famciclovir and penciclovir.
• Based on a double-blind, placebo controlled, randomized trial done on patients with recurrent herpes simplex orofacial infection showed efficacy of 5% acyclovir cream containing propylene glycol in reducing the period of vesiculation (P = 0.016), healing time (P = 0.022) and itching duration.
• Another study done on 703 patients with herpes simplex keratitis demonstrated the effectiveness of acyclovir therapy for 12 months in lowering the chance of recurrent herpes simplex orofacial infection, including the ocular infection.
• Data from different studies suggest the use of acyclovir and valaciclovir in herpes labialis. These two medications are also effective in cancer patients who are infected with herpes simplex infection.
• Based on a study done on 701 randomly selected patients, 1500 mg single dose of famciclovir reduce healing period by 2 days, compared to placebo. The following table is a summary of median healing time in 3 different treatments that have been studied.

	Famciclovir - Single dose	Famciclovir - Single day	Placebo
Median Healing Time (days)	4.4	4	6.2

_{There is no significant difference in famciclovir single dose or famciclovir single day treatement, based on the mentioned study.}

• Acyclovir is effective in decreasing the viral shedding period in infected patients (median of 2.5 days when patients recieved acyclovir, compared to 17 days). It also has been reported to be efficient in augmenting pain resolution and healing of the skin lesions.
• In another study total daily dose of 800 mg acyclovir was able to lower the recurrent skin lesions by 53%. Moreover the investigations showed that this dose of acyclovir is related to 71% reduction in tissue culture-positive recurrences, compared to control groups.
• Acyclovir treatment shows less effectiveness in treatment of primary herpetic gingivostomatitis in adults.
• Topical use of acyclovir, docosanol and penciclovir has been reported as an effective treatment in herpes labialis. However their efficacy is less than oral antiviral medications.
• An effective treatment for primary herpetic gingivostomatitis in children is oral suspension of acyclovir. It will shorten the duration of infection significantly, if started within the first 3 days.
• Oral treatment with acyclovir has been related with shorter duration of viral shedding in children which can decrease the chance of transmission. The aforementioned treatment has been effective in lowering the severity of oralfacial lesions and improving eating and drinking difficulties.

Analgesics

• Analgesics such as paracetamol (acetaminophen) or ibuprofen can be used in order to control pain and fever (if present).
• Oral analgesics is recommended in children who are experiencing pain and discomfort.

Topical Anesthetics

• Medications such as lidocaine, prilocaine, tetracaine and benzocaine can be prescribe in order to reduce some symptoms such as pain and itching.
• Topical anesthetics are able to decrease symptoms in children in order to improve eating and drinking difficulties due to oral lesions.

Topical Corticosteroids

• Topical corticosteroids (such as clobetasol 0.05% gel) combined with antiviral medications has been reported to be effective in improving the healing process of skin lesions.

Future or Investigational Therapies

• There have been some investigations of a vaccine to prevent orofacial herpes simplex infection. Attacking messenger RNA (mRNA) of essential HSV-1 genes (such as UL20 gene) is how one of the investigated vaccines works. The aforementioned vaccine has been studied on rabbits and showed lower risk of ocular infection due to HSV-1 in them.
• Another idea which requires more study to be approved suggests a medication (such as antagomir) to force all copies of HSV-1 virus to become active at a same time (from the latent status). Since there would be no latent virus in body, antiviral treatments could be successful in destroying the whole virus population.
• Another possible treatment try to target microRNA in order to prevent viruses from become latent.
• A study done on mice reported the possible effectiveness of phosphonoacetic acid in preventing skin lesion development. Based on this study phosphonoacetic acid prevented viruses from become latent when this ointment has been applied three times a day topically.
• Oral or topical use of a new antiviral agent named 2'-Nor-2'-deoxyguanosine (2'NDG) on mice demonstrated reduced severity in orofacial lesions. Minimum effective dose has been estimated as 0.2 mg/kg per day in one study.

Prevention

• Antiviral treatment lower the risk of symptom development in a seropositive patient by 50%, based on a study.
• A 4 month period of 500mg per day valacyclovir oral intake has been reported to be effective in prevention of recurrent herpes labialis in a double-blind, placebo-controlled study.
• Use of condom is also effective in prevention of HSV-1 infection.
• Combination of antiviral treatment and condom use can reduce the chance of transmission by 75% annually.
• Risk of transmission from mother to infant is between 30% to 60% when mother become infected around delivery. Conversly transmission risk decreases to 3% if mother has recurrent infections.
• Suppressive treatment with acyclovir is safe during pregnancy and has been recommended in last months of pregnancy. In contrast valaciclovir and famciclovir use has not been proved to be safe during pregnancy.