Herpesviruses 1 & 2, Nonoral & Nongenital

Essentials of Diagnosis

• Spectrum of illness from stomatitis and urogenital lesions (see Herpesviruses 1 & 2, Oral & Genital) to facial nerve paralysis (Bell palsy) and encephalitis

• Variable intervals between exposure and clinical disease, since herpes simplex virus (HSV) causes both primary (often subclinical) and reactivation disease

General Considerations

• Risk factors for HSV transmission include

  • Black race

  • Female sex

  • History of sexually transmitted infections

  • An increased number of partners

  • Contact with commercial sex workers

  • Lower socioeconomic status

  • Young age at onset of sexual activity

  • Total duration of sexual activity

• Asymptomatic shedding of either virus is common and may be responsible for transmission

• Asymptomatic HSV-2–infected individuals shed the virus less frequently than those with symptomatic infection

• HSV-2 seropositivity

  • Increases the risk of HIV acquisition (it is threefold higher among persons who are HSV-seropositive than among those who are HSV-2 seronegative)

  • Reactivates more frequently in advanced HIV infection

Symptoms and Signs

Ocular disease

• Uveitis

• Keratitis

  • Usually unilateral and associated with impaired visual acuity

  • Lesions limited to the epithelium usually heal without affecting vision

  • Stromal involvement can cause uveitis, scarring, and eventually blindness

  • Recurrences are frequent

• Blepharitis and keratoconjunctivitis

• Acute retinal necrosis

Neonatal and congenital infection

• Both types 1 and 2 rarely infect the fetus and induce congenital malformations (organomegaly, bleeding, and central nervous system [CNS] abnormalities)

• Maternal infection during the third trimester is associated with the highest risk of neonatal transmission

CNS disease

• Herpes simplex encephalitis

  • Presents with nonspecific symptoms: a flu-like prodrome, followed by headache, fever, behavioral and speech disturbances, and focal or generalized seizures

  • Temporal lobe is often involved

• HSV-1 infection may enhance the development of Alzheimer disease by promoting tau phosphorylation

• Both HSV-1 and HSV-2 are increasingly recognized as a cause of mild, nonspecific neurologic symptoms and are also associated with benign recurrent lymphocytic (Mollaret) meningitis

• Primary HSV-2 infection in women often presents as aseptic meningitis

• Recurrent meningitis from HSV-2 occurs in both younger and older individuals

Disseminated infection

• Occurs in the setting of immunosuppression, or rarely with pregnancy

• Skin lesions are not always present but are a particular complication in patients with atopic eczema (eczema herpeticum) and burns

• Pneumonia can occur in both immunocompetent and immunosuppressed persons

Bell palsy

• HSV-1 infection is a cause of Bell palsy

Esophagitis, urethritis, and proctitis

• HSV-1 can cause

  • Esophagitis in immunocompromised patients

• Urethritis may occur in men

• Proctitis often occurs mainly in men who have sex with men

Erythema multiforme

• HSVs are a leading cause of erythema multiforme minor and of the more severe Stevens-Johnson syndrome/toxic epidermal necrolysis

Other

• Acute liver failure, particularly in pregnant women and immunosuppressed patients

• Lower respiratory tract infection is common in mechanically ventilated patients

• HSV-1 pneumonia

• Perinephric abscess

• Febrile neutropenia

• Chronic urticaria

• Esophagitis and enteritis in systemic lupus erythematosus

• Helicobacter pylori–negative upper gastrointestinal tract ulcers

Laboratory Findings

Ocular disease

• Branching (dendritic) ulcers that stain with fluorescein diagnostic of keratitis; extent of epithelial injury correlates well with PCR positivity

• Uveitis from HSV is often diagnosed clinically, although PCR assays (including a multiplex assay which includes VZV) on anterior chamber aspirated material may assist in making the diagnosis

Encephalitis and recurrent meningitis

• Cerebrospinal fluid pleocytosis is common, with a similar increase in the number of red cells

• HSV DNA PCR of the cerebrospinal fluid is a rapid, sensitive, and specific tool for early diagnosis

• Antibodies to HSV in cerebrospinal fluid

  • Can confirm the diagnosis

  • However, they appear late in the disease course

• Hyponatremia is a predictive marker for encephalitis before lumbar puncture data are available

• MRI scanning is a useful adjunct showing increased signal in the temporal and frontal lobes

• Electroencephalograms (EEGs) may show temporal lobe seizure foci

Esophagitis and proctitis

• Endoscopic biopsy and cultures help diagnose esophagitis

• Rectal swab for PCR or culture, or both, help diagnose proctitis

• Complicated proctitis cases may require biopsy

• Concomitant hepatitis and colitis has been reported

Pneumonia

• CT findings include diffuse or multifocal areas of ground-glass attenuation or consolidative changes or both and are best confirmed using high-resolution CT techniques

• Drugs that inhibit replication of HSV-1 and HSV-2 include trifluridine and vidarabine (both for keratitis), acyclovir and related compounds, foscarnet, and cidofovir (Table 32–1)

Keratitis

• Oral antiviral agents such as valacyclovir or famciclovir are first-line therapies

• Alternatives include topical antiviral agents (ophthalmic trifluridine, vidarabine, acyclovir, and ganciclovir), which are all nearly equivalent in efficacy

• Intravenous acyclovir is used for acute retinal necrosis

• Topical corticosteroids may exacerbate the infection, although systemic corticosteroids may help with selected cases of stromal infection

• Long-term treatment (> 1 year) with acyclovir at a dosage of 800 mg/day orally decreases recurrence rates of keratitis, conjunctivitis or blepharitis

Uveitis

• Oral systemic (not topical) acyclovir, although HSV resistance among HIV-infected patients is reported

Neonatal disease

• Intravenous acyclovir (20 mg/kg every 8 hours for 14–21 days) is effective for the treatment of disseminated lesions

• Counseling with serologic screening should be offered to pregnant mothers

• Maternal antenatal suppressive therapy with acyclovir (typically, 400 mg three times daily) beginning at 36 weeks gestation decreases the

  • Presence of detectable HSV

  • Rates of recurrence at delivery

  • Need for cesarean section

• Cesarean section is recommended when active genital lesions or typical prodromal symptoms are present

Encephalitis and meningitis

• Intravenous acyclovir, 10 mg/kg every 8 hours for 10 days or more, adjusting for kidney dysfunction) should be

  • Started when HSV encephalitis is suspected

  • Stopped only if another diagnosis is established

• Aseptic meningitis may require a course of intravenous acyclovir or valacyclovir

Disseminated disease

• Responds best to parenteral acyclovir when initiated early

Bell palsy

• Prednisolone, 25 mg orally twice daily for 10 days started within 72 h of onset

• Valacyclovir (but not acyclovir), 1 g orally daily for 5 days, plus corticosteroid therapy may be beneficial if started within 7 days of symptom onset

Esophagitis and proctitis

• Either intravenous acyclovir, 5–10 mg/kg every 8 hours, or oral acyclovir, 400 mg five times daily

• Maintenance therapy for AIDS patients is with acyclovir, 400 mg three to five times daily

Erythema multiforme

• Oral acyclovir, 400 mg twice a day for 6 months

• Valacyclovir, 500 mg twice a day, may be effective in cases unresponsive to acyclovir

Prevention

• Counseling

• Use of condom barrier precautions during sexual activity

• Hand-washing, glove-gowning procedures, and patient isolation helps prevent spread to hospital staff and other patients

Prognosis

• Neonatal infection can result in frequent recurrences during the first year of life and can have devastating consequences for the neonate, including death