Infectious Diseases

Herpes Zoster, including varicella and virology

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Varicella - Zoster Virus (VZV)

VZV is an alpha herpes virus that is a double stranded DNA virus.

What is the best treatment?

Localized zoster treatment

The goals of therapy are to increase the healing of skin lesions, decrease shedding of the virus to prevent its spread, and prevent and lessen acute neuritis, as well as reduce post-herpetic neuralgia.

  • Conservative treatment with sterile saline dressings may provide relief of pruritus. Narcotic and non-narcotic analgesics may be required for adequate pain control. Gabapentin and topical lidocaine are also effective in treating the pain of acute neuritis associated with zoster.

  • Standard treatment of immunocompetent patients includes oral acyclovir or its second generation derivatives, valacyclovir and famciclovir. Antiviral treatment of acute zoster decreases time to resolution, acute neuritis and may prevent or decrease the serverity of post-herpetic neuralgia (PHN).

  • Valacyclovir and famciclovir have superior pharmacokinetics and more convenient dosing regimens although they may be more expensive than acyclovir. Acyclovir is administered at 800 mg five times daily for 7-10 days. Valacyclovir is administered at 1 g PO q8hr and famiclovir at 500 mg q8hr for 7 days.

  • Controlled studies have examined antiviral treatment when started within 48-72 hours after symptom onset and treatment should therefore be begun as early as possible. Benefit may still accrue if treatment is started later, however.

  • Foscarnet may be used in the treatment of acyclovir-resistant herpes zoster (usually found in HIV patients). The drug is administered at a dose of 90 mg/kg IV every 12 hours.

Disseminated zoster treatment

Disseminated zoster usually occurs in immunocompromised patients. The goals of treatment encompass the traditional goals for localized zoster but also to prevent dissemination and other systemic complications. Although uncomplicated zoster does not require hospitalization, it is the practice of most specialists to err on the side of caution with immunocompromised patients and those with complicated presentations. The latter include myelitis, ophthalmic involvement, meningoencephalitis and involvement of more than two dermatomes.

  • Acyclovir is administered 10 mg/kg IV three times daily. The duration of therapy is usually 10-14 days, however, therapy may need to be extended until resolution is complete. If there is improvement in the clinical state of the patient, change to an oral regimen may be considered.

Ophthalmic Zoster (zoster ophthalmicus)

Ophthalmic zoster occurs when VZV reactivation involves the ophthalmic branch of the trigeminal nerve. Eye involvement is common and treatment should be instituted promptly and the patient referred for urgent evaluation by an ophthalmologist. Intravenous therapy may be required in severe cases and in the immunosuppressed.

Post herpetic neuralgia (PHN)

The chronic pain that commonly occurs after resolution of lesions, particularly in the elderly and after ophthalmic zoster, is referred to as PHN. PHN can be severe, life-altering and difficult to manage. The most effective preventive strategy is prompt treatment of acute zoster with antivirals. Gabapentin has been shown to be effective in PHN but has the side effects of somnolence, dizziness, and ataxia. A similar medication, pregabalin, can be given at a dose of 100-150 mg every 8-12 hours. Regional nerve blocks can also be used. One can also use opioids for pain control. Lastly, tricyclic anti-depressants can be used; however, adverse effects include dry mouth, constipation, and dizziness.

Side effects

The side effects of antiretrovirals include, but are not limited to, nausea, diarrhea, abdominal pain, headaches, dizziness, and confusion (with toxicity).

Mechanisms of action

Antiretroviral therapy, with nucleoside analogues (acyclovir, valacyclovir, and famciclovir), act as competitive inhibitors and chain terminators of DNA synthesis. They are converted to their active form by a viral thymidine kinase.

Foscarnet, a drug used in acyclovir resistant herpes zoster, works by interfering with the binding of pyrophosphate to viral DNA polymerase and, thus, preventing viral replication. This medication is not dependent on viral thymidine kinase, thereby making it the treatment of choice of acyclovir-resistant patients.

Adjunctive treatments

There has been controversy surrounding the use of glucocorticoids to prevent inflammation associated with herpes zoster. Clinical trials have shown no consistent evidence supporting the use of glucocorticoids routinely in the treatment of herpes zoster. There are a few clinical trials that show a possible decrease in the duration of the active disease state, as well as a decrease in viral shedding and complications. The trials, however, have shown the treatment to be beneficial only with the concurrent use of antiretrovirals and, therefore, is not recommended in routine practice.

Resistance to antiretrovirals/alternative therapy

Resistance to acyclovir occurs mostly in immunocompromised patients. Resistance may be due to mutations in the viral thymidine kinase or DNA polymerase genes. Resistance testing of clinical isolates is not widely available, and, therefore, clinical judgment should be used in determining whether acyclovir or its analogues are the appropriate treatment. The treatment of choice in cases of clinical failure with acyclovir is to treat with foscarnet at a dose of 40 mg/kg every 8 hours.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

  • Zoster increases after age 50 as does risk of post-herpetic neuralgia

  • Immunosuppression increases risk of zoster and complications

  • There are an estimated one million cases in the US annually, and incidence may be increasing

  • Zoster incidence is probably lower with vaccine than with natural infection

  • Zoster is possibly more common in women than men and lower in African Americans

Infection control issues

VZV may be spread to susceptible individuals through direct contact with zoster skin lesions prior to their crusting over and through airborne spread through respiratory secretions. Airborne spread is more likely from zoster patients who are immunosuppressed or who have disseminated zoster.

  • If the patient is immunocompetent with:

- localized herpes zoster, then standard precautions should be followed and lesions should be completely covered.

- disseminated herpes zoster, then standard precautions plus airborne and contact precautions should be followed until lesions are dry and crusted.

  • If the patient is immunocompromised with:

- localized herpes zoster, then standard precautions plus airborne and contact precautions should be followed until disseminated infection is ruled out. Then standard precautions should be followed until lesions are dry and crusted.

- disseminated herpes zoster, then standard precautions plus airborne and contact precautions should be followed until lesions are dry and crusted.

Management of exposure

  • Varicella zoster immune globulin (VariZIG) is recommended for those who cannot receive the vaccine, usually due to immunosuppression, are susceptible and at risk of severe disease

  • Immunocompromised patients without evidence of immunity to varicella, such as:

- children with leukemia or lymphoma who have not been vaccinated

- people on medications that suppress the immune system, such as high-dose systemic steroids or chemotherapeutic agents

- people with cellular immune-deficiencies or other immune system problems

- Newborns whose mothers develop varicella from 5 days before to 2 days after delivery

- Premature babies exposed to varicella or herpes zoster

  • Administer zoster immune globulin as soon as possible and within 10 days of exposure

  • Healthcare personnel without evidence of vaccination

- Should be vaccinated and observed

- They should be removed from patient care for 8-21 days after exposure

  • Fully vaccinated personnel should be monitored daily

  • All personnel who develop varicella should remain away until all lesions are dried and crusted.

Vaccination

Herpes zoster vaccination with Zostavax reduces the risk of zoster by about 50% overall but the efficacy of the vaccine declines significantly with and was less than 18% in those over 80 (and post-herpetic neuralgia by about 70%). It is licensed for age > 50, but recommended for those over 60. It is a live vaccine, consisting of more attenuated virus than the primary varicella vaccine. It is contraindicated in pregnancy and in the immunosuppressed, including those with

  • history of primary or acquired immunodeficiency states

  • leukemia, lymphoma, or other malignant neoplasms affecting bone marrow or lymphatic system

  • AIDS or other clinical manifestations of infection with HIV

  • immunosuppressive therapy

  • active tuberculosis

There is a new vaccine in late stage clinical trials based on a VZV glycoprotein that therefore does not contain live virus. Trials suggest superior efficacy to the current live vaccine in preventing zoster although its efficacy in preventing PHN has not been formally demonstrated. In addition, its efficacy was maintained in those over 70.

What host factors protect against this infection?

Research has shown that T-cell mediated immunity protects an individual from herpes zoster reactivation later in life. The patients most at risk are the elderly, as they have decreased cell mediated immunity, and immunocompromised individuals. Patients on immunosuppressive medications, including, but not limited, to cyclophosphamide, azathioprine, and high dose prednisone are at increased risk.

What are the clinical manifestations of infection with this organism?

  • Prodromal symptoms include headache, fever, malaise, and intense pain.

  • A rash starts out as erythematous plaques and transforms into vesicles and bullae. The rash is usually located in one dermatome unilaterally (i.e., doesn't cross the midline), but it can include multiple adjacent dermatomes. It is most commonly located in the thoracic and lumbar dermatomes but can also be seen in other areas, including the distribution of cranial nerves.

  • Neuritis, which occurs in about 75% of the patients, is a burning, stabbing pain located in the dermatomal region of the associated rash.

  • Zoster sine herpetae occurs when there is a herpes pain syndrome or CNS involvement without obvious rash.

  • Ramsey Hunt syndrome occurs when there is ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal. The syndrome occurs with infection of the geniculate ganglion.

  • Hutchinson's sign is a herpes lesion located on the tip of the nose and is associated with ocular involvement.

What common complications are associated with infection with this pathogen?

  • Acute pain with onset of rash and sub-acute pain about one month after rash

  • Post-herpetic neuralgia- Pain and numbness in the dermatomal pattern after the resolution of the infection, which lasts more than 120 days after appearance of rash; the condition is worse with age and occurs in up to 20% of patients

  • Bacterial skin infections, including cellulitis (2.3%)

  • Ocular involvement, including uveitis

  • Acute retinal necrosis, which is a necrotizing retinitis that leads to retinal detachment, uveitis, scleritis, and ptosis

  • Motor neuropathy, which leads to weakness (0.9%)

  • Aseptic meningitis (0.5%)

  • Zoster oticus with hearing loss

  • Transverse myelitis

  • Encephalitis, which usually occurs in immunocompromised individuals

  • Gullian-Barre syndrome

  • Cranial nerve palsies

  • Stroke (VZV vasculopathy), which is secondary to infection of cerebral arteries and a granulomatous vasculitis

  • Disseminated zoster with visceral involvement of virtually any organ

How should I identify the organism?

There are multiple detection methods for herpes virus. For the most part, diagnosis of herpes zoster is based on clinical symptoms and distribution of dermatomal rash exhibited by the patient. Diagnostic testing may be performed on fluid from the vesicles or from cerebrospinal fluid. A polymerase chain reaction (PCR) test, which has the greatest specificity and sensitivity, confirms the presence of VZV DNA. PCR testing is preferred in almost all situations. The direct immunofluorescent antibody test has a lower sensitivity and specificity of 70-76%. Finally, the viral culture, which was previously used, has a low sensitivity of 20% and takes longer to process, and as such it is rarely used.

How does this organism cause disease?

Younger patients are either infected with varicella virus, causing chickenpox, or vaccinated with the live varicella vaccine. The virus then remains dormant in individuals as long as cell mediated immunity is intact.

VZV remains dormant in the dorsal root ganglion, and zoster occurs once the virus reactivates. The virus then travels down the cell axon to the sensory terminals located near the skin. The rash is created once the virus invades the skin and causes an inflammatory response.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

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