Lecturer Dr. Heddie O. Sedano, DDS, Dr. Odont

Herpes viruses
Primary infection or primary herpetic gingivostomatitis
Treatment of primary herpetic infection
Recurrent herpetic infection
Treatment of recurrent infection
Differential diagnosis
References

HERPES VIRUSES
The herpes simplex virus is composed of a central chain of DNA which is protected by an inner envelope known as capsid and an outer envelope or capsule. The capsid is formed by protein units or capsomere and the capsule is formed by glycolipids.

Fig. 1 Schematic representation of the Herpes Simplex Virus.

The viruses in the Herpes family are: Herpes simplex 1 (HSV 1), Herpes simplex 2 (HSV 2), Varicela-zoster virus(VZV), Human herpesvirus 6 (HH6), Human herpesvirus 8 (HH8), Epstein Barr virus (EBV) and Cytomegalovirus (CMV). HSV 1 is mostly associated with oral and ophthalmic lesions, HSV2 produces genital disease. Some cases of oral herpetic infection are associated with HSV 2 and some cases of genital herpetic infection are produced by HSV 1. This cross-over is most likely due to oral-genital contact. HSV2 is considered to have oncogenic capabilities as opposed to HSV1 which have been shown not to participate in oncogenesis. VZV, as the name implies, is responsible for Varicella, mostly affecting children, and Herpes Zoster (shingles) in adults. EBV is responsible for some lymphatic neoplasia such as the Burkit's tumor and also produces infectious mononucleosis. HH6 and CMV are lymphotropic, (as well as EBV), but their pathogenic potential is still not well understood. HH8 (Kaposi's sarcoma-associated) has been identified in saliva of HIV infected men with Kaposi sarcoma (KS). This virus also has been identified in tissue samples of the classical, endemic and immuno-suppressed KS. These findings speak in favor of a possible causative or participating role of this virus in the etiology of KS. All of the herpes viruses are ectodermotropic, that is they have the capability of infecting and reproducing in epithelial cells and other cells derived from the ectoderm, including neural cells.

Viruses can not replicate by themselves, that is the reason why they need host cells to utilize their reproductive capability. Viruses are highly species and tissue specific. They infect the host cells by having surface molecules called ligands that are capable of adherence to surface cellular receptors, these receptors are specialized proteins some of which are tropic to viral ligands. The virus has the capability to penetrate intact mucosa but in the skin the viral penetration is through a surface break or wound. Once the virus penetrates the cell's cytoplasm, it is denuded of its capsule and approaching the cellular nucleus it loses its capsid. The viral DNA is then incorporated into the cell's DNA (due to its cell specificity) and when the cell divides it reproduces the viral DNA through the regular mechanism of cell division. As a consequence the host cell generally is damaged and undergoes necrosis. The newly formed virons are freed from the cell and go on to infect other similar cells. Some viruses only infect certain animals or certain plants, i.e. tabacco virus is specific to tabacco, and some other viruses only infect humans. There are some viruses, like the AIDS virus, in which the central core consists of RNA instead of DNA. The RNA is converted to DNA in the infected cell's cytoplasm by a special enzyme (reverse transcriptase).

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PRIMARY INFECTION OR PRIMARY HERPETIC GINGIVOSTOMATITIS (PHG )

Around 90% of the U.S. population is affected with this disease. Ninety-nine percent of affected individuals undergo a sub clinical infection which generally does not have any clinical manifestations. The sub clinical infection in children may be confused with eruption gingivitis. One percent of affected individuals develop the full-blown disease. PHG occurs mostly in children from age six months to puberty.

Fig. 2 PHG in a child, showing markedly hypertrophic and erythematous gingiva. Also note areas of ulceration previously occupied by vesicles on the vermilion of the lower lip.

Cases in adults are also seen. One single virus can not produce disease and in order to achieve a substantial number of viruses intracellular replication take place in a prodromal period which is estimated to last one week, during which the patient does not present any symptomatology. The initial symptoms are a lack of sensation or a tingling sensation in the affected areas which are usually keratinized (masticatory) mucosas.

Fig. 3 Another example of PHG showing large edematous interdental papillae which is one of the salient clinical appearances of this disease.

Vesicles, which are the basic manifestations of the disease, follow the initial sensation. These vesicles are intraepithelial in location, and they eventually coalesce forming bullae which extend to the dermis becoming subepithelial. Vesicles and bullae break, especially in intraoral locations, mostly associated to mastication. Upon opening the vesicles leave painful superficial ulcers.

Fig. 4 This child presented with a systemic temperature of 100 F. Note the areas of ulceration on the vermilion of the lower lip and the hypertrophic edematous gingiva.

The ulcers are seen in any of the oral mucosas and the oropharynx. Occasional crusting over these ulcers, especially on the lip, is also seen in the late stage of the infection. PHG is essentially an ulcerative gingivitis. The gingiva is characterized by marked erythema, especially of the interdental papillae.

Fig. 5 Once again the classical clinical presentation of PHG with markedly swollen interdental papillae and bleeding areas.

There is increased body temperature, regional lymphadenopathy and incapacity to eat properly due to the painful lesions. The primary infection lasts up to two weeks and resolves itself without leaving scars or sequelae. These primary lesions are highly contagious. The saliva of infected patients contains large number of shed virons. The clinical manifestations are more severe in immunocompromised patients especially those with advanced AIDS, leukemia or transplant patients.
After the clinical and/or sub clinical infection subsides the virus goes into latency by reaching the regional ganglion, such as the Gasser ganglion, migrating through the nerve axon. The affected patient then becomes a carrier.

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TREATMENT OF PRIMARY HERPETIC INFECTION

The following prescriptions can be used in patients with primary herpetic infection as local palliative.

Rx: Diphenhydramine HCL (Benadryl elixir) or Promethazene 12.5 mg/5ml 50/50 with Kaopectate (or Malox)
Disp: 8 oz (or 200 ml)
Sig: 1-2 tsp q2h rinse and spit out.

Benylin cough syrup can be used instead of Benadryl, because it has less alcohol.

Rx: Diphenhydramine HCL (Benadryl elixir) or Promethazene 12.5 mg/5ml mixed with Kaopectate and 2% Lidocaine HCL viscous Ratio 1:1:2
Disp: 200 ml
Sig: Rinse with 1 tsp every 3 hours and spit Not more than 8 doses in 24 hours.

• Do not use Lidocaine in children that can not expectorate.
• Lidocaine may prolong the healing of oral ulcers.

SYSTEMIC TREATMENT

Rx: Zovirax (Acyclovir) 200 mg capsules
Disp: 35 capsules
Sig: 1 capsule every 3 hours while awake for 5 to 7 days Not to exceed 5 capsules a day.

Systemic antiviral therapy (Ayclovir) is indicated for the treatment of primary herpetic gingivo-stomatitis or recurrent lesions only in immunocompromised patients.

PREVENTION OF SUPERIMPOSED INFECTION

Rx: Penicilin V tablets
Disp: 30 tablets
Sig: 1 tablet QID for 7 days.

Systemic antibiotics are prescribed to prevent secondary infections in susceptible patients ONLY. Patients allergic to penicillin can be treated with erythromycin. DO NOT USE ANTIBIOTICS ROUTINELY!

Fig. 6 This 22 year-old man presented a severe case of PHG with a secondary superimposed infection. Note the sero-purulent exudate. The photo to the right shows several ulcers on the lower lip mucosa of the same patient.

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RECURRENT HERPETIC INFECTION (Herpes labialis)

Excitants such as: GI upsets, stress, menses, solar radiation, extreme cold or other infections, will reactivate the virus in around 40% of carriers. This reactivation induces migration from the ganglion to the peripheral epithelial cells where the virus replicate. This new viral load will produce recurrent lesions which are generally less severe than the primary ones. The recurrent lesions on the lips go through several clinical stages which are: burning sensation, erythema of the affected area, vesiculation, ulceration and crust formation. Recurrent herpes simplex, also known as recurrent herpes labialis (cold sores), as the name implies, develops on the lips, generally at the junction of the vermilion and the skin. It begins as a burning sensation which last several hours to one day. Erythema is the second stage which is followed by small coalescing vesicles, which are short lived.

Fig. 7 Recurrent herpes simplex (RHS) on the skin neighboring the lower lip in a 12 year-old child. Note the cluster of clear vesicles in an almost linear disposition.

Fig. 8. RHS or herpes labialis manifesting as a large bullae on the vermilion of the lower lip and almost extending to the skin of a 24 year-old woman.

Fig. 9. Upon the rupture of the vesicles ulcers are formed, as in this case on the lower lip of another adult patient.

These vesicles and some bullae rupture, leaving areas of ulceration surrounded by a erythematous halo.

Fig. 10. This 26 year-old man presented an ulcer on the vermilion of the upper lip which extended to the neighboring skin. Note the yellowish pseudo-membrane covering the lesion and the peripheral erythematous halo. This halo is typically seen in dermatologic RHS lesions.

Eventually the ulcer becomes covered by a dark red-brown crust. As a rule these episodes last 10 to 14 days. Recurrences may vary from 1 to several a year. Secondary lesions also heal without scar formation. The oral recurrent lesions generally occur in the lip's vermilion, but lesions may also develop in the attached gingiva and/or hard palate. All these intraoral locations are covered by keratinizing epithelium. The gingival and palatal lesions resemble intraoral burns and are quite painful.

Fig. 11 This large ulcer on the hard palate represents an intraoral lesion of RHS. Other site for the recurrent intraoral lesions is the masticatory portion of the gingiva.

As well as the primary lesions, the recurrent ones are also highly contagious.

Fig. 12 These are RHS lesions which have been secondarily infected. Note pus inside of the vesicles and also areas of ulceration on the vermilion.

Another form of herpes simplex is known a herpetic whitlow (HW) which is generally acquired as a contagious disease. HW mostly affects the fingers of dentists and dental hygienist which had become in contact, unprotected, with primary or recurrent oral lesions in patients with HS.

Fig. 13. These vesicles and bullae were present on the index finger of a Dental Hygienists which accidentally injured herself while working on a patient with PHS. This represents a typical example of herpetic whitlow. Presently the use of gloves avoid such incidents to take place.

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TREATMENT OF RECURRENT INFECTION

The viral load in the recurrent lesions varies with the stage of the disease. During the prodromal period (burning sensation) there are few viruses present but their number increases with the progression of the disease to reach a maximun concentration at the vesicular stage. The number diminishes when the ulcers develop, to disappear when complete healing takes effect. Therefore, the medication for the recurrent lesions is based on the values of the viral load. The antiviral systemic medication should be administered during the burning stage because it is when there are less number of viruses and the medication will arrest the development of the lesion within 5 days. If this medication is given later in the course of the disease, it will not be effective.

LOCAL TREATMENT
Rx: Penciclovir 1% cream (Denavir)
Disp: 1 tube of 2 grams
Sig: Apply over affected area every 2 hours for 4 days

NB: This medication should be started during the prodromal symptoms

Abreva (docosanol 10%)
Use 5x daily applying locally rubbing vigorously
Abreva is a non-prescription medication which comes in 2 grams tube and it is FDA approved.

SYSTEMIC TREATMENT
Rx: Famciclovir (Famvir, Novartis) 500 mg. tablets
Disp: 15 tabs
Sig: 1 tab, 3X daily for 5 days

Rx: Valacyclovir (Valtrex, Glaxo Smith Kline) 1000 mg caplets
Disp: 4 caplets
Sig: take 2 caplets at prodromal and 2 caplts 12 hours later

Zovirax (Acyclovir) capsules can be used in the treatment of recurrent lesions as indicated under treatment of PHG. All these medications should be started at the beginning of the prodromal symptoms. It is recommended that these systemic treatments be used only in immunocompromised patients. Both local and systemic antiviral medications interfere with viral replication through and interaction between thymidinekynase, coded by the virus, which converts the monophosphated acyclovir to triphosphate. Triphosphate inhibits the replication of viral DNA.

These medications reduce the length of the clinical manifestations but do not prevent the development of future recurrences.

PREVENTIVE THERAPY FOR RECURRENT HERPES SIMPLEX

Many sunscreen lotions, for children and adults, can be obtained OTC. These lotions should be applied liberally on the face, especially around the perioral regions, one hour before sun exposure and every hour thereafter.

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DIFFERENTIAL DIAGNOSIS

ERYTHEMA MULTIFORME
Erythema multiforme (EM) is a symptom complex characterized by maculopapular or vesiculobullous eruption of the skin and mucous membranes. EM is a hypersensitivity reaction. Several causes are known to precipitate the condition--e.g., bacterial and viral infections, radiation therapy, and drug intake, but most frequently a herpes simplex infection might precede EM by 1 to 3 weeks.

EM is clinically classified as: (1) EM minor, (2) Chronic EM minor and (3) EM major. The Stevens-Johnson syndrome is considered a markedly acute form of EM major and a condition known as toxic epidermal necrolysis is also thought to be a severe form of EM which, in the majority of cases, eventuates in death. EM minor generally occurs in young adults with a slight predilection for males. The disease has a rapid onset, and lesions may be symmetrically distributed. They are particularly common on the hands, feet, and oral mucosa. A variety of lesions may occur, usually one type predominating in a given attack. Target or iris skin lesions are pathognomonic when present but are frequently absent. Upper respiratory tract infection, fever, malaise, nausea, and arthralgia may occur during the early (prodromal) stages of the disease.
Lesions may be present anywhere on the oral mucosa. Necrotic pseudomembrane formation commonly occurs. Vesiculobullous lesions of the lips and skin rupture and become crusted. The mucous membranes of the penis, vulva, and gastrointestinal tract may be involved.

Oral lesions usually occur after skin involvement, although the sequence may be reversed in some patients. The disease is self-limiting and may last from 1 to several weeks. Recurrences are common.
Chronic EM minor is the less severe form of EM and its clinical manifestations, both systemic and oral are similar to those described for EM minor. EM major represents the acute form of EM, the clinical manifestations are markedly severe. The Stevens-Johnson syndrome is the most severe acute form of EM, patients develop the typical skin and oral lesions with concomitant purulent conjunctivitis, photophobia, and leukopenia.

RECURRENT APHTHOUS STOMATITIS (RAS)

Presently RAS is classified as: aphthous minor, aphthous major and herpetiform ulcers. RAS is also associated to systemic conditions such as the Behçet syndrome, Crohn disease and celiac disease. RAS in any of its form is considered to be of immune origin, most likely an autoimmune reaction.
Aphthous minor (AM) is the most common of the RAS clinical forms and it affects over 20% of the USA population. AM in some patients is precipitated by such agents as trauma, psychologic stress, viruses, bacteria, endocrine dysfunction, and allergy. The ulcer may be single or multiple and it is usually recurrent. These lesions are extremely painful and generally preceded by a burning sensation. Any area of the oral mucosa may be affected especially the gland bearing areas, the gingiva is generally spared. Occasionally,the mucous membranes of the oropharynx may be involved. The initial lesion is an erythematous area that soon becomes an ulcer 2 to 10 mm. in diameter with an area of central necrosis. Later a thin, grayish pseudomembrane forms. The lymph nodes are tender and palpable. The ulcers heal without scarring within 1 to 2 weeks. In severe cases, eating may be impaired. Low-grade fever and malaise also may be present, especially if the aphthae are multiple.

Aphthous major are easily differentiated from herpes simplex lesions because they are very large, crateriform ulcers which last from several weeks to several months and they heal leaving visible scars.

Herpetiform ulcers (HU) are the least frequent form of RAS and they are generally misdiagnosed as herpes simplex because its clinical appearance is very similar to that of PHG. HU is characterized clinically by small shallow ulcers generally developing in the gland bearing mucosas.These episodes may last from several weeks to several months. HU generally affects adults and it is seldom present in adolescent. The differential diagnosis with PHG is based mostly in the duration of these lesions.

REFERENCES

Amir J et al. The Natural History of Primary Herpes Simplex Type 1 Gingivostomatitis in Children. Pediat Dermatol 1999;4:259-63.

Cengizlier R, Uysal G, Guven A, Tulek N. Herpetic finger infection. Cutis. 2002;69:291-2.

Siegel MA. Diagnosis and management of recurrent herpes simplex infections. J Am Dent Assoc. 2002;133:1245-9.

Simmons A. Clinical manifestations and treatment considerations of herpes simplex virus infection. Infect Dis. 2002;186 Suppl 1:S71-7.

Oh TJ, Eber R, Wang HL. Periodontal disease in the child and adolescent. J Clin Periodontol 2002;29:400-10.

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