Herpes Zoster

INTRODUCTION ˇ@

Background: Herpes zoster was known to the ancient Greeks and Romans, but it was not until 1885 that von Bokey noted the association between varicella zoster virus (VZV) and shingles. VZV is the causative agent of both varicella (chickenpox) and herpes zoster (shingles). Chickenpox is the primary infection, whereas herpes zoster represents reactivation of previous infection.

Chickenpox is a common and generally benign illness of childhood that is characterized by an exanthematous vesicular rash. Approximately 90% of US children are exposed by age 15 years. Following this primary infection, VZV becomes latent in dorsal root ganglia. Generally, a decrease in cellular immunity is believed to trigger the reactivation of the virus.

Herpes zoster presents as a vesicular rash in a dermatomal distribution that usually is associated with pain. After resolution of the acute eruptive phase, patients may develop postherpetic neuralgia, a sometimes incapacitating pain that can last for months.

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Pathophysiology: VZ belongs to the herpes family, which includes the herpes simplex viruses (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes viruses 6 and 7. It is the most infectious of the human herpes viruses.

Once attached to target cells via specific receptors, the capsid penetrates through the cell wall and releases the viral genome. Upon completion of viral double-stranded DNA replication, capsid and membrane synthesis take place. After the primary infection, the virus migrates along sensory nerve fibers and becomes latent in satellite cells of dorsal root ganglia. It remains there for the remainder of the patient's life. Zoster is caused by reactivation of the dormant virus.

Reactivation typically occurs in elderly and immunocompromised patients when cellular immunity is decreased. VZ reappears in neurons and satellite cells and spreads to the skin through peripheral nerves. Skin biopsy specimens during the acute phase of shingles reveal inflammation and partial denervation. Inflammation, hemorrhagic necrosis, and neuronal loss also are observed in dorsal root ganglia.

Inflammation in involved peripheral nerves can persist for months and lead to demyelination, wallerian degeneration, and sclerosis. This can lead to scarring of the dorsal root ganglia, peripheral nerves, and skin. In addition, degenerative and inflammatory changes also can occur in the central nervous system.

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Frequency:
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Mortality/Morbidity: Cutaneous herpes zoster very rarely causes fatality in patients who are immunocompetent but can be life threatening in immunocompromised patients.

Race: No clear predominance exists among any race or ethnic group.

Sex: Although no significant sex predominance has been observed in HZ, women may have increased risk of postherpetic neuralgia.

Age: All ages can be affected, but zoster primarily is a disease of elderly people. Incidence and severity increase with age.

CLINICAL ˇ@

History: The clinical manifestations of herpes zoster can be divided into the pre-eruptive phase (pre-herpetic neuralgia), acute eruptive phase, and chronic phase (postherpetic neuralgia).

Physical: Presentation with a characteristic rash facilitates making the diagnosis of herpes zoster. Other findings can include lymphadenopathy and sensory changes.

Causes:

DIFFERENTIALS ˇ@

Herpes Simplex
Impetigo

Other Problems to be Considered:

Atopic dermatitis
Atypical measles
Poison ivy

WORKUP ˇ@

Lab Studies:
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Imaging Studies:
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Procedures:
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Histologic Findings: During the acute phase, significant inflammation of the skin, dorsal root ganglia, and peripheral nerves is present. Evidence for early denervation of skin tissue, hemorrhagic necrosis, and neuronal loss in dorsal root ganglia is present. Inflammatory changes may persist for months and lead to scarring.

TREATMENT ˇ@

Medical Care: Medical therapy will be discussed in 3 scenarios that include the treatment of acute herpes zoster, prevention of postherpetic neuralgia, and treatment of postherpetic neuralgia.

Surgical Care:

Consultations:

Diet: No specific dietary changes are recommended.

Activity:

MEDICATION ˇ@

The goal of drug therapy is to suppress inflammation, pain, and infection. Multiple drug regimens have been studied for the treatment of acute herpes zoster and the neuropathic pain that persists after the resolution of cutaneous eruptions (postherpetic neuralgia).
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Drug Category: Antivirals -- Reduce pain and time to lesion resolution during the acute phase of shingles and may reduce risk or duration of postherpetic neuralgia.

Drug Name
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Acyclovir (Zovirax) -- Synthetic purine nucleoside analogue with inhibitory activity against HSV types 1 and 2 and VZV.
Adjust dosage in patients with renal insufficiency.
Adult Dose 800 mg 5 times per d PO for 7-10 d
500 mg/m2 IV or 10 mg/kg IV q8h for 7 d
Pediatric Dose Immunocompromised children:
250-600 mg/m2 PO 4-5 times per d PO for 7-10 d
500 mg/m2 IV or 7.5-10.0 mg/kg IV q8h for 7 d
Contraindications Documented hypersensitivity
Interactions Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Exercise caution in renal failure or when using nephrotoxic drugs
Drug Name
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Valacyclovir (Valtrex) -- Prodrug rapidly converted to the active drug acyclovir. More expensive but has a more convenient dosing regimen than acyclovir.
Adult Dose 1000 mg PO tid for 7 d
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Probenecid, zidovudine, or cimetidine coadministration prolongs half-life and increases CNS toxicity of valacyclovir
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Caution in renal failure and coadministration of nephrotoxic drugs; associated with onset of hemolytic uremic syndrome; allogenic bone marrow transplant recipients and renal transplant recipients
Drug Name
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Famciclovir (Famvir) -- After ingestion, drug is rapidly biotransformed into active compound penciclovir and phosphorylated by viral thymidine kinase. By competition with deoxyguanosine triphosphate, penciclovir triphosphate inhibits viral polymerase.
Adjust dose in patients with renal insufficiency or hepatic disease.
Adult Dose 500 mg PO q8h for 7 d
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Coadministration of probenecid and cimetidine may increase toxicity of penciclovir; coadministration increases bioavailability of digoxin
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in renal insufficiency or hepatic disease; not studied in immunocompromised patients or disseminated disease
Drug Name
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Foscarnet (Foscavir) -- Pyrophosphate analogue that is a noncompetitive inhibitor to viral DNA polymerase. Does not require activation by thymidine kinase.
Adjust dosage for patients with renal insufficiency.
Adult Dose Patients with normal creatine clearance:
40 mg/kg IV q8h for 14-28 d as induction
Pediatric Dose Not established; 40 mg/kg IV q8-12h suggested; benefits must outweigh risks
Do not exceed recommended dosage
Contraindications Documented hypersensitivity; creatine clearance <0.4 mL/min/kg
Interactions Avoid use of foscarnet in combination with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) unless potential benefits outweigh risks; coadministration with IV pentamidine may cause hypocalcemia; pentamidine increases hypocalcemia
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause decline in renal function; for correct dosing, obtain 24-h serum creatinine at baseline and continue to monitor (discontinue if serum creatinine is <0.4 mL/min/kg); hydration may reduce nephrotoxicity; carefully monitor electrolytes (eg, calcium, magnesium); assess for electrolyte and mineral level abnormalities if mild perioral numbness, paresthesias symptoms, or seizures occur; granulocytopenia and anemia may occur (regularly monitor CBC); infuse foscarnet solutions into veins with adequate blood flow to avoid local irritation; to avoid toxicity do not administer by rapid or bolus IV injection

Drug Category: Corticosteroids -- Have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. May help reduce pain, but reports are inconclusive.

Drug Name
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Prednisone (Deltasone) -- Decreases inflammation by suppressing neutrophils and reversing increased capillary permeability. Also suppresses immune system.
Adult Dose 10-50 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections
Interactions Coadministration with estrogens may decrease prednisone clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Topical anesthetics -- Decrease pain associated with postherpetic neuralgia.

Drug Name
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Capsaicin (Dolorac, Capsin, Zostrix) -- Derived from plants of the Solanaceae family. May render skin and joints insensitive to pain by depleting substance P in peripheral sensory neurons.
Adult Dose Apply to affected area tid/qid
Pediatric Dose <2 years: Not recommended
>2 years: Administer as in adults
Contraindications Documented hypersensitivity; broken or irritated skin
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions For external use only; avoid contact with eyes, mucous membranes, wounds, or damaged skin; do not use tight bandage; discontinue use if condition worsens or symptoms persist for 14-28 d

Drug Category: Tricyclic antidepressants -- Have been shown to have a role in the treatment of postherpetic neuralgia.

Drug Name
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Amitriptyline (Elavil) -- Blocks reuptake of norepinephrine and serotonin. Decrease pain by inhibiting spinal neurons involved in pain perception.
Adult Dose 10-100 mg PO hs; dose can be titrated slowly up to 300 mg PO hs
Pediatric Dose 0.1 mg/kg PO hs; may be increased slowly to a maximum of 2 mg/kg PO hs
Contraindications Documented hypersensitivity; taking MAOIs in past 14 d; history of seizures; cardiac arrhythmias; glaucoma; urinary retention
Interactions Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine and quinidine) may increase amitriptyline levels; amitriptyline inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy D - Unsafe in pregnancy
Precautions Caution in cardiac conduction disturbances, history of hyperthyroidism, and renal or hepatic impairment; avoid using in elderly patients
Drug Name
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Desipramine (Norpramin) -- Tricyclic antidepressants block reuptake of norepinephrine and serotonin. Decrease pain by inhibiting spinal neurons involved in pain perception.
Adult Dose 75 mg PO qd divided tid/qid initially; gradually increase to a maximum dose of 300 mg qd
Elderly patients: 10-25 mg qd initially
Pediatric Dose 1.5 mg/kg PO qd or in 2-4 equally divided doses
Contraindications Documented hypersensitivity; narrow-angle glaucoma; recent postmyocardial infarction; patients currently receiving MAOIs or fluoxetine patient who have taken them in the previous 2 wks
Interactions Increases effect of sympathomimetics and benzodiazepines; decreases effect of clonidine, phenytoin, carbamazepine, and barbiturates; increases toxicity of anticholinergics, MAOIs, cimetidine, CNS depressants, and alcohol
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement therapy
FOLLOW-UP ˇ@

Further Inpatient Care:
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Patient Education:
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MISCELLANEOUS ˇ@

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BIBLIOGRAPHY ˇ@