An introduction to the herpes viruses.

INTRODUCTION

The word herpes evokes an emotional response from almost everyone. Eighty percent of the world's population has serological evidence of the herpes simplex virus type one (HSV-1, generally orolabial herpes), while 20 to 30 percent of the U.S. population is seropositive for the herpes virus type 2 (HSV-2, generally genital herpes). (1)

Add chickenpox, shingles, the immunosuppressant drugs used by cancer and organ-transplant patients, along with the increasing number of immunosuppressed patients who have HIV and AIDS, and it's not hard to understand why we are now seeing a greater incidence of herpes infections.

COURSE OBJECTIVES

Upon completion of this course, the dental professional should be able to:

* Describe the symptoms of an active herpes infection.

* Identify the signs of an active herpes infection.

* Differentiate between herpes type 1, herpes type 2 and varicella infections.

* Discuss how the herpes type 1 and 2 viruses are transmitted.

* Explain how the varicella virus is transmitted.

* Summarize the principal complication of a "shingles" outbreak.

COURSE OUTLINE

I. Introduction

II. Course Objectives

III. Course Outline

IV. Glossary

V. Common Problems

VI. Transmission

VII. Epidemiology

VIII. Pathogenesis

IX. Treatment

X. The Varicella Zoster Virus

XI. Herpes Zoster (Shingles)

XII. Summary

XIII. References

XV. Post-test

COMMON PROBLEMS

The most common problems are with HSV-1, HSV-2 and the varicella zoster virus (VZV), all of which are categorized as "herpes" viruses. The HSV-1, HSV-2 and herpes zoster viruses all belong to the human herpes virus (HHV) family. This family of viruses produces a wide spectrum of skin manifestations. It has been estimated that there are more than 500,000 new cases of genital herpes a year and more than three million cases of primary VZV infections a year in the United States. Recurrent infections with HSV and VZV are common, with the latter occurring with an increased frequency with advancing age.

TRANSMISSION

Most adults acquire HSV-1 in childhood, usually from a kiss by a person unknowingly shedding the herpes virus. Primary infections may be manifest as severe gingivostomatitis. HSV-2 is considered a sexually transmitted disease. After the initial infection, further infections of HSV-1 and HSV-2 are usually self-limited, provoked by fever, viral infection, fatigue, menses and perhaps bright sunlight. HSV-1 and HSV-2 infections can be latent for many years, and then reactivate. These infections occur worldwide, equally in males and females. Lower socioeconomic groups are infected more often, perhaps because of crowded living conditions. Transmission of the HSV virus requires direct contact with bodily fluids containing the virus.

Common infection sites for the HSV-1 virus include the oral and ocular and respiratory mucosa, while HSV-2 generally affects the genitalia; however, the patient's sexual practices can transfer the virus from one site to another. Patients with HIV/AIDS, the elderly and those undergoing chemotherapy for cancer treatment have compromised immune systems. These immunosuppressed patients are more likely to have severe herpes infections, which may disseminate to any part of the body. (2) Direct contact with lesions may spread to any site of the body, including unprotected hands and fingers. This can lead to vesicle development at these sites and is called herpetic whitlow.

EPIDEMIOLOGY

"Fever blisters" and "cold sores" are the most common presentations of HSV-1. Lesions occur on the lips and start as small grouped vesicles on a red base, progressing to ulcerated areas that heal without scarring. Lesions crust-over in four to five days, and heal in about 10 days. Approximately 40 percent of patients infected with HSV-1 experience a recurrence. HSV-2 lesions present in the same manner as HSV-1, but since HSV-2 is usually located in the genital area, it is considered a sexually transmitted disease. In the United States, antibodies to HSV-2 are found in fewer than 1% of children under the age of 15, rise to 20% in adults between 30 and 40, and increase to about 23% in the 60- to 74-year-old age group. Both HSV-1 and HSV-2 can survive briefly on open surfaces, so transmission by fomites (inanimate objects that can transmit infectious material) such as doorknobs and toilet seats is theoretically possible but unlikely.

VZV presents as an itchy or burning area along a dermatome, an area of skin innervated by specific spinal nerves. With the VZV, a thoracic dermatome is usually affected. This follows with a painful vesicular rash that clears in about 10 days. Severe pain, which is known as postherpetic neuralgia, can remain for years, even after the lesions disappear.

PATHOGENESIS

HSV-1 and HSV-2 are selective in the tissue they affect; HSV-2 replicates to a higher level in genital mucosa than does HSV-1. After HSV enters the mucous membranes, abraded skin, or the eyes, the virus enters the epithelial cells and replicates within them. The destruction of the affected cells and inflammation result in the formation of vesicles on a raised red base. The virus then spreads along sensory nerve pathways to ganglion cells (which are groups of nerve-cell bodies that lie outside of the brain), such as the trigeminal ganglion in the cervical spine in orolabial herpes or the sacral ganglion in the lower back with genital herpes. Latent infection is then established; however, the patient may still intermittently shed the virus.

Clinical HSV infection is divided into three categories: the primary first episode, the nonprimary first episode and the recurrence. The primary first episode is the first clinical episode of HSV in a person who has no antibodies to HSV-1 or HSV-2. The primary first episode may be relatively severe, with systemic signs and symptoms such as fever, malaise, lymphadenopathy and lethargy. A nonprimary first episode is defined as the initial clinical infection in a person who has HSV antibodies to the type that is not the cause of the current infection. This type of infection tends to be less severe than a primary first episode. Recurrence of HSV-1 and HSW2 infections is generally shorter and milder than the primary episode. In about one-third of patients, the first clinical episode is the recurrence of an unidentified primary infection. Such patients have sufficient antibodies to weaken the physical outbreak, so symptoms may not be very severe.

Herpes can be diagnosed by exfoliative cytology. Culture of the virus is possible if a viral laboratory is available; however, because patients may have acquired the virus months or even years before the symptoms present, it is usually not possible to identify the source of the infection.

Tingling, burning or stinging at the site of the outbreak, the so-called prodrome, often heralds recurrent orofacial herpes. After 12 to 24 hours, small vesicles occur, and over the next two to three days the vesicles ulcerate and then crust. Regional lymph nodes may be swollen and tender. The lesions are not infectious when the crusts have fallen off. A patient with genital herpes may also report prodromal symptoms such as pain, tingling or itching. Female patients usually complain of malaise, dysuria, dyspareunia and leukorrhea. Examination of the patient may reveal vesicles on the cervix, perianal skin, vulva and vagina. With male patients, vesicles develop on the glans, foreskin and shaft of the penis. Ruptured vesicles appear as shallow, painful ulcers. Inguinal lymphadenopathy may be present.

HSV infections are more active and more severe in immunocompromised patients. Both primary and recurrent infections can be very severe, and one recurrence may not heal completely before the next one erupts. In addition, systemic spread is more likely in the immunocompromised patient. (3)

The herpes simplex virus may also cause keratitis, which is an inflammation of the cornea, or keratocon-junctivitis, which is inflammation of the cornea and conjunctiva. These HSV infections present with acute pain, blurred vision and tearing. Dendritic (branch-like) ulcers, best seen with fluorescein stain under ultraviolet light, are diagnostic of this infection. Herpetic eye infections are the most common cause of corneal blinding in the United States. Urgent ophthalmologic evaluation is needed with all herpetic eye infections.

TREATMENT

Anesthetic mouthwashes, such as viscous lidocaine, can decrease the pain of gingivostomatitis. Acyclovir (Zovirax) is the drug of choice for treating HSV infections. This medication works best if started as early as possible once symptoms present. The dosage of oral Acyclovir is 400 mg three times a day for ten days. (1,4)

For patients with frequent recurrences, suppressive therapy is appropriate. The standard dose of Acyclovir for suppressive therapy is 400 mg twice a day. (1,4) This dosage can be taken for an indefinite period of time, although most clinicians stop the medication after one year and observe the patient. If an outbreak recurs, the medication is represcribed and the patient is rechecked after another year. This regimen prevents outbreaks in the vast majority of patients.

THE VARICELLA ZOSTER VIRUS

The varicella zoster virus is another herpes virus that follows the pattern of the herpes simplex virus, that is, infection, latency and reactivation; however, the primary infection with the VZV is typically a case of childhood chickenpox. Recurrence of the infection is more localized and is known as herpes zoster, more commonly called shingles.

Respiratory droplets as well as direct contact with cutaneous lesions spread varicella. Chickenpox is highly contagious, rapidly spreading in areas of crowding, such as schools and day care centers. By adulthood, more than 90 percent of the population has had chickenpox; reactivation in the form of herpes zoster occurs in 20 percent of these patients.

The medical importance of chickenpox continues to be significant; causing about 100 deaths per year in the U.S. Neurological complications are uncommon but potentially serious. In about one case in 1000, encephalitis, which can be lethal, develops a few days after the appearance of the rash. More rare neurological developments include Guillain-Barre syndrome (a rapidly progressive neuropathy) and Reye's syndrome (a fatty degeneration of the liver and other viscera).

Varicella has an incubation period of 13 to 17 days. After entry into the host, the VZV replicates and spreads via the white blood cells to the skin. Further replication of the virus in the skin results in the characteristic vesicles with a red base. (5)

Chickenpox usually presents as an itchy, vesicular rash, usually preceded by systemic symptoms such as fever, chills and malaise. New vesicles generally stop forming in four to five days, and most have crusted within six to seven days. Patients are noncontagious and allowed to return to school or the workplace once all the lesions have crusted.

The advent of the varicella immunization, as well as many school districts requiring the immunization for school admission should decrease the number of cases, as well as the severity of complications.

HERPES ZOSTER (SHINGLES)

After chickenpox resolves, the virus is thought to remain latent in the dorsal root or cranial ganglion. In 90 percent of herpes zoster (HZ) cases, reactivation is presaged by pain and cutaneous sensitivity along a dermatome (usually thoracic). Three or four days later, the lesions erupt. Over the course of several days, groups of vesicles on a red base develop along the dermatome. The vesicles then become pustular as white blood cells infiltrate to kill the virus. The pain of shingles can be severe. The principal complication of shingles is postherpetic neuralgia (PHN); the pain continues and can increase as time passes, even after the lesions have healed. A pain management specialist may have to be consulted for the treatment of PHN. Acyclovir, 800 mg five times a day for ten days, is the recommended treatment for HZ. (1,4)

Famciclovir, 500 mg three times a day for seven days, or Valacyclovir, 1000 mg three time a day for ten days, are also options. (1,5) Patients with lesions involving the tip of the nose require hospitalization and consultation with an ophthalmologist. Lesions such as these imply that the trigeminal nerve is involved, which may result in corneal lesions.

SUMMARY

The herpes viruses continue to affect patients worldwide. The use of immunosuppressant medications, the AIDS epidemic and crowded living conditions will continue to present a challenge to our health care system.

REFERENCES

(1.) Ohana B, Lipson M, Vered N, et al. Novel approach for specific detection of herpes simplex virus type 1 and 2 antibodies and immunoglobulin G and M antibodies. Clin Diag Lab Immun 2000;7(6):904-908.

(2.) Namvar L, Olofsson S, Bergstrom T, Lindh M. Detection of typinn Herpes Simplex Virus (HSV) in mucocutaneous samples by TeqMan PCR targeting a gB segment homologous for HSV Types 1 and 2. J Clin Microbiol 2005;43(5):2058-2064.

(3.) Robert C. Genital Herpes in Young Adults: Changing Sexual Behaviors, Epidemiology and Management. Herpes 2005;12 (1):10-14.

(4.) Physician's Desk Reference, 58th Ed., 2004. Montvale, NJ: Medical Economics.

(5.) Rosen T, Ablon G. Cutaneous herpes virus infection update: part 2: varicella zoster virus. Consultant 1997;3(9):2443-2455.

GLOSSARY

Chickenpox--Disease with skin lesions, caused by the varicella-zoster virus.

Contagious--Communicable by contact.

Cutaneous--Pertaining to the skin.

Dermatome--Area of skin innervated by specific spinal nerves.

Disseminate--Scatter or distribute over a considerable area.

Dorsal--Pertaining to, on, or situated near the back.

Dyspareunia--Painful coitus experienced by women.

Dysuria--Painful or difficult urination.

Encephalitis--Inflammation of the brain.

Episode--An incident in a series of events.

Epithelial--Layer of cells forming the epidermis of the skin; the surface layer of mucous and serous membrane.

Fluorescein stain--Red crystalline powder used to diagnose foreign bodies or corneal lesions in the eye.

Fomites--Substances that absorb and transmit infectious material.

Ganglion--A mass of nervous tissue composed principally of nerve-cell bodies lying outside the brain or spinal cord.

Gingivostomatitis--A systemic viral disease, accompanied by signs of an acute, generalized infection with distinct clinical lesions involving the mouth and sometimes the oropharynx. Host--The organism from which a parasite obtains its nourishment.

Immunosuppressed--A substance or condition that interferes with normal immune response.

Incubation--Time between infection and the appearance of signs and symptoms.

Infiltrate--To pass into or through a substance or space.

Inguinal--Pertaining to the region of the groin.

Innervate--To stimulate a part of the nerve supply of an organ.

Keratitis--Inflammation of cornea.

Latent--Lying hidden; time during which a disease exists without manifesting itself.

Lesion--Circumscribed area of pathologically altered tissue.

Lethargy/lethargic--Condition of functional torpor or sluggishness; stupor.

Leukorrhea--White or yellowish mucous discharge from the cervical canal or the vagina.

Lymphadenopathy--Disease of the lymph nodes.

Malaise--Discomfort, uneasiness, indisposition, often indicative of infection.

Manifest--Readily perceived; obvious; give evidence of.

Menses--Monthly flow of bloody fluid from the uterine mucous membrane.

Neuralgia--Severe, sharp pain along the course of a nerve.

Ocular--Concerning the eye or vision.

Prodrome--Symptom indicative of an approaching disease.

Pustular--Characterized by elevation of skin filled with lymph or pus.

Recurrences--Return of symptoms after a period of quiescence.

Serological--Pertaining to or the study of serum.

Seropositive--A positive reaction to serological tests.

Shingles--Eruption of acute, inflammatory, herpetic vesicles on the trunk of the body along a peripheral nerve.

Systemic--Pertaining to a whole body rather than to one of its parts.

Trigeminal--Pertaining to the trigeminus or fifth cranial nerve.

Ulcerate--To produce or become affected with an open sore or lesion of the skin or mucous membrane of the body.

Varicella (chickenpox)--An acute, highly contagious viral disease characterized by an eruption that makes its appearance in successive crops, and passes through stages of macules, papules, vesicles, and crusts.

Vesicles/vesicular--Blister-like small elevation on the skin containing serous fluid.

Joe Knight is a family practice Physician Assistant and a medical and science writer in Fresno, California. His medical interests include academic dentistry and sport medicine.

AN INTRODUCTION TO THE HERPES VIRUSES
POST-TEST

Choose the one best answer.

1. Common infection sites for the HSV-1 virus
occur in all of the following except:

a. ocular mucosa.
b. oral mucosa.
c. respiratory mucosa.
d. genitalia.

2. Most adults acquire HSV-1 during

a. childhood
b. adolescence
c. young adulthood
d. late adulthood
e. golden years

3. --of the world's population has
serological evidence of HSV-1.

a. 20%
b. 30%
c. 50%
d. 60%
e. 80%

4. The principal complication of shingles is
--.

a. ocular lesions
b. genital lesions
c. postherpetic neuralgia
d. vesicular rash

5. --of patients infected with HSV-1
experience a recurrence.

a. 15%
b. 30%
c. 40%
d. 60%
e. 80%

6. --have the highest percentage of
antibodies to HSV-2.

a. Children under 12
b. Adolescents
c. Young adults
d. Adults 30-59
e. Adults over 60

7. Transmission of HSV-1 is usually by--.

a. direct contact
b. indirect contact
c. fomites
d. cross-infection
e. secondary infection

8. --usually has a case of childhood
chickenpox as the primary infection.

a. HSV-1
b. HSV-2
c. VZV
d. Keratitis
e. Keratoconjunctivitis

9. By adulthood, more than 90% of the population
has had chickenpox.--have a
recurrence with the form of herpes zoster.

a. 10%
b. 20%
c. 35%
d. 50%
e. 75%

10. HSV-1 and HSV-2 are selective in the tissue
they affect. HSV-1 replicates to a higher level in
genital mucosa than does HSV-2.

a. Both statements are true.
b. Both statements are false.
c. The first statement is true, the second false.
d. The first statement is false, the second true.