Herpes Simplex Virus

Herpes Simplex Virus Type I (HSV-1) and Herpes Simplex Virus Type 2 (HSV-2) are very common infections. HSV-1 is primarily associated with lesions of the mouth, face, eyes and CNS. HSV-2 is primarily associated with lesions of the anogenital region, although both viruses can infect any area. 

Epidemiology

  • Most adults are infected with HSV and carry latent viruses. The prevalence of HSV-1 infection increases with age, but most children are infected with HSV-1 by the time they are 5 years old. 
  • HSV-2 is primarily sexually transmitted, so it is less common than HSV-1 in children. HSV-2 does, however, get transmitted from mother-to-neonate during pregnancy and the post-partum period. 
  • Neonatal herpes affects approximately 1,500 to 2,000 infants per year in the U.S. Infants are far more likely to be infected if their mother's initial herpes infection occurs during the pregnancy. 
  • HSV-2 is more prevalent sub-Saharan Africa and Central and South America. The prevalence is lower in western and southern Europe than in Northern Europe and North America. The lowest rates of HSV-2 infection are in Asia. 

Pathophysiology

  • All herpes viruses are enveloped, double-stranded DNA viruses. The DNA sequences of HSV-1 and HSV-2 are very similar, but differences in their envelope proteins allow for serologic distinction between the two. 
  • HSV-1 is primarily associated with infections of the mouth, face, eyes and CNS.
  • HSV-2 is primarily associated with infections of the anogenital region, although both viruses can infect any area. 
  • Infection is transmitted through exposure to mucus membranes or skin with active lesions, or through exposure to secretions from an individual with an active infection. The virus is transmitted most easily through saliva, but can also be transmitted through respiratory droplets and from mucosal contact with someone who is shedding virus but has no symptoms. 
  • In the initial infection, the incubation period ranges from 2-12 days. 
  • The active viral shedding period starts during the first week of infection and may last for several weeks.
  • Most patients do not have any symptoms during their first HSV infection. 
  • After the initial infection, the virus remains latent in the sensory ganglia of the autonomic nervous system. Here, the virus replicates without detection by the host's immune system. 
    -HSV-1 tends to reside in the trigeminal ganglion.
    -HSV-2 tends to take up residence in sacral ganglia. 
  • Reactivation can be triggered by stress, sun exposure, fatigue, and menstruation. The virus travels along the ganglion to reactivate in the same location as the initial infection. During subsequent reactivations, symptoms last less long, are often less severe, and shedding only lasts 3-4 days. 

Clinical Presentation

  • HSV-1 typically causes painful lesions around the oral cavity. They are classically described as "grouped vesicles on an erythematous base." The vesicles evolve over the course of 1-3 days, becoming crusted papules and plaques. The lesions may erode into grayish ulcerations. The initial infection can lead to extensive gingivostomatitis (see below). 
  • HSV-2 typically causes painful herpetic lesions around the anogenital area. 
  • Skin lesions may be preceded by a prodrome: burning/paresthesias at the site, lymphadenopathy, fever, malaise, myalgias, HA, and anorexia. 
  • Many initial infections are subclinical and escape the patient's detection. Reactivations tend to be of shorter duration with milder symptoms.

HERPETIC GINGIVOSTOMATITIS

  • Most often caused by HSV-1, herpetic gingivostomatitis presents as multiple herpetic lesions on the palate, tongue and gingivae. A typical prodrome often precedes the infection. Children may present with extensive erythema, drooling, bad breath, and anorexia. The main complication of gingivostomatitis is dehydration because of decreased fluid intake. Patients require pain control and rehydration. 

HERPES LABALIS

  • Herpes labalis is the most common manifestation of a HSV-1 infection. Most initial infections go unnoticed, so reactivation lesions are usually the first lesions reported by patients. The outer vermillion border of the lip is a common site. Secondary bacterial infections with staph or strep can occur, resulting in honey-colored crusting that can easily be confused with impetigo. 

​GENITAL HERPES

  • Genital herpes is usually caused by HSV-2, but reports of genital herpes secondary to HSV-1 infection are increasing.
  • Sexual abuse must always be considered in children who present with possible genital herpes.
  • Complications include urinary retention, psychological issues, and aseptic meningitis. 

​HERPETIC KERATOCONJUNCTIVITIS

  • Most often caused by HSV-1, herpetic keratoconjunctivitis is a common cause of blindness worldwide. Vesicles appear first, followed by erosion or ulceration of the cornea.
  • Patients with suspected HSV-1 require prompt referrals to opthamology, as complications include permanent scarring, secondary bacterial infection, meningoencephalitis, and blindness. Neonates infected with ocular HSV may also have systemic or CNS disease. 

HERPETIC WITLOW

  • Herpetic witlow presents as swelling, erythema, vesicles, and ulcerations of the distal fingers.
  • This infection is common in children who have primary oral or genital herpes infections; they transfer the infections to their fingers  (autoinocculation).
  • Teens and healthcare workers can also contract herpetic witlow via genital contact; the HSV-2 virus is frequently the cause in these cases. 

​HERPES GLADIATORUM

  • Herpes gladiatorum is HSV infection of the skin on the face, ears, neck, or upper extremities.
  • It is common in athletes who participate in contact sports: wrestling, football, boxing, soccer, and rugby.
  • Athletes with herpes lesions must sit out from contact sports until crusts are dry, firm and adherent, and until their culture results are negative. 

​HERPES ENCEPHALITIS AND MENINGITIS

  • HSV encephalitis can result from a primary or reactivated infection. Patients present with nonspecific CNS signs and symptoms: altered mental status, seizures, focal neurological findings, and personality changes.
  • HSV meningitis is characterized by CSF pleocytosis, with lymphocytosis and RBCs. Complications include post-herpetic pain syndromes, Bell's palsy, trigeminal neuralgia, and postinfectious encephalomyelitis. 

​NEONATAL HERPES

  • Neonatal herpes develops in the first 4 weeks after birth. It is most often transmitted during delivery, but can also be transmitted in utero and through post-delivery contact (but not through breast milk). There are three different types of neonatal herpes, and they are categorized by the location of the infection:
  1. Skin, eyes and mouth (SEM): These patients have cutaneous lesions on the scalp, face, mouth, nose, and eyes, acquired from contact with the mother's genital lesions during delivery. 
  2. CNS: Patients may present with seizures, lethargy or changes in tone. 60% of cases of neonatal herpes have CNS involvement. Permanent neurological dysfunction is not uncommon. 
  3. Disseminated infection: Patients may present with DIC, shock, and multi-organ failure (the disease often involves the liver, adrenals and lungs). Mortality rate is 50%. 
  • As neonatal herpes can have devastating consequences, a high level of suspicion is required for neonates with skin lesions. 

​CONGENITAL HSV

  • Congenital HSV refers to a herpes infection that is passed to the neonate prenatally.
  • Many infected fetuses die in utero, but those who survive to term present with vesicular lesions, chorioretinitis, micropthalmia, microcephaly, and abnormal brain scans.
  • Prognosis for these patients is poor; most infants have developmental delay.

​ECZEMA HERPETICUM

  • This HSV infection occurs on skin that has already been disrupted by atopic dermatitis, pemphigus, burn trauma, or dermatologic procedures. The lesions may cover large areas and may also become disseminated. 

​HSV-ASSOCIATED ERYTHEMA MULTIFORME

  • HSV-associated erythema multiforme is a complication of a herpes outbreak that results in erythema multiforme-type skin lesions. 
  • Patients present with diffuse bulls-eye ("targetoid") lesions that involve the palms and soles. The lesions usually appear within 10 days of the herpes outbreak. 
  • This complication usually resolves spontaneously. 

Diagnosis

  • HSV-1 infections are often diagnosed clinically, as it is possible to recognize the typical herpetic lesions around the oral cavity. 
  • The gold standard for diagnosis of a herpes infection is a viral culture. Virus can be cultured by swabbing the base of an unroofed vesicle. Under the microscope, pathologists look for mutli-nucleate giant cells and desquamated epithelial cells with intranuclear inclusions. 
  • The Tzank smear is a fast and inexpensive way to diagnose herpes. Cells are scraped from the base of an unroofed vesicle, stained and evaluated by a pathologist. Of note, the test can confirm the presence of HSV or VZV, but cannot distinguish between the two. 
  • DFA testing, an immunohistochemistry test that utilizes tagged antibodies to viral antigens, can be used to determine the serotype of a HSV infection. This test is fast, cheap and sensitive, so it is often used to confirm a clinically suspected HSV infection and to determine serotype. 
  • HSV PCR can also be can also be used to diagnose HSV. It is especially useful  to detect HSV in the CSF. 
  • Serologic assays that detect HSV antibodies are also available. These assays take longer to complete than other tests, but can be used to diagnose recurrent infections, when there are no fresh lesions to unroof, or when partners of asymptomatic patients are at risk. 

Treatment

  • Treatment of HSV infections is not curative. That said, treatment can reduce the duration of symptoms, decrease symptom severity, prevent complications, and decrease the frequency of recurrence. 
  • Supportive Care: Many patients require hydration and pain control, especially children with extensive stomatitis who resist eating and drinking. 
  • Oral Antivirals: Acyclovir is the first-line oral medication for children. Oral acyclovir is indicated for the treatment of genital infections if it is started within 6 days of disease onset. Acyclovir is recommended for the treatment of recurrent herpes labilais infections if it is started within 2 days of the start of the outbreak, but will only reduce outbreak duration by 1 day. 
  • Chronic Suppressive Therapy with Oral Antivirals: Chronic acyclovir therapy is recommended for patients who have more then six oral, ocular, or genital infections per year. 
  • Parenteral Antiviral Therapy: IV acyclovir is recommended for patients with the potential for severe complications from their infections (including but not limited to neonates with HSV infections, immunocompromised hosts, eczema herpeticum, and HSV encephalitis). As acyclovir carries a risk of nephrotoxicity, it is important to dose by weight and pay close attention to the patient's fluid intake, urine output, and creatinine values. 
  • Topical Antivirals: Topical antivirals are rarely useful in the treatment of HSV infections in the immunocompetent, as they do not reduce duration or severity of the infection. Topical therapy is only recommended for immunocompromised patients, as these ointments may speed healing.
  • Opthalmic preparations are recommended for patients with ocular involvement. 

Prevention

  • Patient education is an important part of the prevention of new HSV infections. Patients need to be educated about the possiblity of viral shedding even when they are asymptomatic. 
  • Key education points include:
    -Many factors can lead to herpes recurrence, including: stress, fatigue, menstruation, sunlight, and trauma. 
    -HSV-2 transmission can be reduced through the use of male and female condoms and abstinence. 
    -Contact sports must be avoided for patients with herpes gladiatorum. 
    -Pregnant women should use condoms or remain abstinent to avoid contracting HSV during their pregnancy. 
  • Neonatal herpes can be prevented by treatment of the mother with acyclovir during the last weeks of pregnancy. Caesarean section delivery is recommended if herpetic lesions are present at the time of birth.
  • Contact precautions are necessary for hospitalized patients with suspected HSV infections. Precautions should include: single room if possible, hand-washing after glove removal, and mandatory gown and glove use. 

References

  1. Catlin EA et al.  A Premature Newborn Boy with Respiratory Distress. New England Journal of Medicine. June 21, 2012. 
  2. Chayavichitsilp P, Buckwalter JV, Krakowski AC, Friedlander SF. Herpes Simplex. Pediatrics in Review. 2009;30:119. 
  3. Corey L and Wald A. Maternal and Neonatal Herpes Simplex Infections. The New England Journal of Medicine. 2009;361:14. 
  4. Kimberlin DW, Baley J and the Committee on Infectious Diseases and Committee on Fetus and Newborn. Guidance on Management of Asymptomatic Neonates Born to Women with Active Genital Herpes Lesions. Pediatrics. 2013;131:e635. 
  5. Shah SS, Aronson PL, Mohamad Z, Lorch SA.  Delayed Acyclovir Therapy and Death Among Neonates with Herpes Simplex Virus Infection. Pediatrics. 2011;128(6):1153.