Treatment
Two decades of carefully controlled trials and clinical experience have made acyclovir the treatment standard for HSV infections, although the prodrug valacyclovir (which is converted to acyclovir) and famciclovir (which is converted to penciclovir) now provide alternative options [see Table 1].1 Either oral acy-clovir (200 mg five times daily) or intravenous acyclovir (5 mg/kg three times daily) for 7 to 10 days is recommended for treatment of primary genital herpes or mucocutaneous herpes (HSV-1 or HSV-2). Alternatively, valacyclovir (500 to 1,000 mg twice daily) or famciclovir (250 mg three times daily) may be used. Short-term (1 to 3 days), high-dose acyclovir or valacy-clovir regimens are promising therapies for both genital and oro-labial recurrent HSV infections.21,22
Suppression of severe and frequently recurring genital herpes can also be accomplished by the administration of oral acyclovir (200 to 400 mg twice daily), oral famciclovir (250 mg twice daily), or oral valacyclovir (500 to 1,000 mg daily) [see Table 2]. Once-daily valacyclovir (500 mg) not only suppresses recurrences of genital herpes but also reduces genital excretion of HSV-2 and transmission to partners.23 Intravenous acyclovir, in a dosage of 10 to 15 mg/kg three times daily for 14 to 21 days, is the treatment of choice for herpes encephalitis. Neonatal HSV infections are treated with intravenous acyclovir in a dosage of 20 mg/kg every 8 hours for 14 to 21 days.
In immunocompromised persons and, in rare instances, in immunocompetent persons, acyclovir-resistant HSV-2 may lead to chronic progressive infections.24 Intravenous foscarnet (40 mg/kg two to three times daily for 2 to 3 weeks) is useful against acyclovir-resistant HSV-2 infection. Topical preparations of fos-carnet, cidofovir, and trifluridine are also under study for acy-clovir-resistant HSV.
Varicella-Zoster Virus
VZV is the causative agent of varicella (chickenpox) and herpes zoster (shingles). Because it is a strongly cell-associated member of the human herpesvirus group, it is difficult to detect or isolate in cell-free specimens. Its host range is largely limited to human cells. As with other herpesviruses, latency and reactivation are characteristic features of VZV.
Epidemiology
Varicella
Varicella is a highly communicable disease of childhood. More than 90% of patients are children younger than 9 years; most adults have antibody to the virus. Infection is spread by respiratory droplets or by direct contact with active lesions. Fomites are not an important mode of transmission. Chickenpox occurs most frequently in the winter and the spring and spreads rapidly to susceptible household members. The incubation period ranges from 11 to 20 days.
Herpes Zoster
Herpes zoster results from the reactivation of VZV infection. Varicella in one patient cannot produce herpes zoster in another; however, persons who are exposed to patients who have herpes zoster can contract varicella. There is no seasonal pattern for herpes zoster. The likelihood of reactivation is related to both age and immune status.28 The incidence of disease in patients older than 60 years is two to three times higher than that in younger persons. The incidence in immunosuppressed patients, particularly those with depressed T cell function (e.g., patients who have lymphomas, leukemias, organ transplants, or AIDS), is as much as 100 times higher than that in immunocompetent hosts.
Herpes zoster occurs more frequently in patients with neoplasms. The risk of developing herpes zoster is 13% to 15% for patients with Hodgkin disease, 7% to 9% for patients with other lymphomas, and 1% to 3% for patients with solid tumors. Approximately 15% to 30% of patients with Hodgkin disease and
Table 1 Drug Treatment for Primary Genital or Mucocutaneous Herpes Infection
|
Drug |
Dose |
Efficacy Rating |
Cost/Mof |
Comment |
|
Acyclovir* |
200 mg p.o. five times a day for 7-10 days or 5 mg/kg I.V. t.i.d. for 7-10 days |
First choice |
Oral, $34.98 |
May be useful in high-dose short-term regimens |
|
Valacyclovir* |
500-1,000 mg p.o., b.i.d. |
Alternative |
$437.94 |
May be used in high-dose (1-2 g), short-term (1-2 day) regimens |
|
Famciclovir* |
250 mg p.o., t.i.d. |
Alternative |
$286.99 |
Used when its dosing of three times a day is preferred to acyclovir’s five times a day |
|
Foscarnet |
40 mg/kg I.V. b.i.d. to t.i.d. for 2-3 wk |
Alternative |
NA |
For chronic acyclovir-resistant HSV-2 infection |
*Short-term, high-dose regimens show promise.
+Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies. HSV-2—herpes simplex virus type 2 NA—not available
herpes zoster exhibit significant dissemination; however, mortality in such patients is low. Localized and disseminated herpes zoster are more common in patients with advanced malignant disease who are receiving intensive chemotherapy or irradiation. The incidence of herpes zoster is also increased after organ or bone marrow transplantation. The incidence of herpes zoster is approximately 8.6% in solid-organ transplant recipients, and it may be more common in women and in patients who are following certain immunosuppressive and prophylactic antiviral regimens.29 In patients with advanced HIV-1 infection, chronic, nonhealing VZV ulcers may persist for several months, and herpes zoster may be precipitated by the introduction of highly active antiretroviral therapy.
Clinical Syndromes
Varicella
After local replication of VZV at the site of virus entry, the virus is carried by blood leukocytes to focal skin areas and visceral organs. Replication at skin sites results in vesicle formation accompanied by degeneration of epithelial cells, accumulation of edema fluid, and infiltration of inflammatory cells; multinucleat-ed giant cells containing intranuclear inclusions are present.
Clinical features Subclinical infections are rare (< 4% of cases). Illness usually presents as a generalized vesicular eruption that is followed by a variable prodrome of headache, fever, and malaise. Vesicles often appear initially on the face or trunk [see Figure 4]. During the next 4 to 7 days, successive crops of lesions appear. Most childhood cases are uncomplicated and resolve in 7 to 10 days without producing scarring.
Complications In adolescents and adults, pneumonia may develop that is characterized by cough, tachypnea, and diffuse reticulonodular infiltrates, which may calcify with time. Pulmonary oxygen diffusion difficulties may persist for a period of weeks to months. Varicella pneumonia may be particularly severe in pregnant women and, among them, is more common in smokers and those with more than 100 skin lesions.30 Although varicella encephalopathies are uncommon, they can occur at any age and can take several forms; the presenting feature may be hyperexcitability, which can progress to coma or cerebellar atax-ia. Other rare complications of varicella infection are Reye syndrome (fulminating encephalopathy and fatty liver), thrombocy-topenia, arthritis, ocular involvement, carditis, gastrointestinal bleeding, nephritis, orchitis, and bacterial superinfection. A pregnant woman who contracts varicella during the first 20 weeks of pregnancy has a small (< 2%) risk of giving birth to an infant with congenital varicella syndrome, which includes limb hypoplasia, skin scarring, and ocular defects.31
Disseminated disease is more likely to develop after varicella infection in children with leukemia, lymphoma, or Hodgkin disease. Visceral dissemination occurs in 20% to 35% of children with cancer who are receiving chemotherapy; mortality in such patients is 7% to 30%. Clinical reinfection, with resultant atypical generalized varicella, can occur in the severely im-munocompromised host; such reinfection tends to be mild and self-limited.
Herpes Zoster
Herpes zoster occurs in patients previously infected with varicella. After an initial episode of varicella infection, the virus persists in neurons of sensory ganglia in a relatively quiescent, ex- trachromosomal, cytoplasmic state.32,33 Both subclinical and clinical reactivations occur. Clinical VZV reactivation is enhanced by many factors, including increasing age, immunosuppression, and local skin injury.
Table 2 Drug Treatment for Suppression of Severe and Frequently Recurring Genital Herpes Infection
|
Drug |
Dose |
Efficacy Rating |
Cost/Mo* |
Comment |
|
Acyclovir |
200-400 mg p.o., b.i.d. |
First choice |
$27.98 |
|
|
Valacyclovir |
500-1,000 mg/day p.o. |
Alternative |
$218.97 |
Has been shown to decrease viral excretion and transmission |
|
Famciclovir |
250 mg p.o., b.i.d. |
Alternative |
$199.98 |
*Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.
Figure 4 The lesions characteristic of varicella-zoster virus infection often appear initially on the face and trunk and may present as maculopapules, vesicles, and scabs simultaneously.
Clinical features Attacks of herpes zoster are often preceded by pain, which may persist for several days before lesions appear. The vesicular eruption is unilateral and most often appears on the thorax [see Figure 5]. Individual attacks are usually limited to one to three dermatomes, although a few isolated skin lesions at sites distant from this area are not uncommon. Vesicles surrounded by an erythematous base may continue to develop for several days; the lesions then dry and crust. Superinfections are common, and scarring can occur.
Complications The most common complication of herpes zoster is postherpetic neuralgia, which may be severe, particularly in the elderly. Postherpetic neuralgia may be refractory to treatment and persist for months to years [see 11:XVI Acute Viral Central Nervous System Diseases]. Other neurologic syndromes associated with herpes zoster are segmental myelitis, Guillain-Barre syndrome, acute retinal necrosis, and Ramsay Hunt syndrome.33 Ramsay Hunt syndrome is an infection of the geniculate ganglion of the seventh cranial nerve, producing facial paralysis; vesicles on the eardrum and side of the tongue can also occur.
VZV encephalitis, another infrequent complication of herpes zoster, may present in two forms.33 Large vessel encephalitis (granulomatous arteritis) occurs predominantly in immunocom-petent persons; it is characterized by acute focal deficits that occur weeks after the appearance of zoster lesions in the contralat-eral trigeminal pattern of distribution. Angiography demonstrates segmental narrowing, primarily in the internal carotid and middle or anterior cerebral arteries. Microscopic examination shows arterial inflammation, multinucleated giant cells, and virus particles. Small vessel encephalitis occurs almost exclusively in immunocompromised persons and is characterized by headache, fever, mental changes, seizures, and focal deficits. Imaging studies show ischemic or hemorrhagic infarcts of gray and white matter, and CSF examination demonstrates mononuclear pleo-cytosis and both VZV DNA and VZV antibody.
Diagnosis
Varicella and herpes zoster can usually be diagnosed solely on clinical grounds. Varicella is sometimes confused with disseminated herpes simplex, impetigo, insect bites, or scabies; on rare occasions, HSV infection presents with zosteriform eruptions. Diagnosis of VZV infection can be confirmed by virus isolation, direct immunofluorescence of lesions, PCR detection of viral DNA, or demonstration of a fourfold rise in antibodies to viral antigens. Herpes zoster provokes a more rapid and greater rise in antibodies than varicella.
Prevention
A live attenuated VZV vaccine is available in the United States and appears both safe and effective. It is recommended for persons older than 1 year who are in good health and have no history of clinical VZV infection. A single subcutaneous dose is recommended for children 1 to 12 years of age, whereas two doses separated by 4 to 8 weeks are recommended for susceptible adolescents and adults. Varicella has declined markedly in surveillance areas secondary to vaccine use.34,35 However, breakthrough infections in vaccinated children suggest that booster doses of vaccine may be necessary to maintain optimal immunity.
Nosocomial transmission of VZV has been reported. Thus, hospitalized patients with varicella or herpes zoster should be isolated to prevent spread of virus to other susceptible persons. Susceptible immunocompromised patients who are exposed to infected persons should receive prophylaxis with varicella-zoster immune globulin (one dose up to 4 days after exposure) to prevent or modify clinical illness. Small studies suggest that high-dose acyclovir (40 to 80 mg/kg for 7 days, beginning 7 to 9 days after exposure) or VZV vaccine (one dose on the day of exposure or up to 3 days after exposure) may also be useful in post-exposure prophylaxis.32
Treatment
Considerable success in the treatment of VZV infections in immunocompromised hosts has been achieved with parenter-al administration of acyclovir (for adults, 10 mg/kg every 8 hours for 7 days). High-dose oral acyclovir (800 mg five times daily for 7 days), when begun early, may also shorten the course and reduce the severity of herpes zoster in otherwise healthy hosts. Oral valacyclovir (1 g three times daily) or fam-ciclovir (500 mg three times daily) may also be used [see Table 3]. The use of corticosteroids in combination with acyclovir for the treatment of acute herpes zoster remains controversial.37,38 Steroid use may be justified in persons older than 50 years who have no relative contraindications, such as diabetes, hypertension, or glaucoma.
Figure 5 Herpes zoster is most often thoracic and dermatomal in distribution. Cutaneous dissemination, as seen in this patient, as well as visceral dissemination, may occur when immunity is severely compromised.
Table 3 Drug Treatment for Varicella-Zoster Virus Infection
|
Drug |
Dose |
Efficacy Rating |
Cost/Mo* |
Comment |
|
Acyclovir |
10 mg/kg I.V. q. 8 hr for 7 days |
First choice |
NA |
For immunocompromised patients |
|
800 mg p.o. five times/day for 7 days |
Alternative |
$89.98 |
May shorten course and reduce severity of herpes zoster and varicella in otherwise healthy patients |
|
|
Valacyclovir |
1 g p.o., t.i.d. |
Alternative |
$542.99 |
May shorten course and reduce severity of herpes zoster and varicella in otherwise healthy patients |
|
Famciclovir |
500 mg p.o., t.i.d. |
Alternative |
$599.97 |
May shorten course and reduce severity of herpes zoster and varicella in otherwise healthy patients |
|
Foscarnet |
40 mg/kg I.V. q. 8 hr |
Alternative |
NA |
For acyclovir-resistant VZV infection in immunocompro-mised patients |
*Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies. NA—not available
Acyclovir resistance has been described in VZV isolates from patients with HIV infection who received long-term acyclovir therapy. Foscarnet (40 mg/kg every 8 hours) is the drug of choice for acyclovir-resistant VZV infections in immunocompro-mised hosts [see Table 3].39 Acyclovir, famciclovir, and valacy-clovir are also effective in reducing the severity and shortening the course of chickenpox in patients who are immunologically competent, although children are generally not treated for uncomplicated varicella.
Postherpetic neuralgia, the most common complication of herpes zoster, is difficult to treat, particularly in elderly patients; suggested treatments include topical anesthetics, oral analgesics, tricyclic antidepressants, gabapentin, and intrathecal methyl-prednisolone acetate.
Cytomegalovirus
Although cytomegalic inclusion disease of infants was recognized as a clinical entity at the turn of the 20th century, the etio-logic agent, CMV, was not isolated until the mid-1950s. CMV has since become recognized as a nearly ubiquitous virus that plays an important role in many diseases, including a form of mononucleosis and disseminated disease in the immunocom-promised host.
Epidemiology and Etiology
CMV has a worldwide distribution. Approximately 1% of newborns in developed countries are infected with CMV, and the incidence is much higher in developing areas. In immuno-compromised patients (e.g., organ or bone marrow transplant recipients and patients with AIDS), CMV infection is a major cause of morbidity and mortality.
Transmission occurs by close contact with infected persons, most commonly by the sharing of secretions or leukocyte-containing blood products. CMV is shed in semen, cervical secretions, saliva, maternal milk, and urine. In late adolescence and adulthood, genital transmission is common. Primary infection in pregnant women may result in transplacental spread to the fetus, sometimes with devastating consequences. Naturally acquired immunity substantially reduces the likelihood of congenital infection, although infection with a different CMV strain can occur and lead to symptomatic infection of the newborn.40,41 Perinatal infection is also common because of spread from maternal milk or other secretions. Communal living and poor personal hygiene facilitate transmission. Spread of CMV in day care centers is common; the infected child often serves as a source of transmission to other family members. Blood transfusions and organ transplantation may also transmit CMV from an asymptomatic donor to a recipient. The proportion of CMV antibody-negative liver transplant recipients receiving organs from CMV antibody-positive donors appears to be increasing.
