Herpes Zoster

Etiology

After reactivation, the virus replicates in neuronal cell bodies, and virions are shed from the cells and are carried down the nerve to the area of skin innervated by that ganglion. In the skin, the virus causes local inflammation and blistering. The pain caused by zoster results from virus-associated inflammation of affected nerves.[5][6][7]

Triggers for herpes zoster include:

• Emotional stress
• Immunosuppressive medications
• Acute or chronic illness
• Re-exposure to the varicella zoster virus
• Presence of a malignant neoplasm

Epidemiology

The incidence of herpes zoster ranges from 1.2 to 3.4 per 1000 persons per year among younger healthy individuals, whereas the incidence is 3.9 to 11.8 per 1000 persons per year among patients older than 65 years. Herpes zoster has no seasonal variation. Recurrences are most common in immunosuppressed individuals.

Pathophysiology

Cutaneous lesions of herpes zoster induce varicella-zoster virus–specific T-cell proliferation, whereas the production of interferon α leads to the resolution of herpes zoster. In immunocompetent patients, specific antibodies (IgG, IgM, and IgA) are produced more rapidly and reach higher titers during reactivation (herpes zoster) than during the primary infection, leading to long-lasting, enhanced, cell-mediated immunity to varicella-zoster virus.

The cutaneous presentation is centripetal and follows a dermatome. In most cases, the lumbar and cervical roots are involved, whereas motor involvement is rare. The infection is contagious to individuals with no prior immunity to the varicella-zoster virus; however, transmission rates are low. The virus can be transmitted either through direct skin contact or by inhaling infected droplets. Furthermore, concurrent herpesvirus infections can also occur. Herpes simplex virus, cytomegalovirus, Epstein-Barr virus, and human herpesviruses have all been identified in patients with shingles.

History and Physical

Zoster characteristically presents with a prodrome of fever, malaise, and excruciating burning pain, followed by the outbreak of vesicles that appear in 1 to 3 crops over 3 to 5 days. Lesions are distributed unilaterally within a single dermatome (see Image. Herpes Zoster). Clinically, lesions start as closely grouped erythematous papules that rapidly become vesicles on an erythematous and edematous base and may occur in continuous or interrupted bands in 1, 2, or more contiguous dermatomes unilaterally (see Image. Herpes Zoster Rash). Commonly involved dermatomes include the thoracic (53%), cervical (20%), trigeminal (15%), and lumbosacral (11%). Herpes zoster can also present with ophthalmic involvement.

The 3 phases of the infection include:

• Preeruptive stage: The preeruptive stage presents with abnormal skin sensations or pain within the affected dermatome. The preeruptive stage occurs at least 48 hours before any obvious lesions appear. At the same time, the individual may experience headaches, general malaise, and photophobia.
• Acute eruptive phase: The acute eruptive phase is marked by the vesicles and the symptoms seen in the preeruptive phase (see Image. Herpes Zoster Vesicles). The lesions initially appear as macules and quickly progress to painful vesicles. The vesicles often rupture, ulcerate, and eventually crust over. Patients are most infectious in this stage until the lesions dry out. Pain is severe during this phase and often unresponsive to traditional pain medications. The phase may last 2 to 4 weeks, but the pain may continue.
• Chronic infection: Chronic infection is characterized by recurrent pain lasting more than 4 weeks. In addition to pain, patients experience paresthesias, shock-like sensations, and dysesthesias. The pain is disabling and may last 12 months or longer.

Herpes zoster has specific presentations when the ear and mouth are involved. For example, shingles oticus is also known as Ramsay Hunt syndrome type 2. This condition results from the virus spreading from the facial nerve to the vestibulocochlear nerve, which innervates the inner ear, causing hearing loss and vertigo (rotational dizziness). Moreover, zoster may occur in the mouth if the maxillary or mandibular division of the trigeminal nerve is affected. Clinically, oral zoster presents with vesicles or erosions occurring over the mucous membrane of the upper jaw (palate and gums of the upper teeth) or the lower jaw (tongue or gums of the lower teeth). Oral involvement may occur alone or in combination with the lesions on the skin over the cutaneous distribution of the same trigeminal branch. Because of the close relationship of blood vessels to nerves, the virus can spread to involve the blood vessels, compromise the blood supply, and cause ischemic necrosis. Complications such as osteonecrosis, tooth loss, periodontitis, pulp calcification, pulp necrosis, periapical lesions, and tooth developmental anomalies can result from oral zoster.

Herpes zoster can also involve the eye and central nervous system. The ophthalmic division of the trigeminal nerve is the most commonly involved branch, causing ophthalmic zoster. The skin of the forehead, upper eyelid, and orbital region may be involved (see Image. Causes of Epiphora). Ophthalmic zoster occurs in approximately 10% to 25% of cases and presents with features of keratitis, uveitis, and optic nerve palsies (see Image. Follicular Conjunctivitis). The Hutchinson eye sign is the presence of vesicles on the tip of the nose or nasal mucosa on the ipsilateral side of herpes zoster ophthalmicus infection, indicating involvement of the nasociliary branch of the ophthalmic division of the trigeminal nerve (see Image. Herpes Zoster Ophthalmicus With Hutchinson Sign). Notably, central nervous system involvement is not uncommon. Because the virus resides in the sensory root ganglia, VZV can affect any part of the brain, causing cranial nerve palsies, muscular weakness, diaphragmatic paralysis, neurogenic bladder, Guillain-Barré syndrome, and myelitis. In severe cases, patients may develop encephalitis.

Disseminated zoster is defined as more than 20 skin lesions developing outside the primarily affected area or dermatomes directly adjacent to it. In addition to the skin, other organs may also be affected, causing hepatitis or encephalitis, making this condition potentially lethal.[8] Zoster sine herpete is a condition characterized by radicular pain along a dermatomal distribution without the presence of an erythematous or vesicular rash.[9] Postherpetic neuralgia is the persistence of pain for 3 months after the onset of herpes zoster. Postherpetic neuralgia is the most common complication seen in older adults with involvement of the ophthalmic division of the trigeminal nerve. Risk factors for postherpetic neuralgia include advanced age, severe prodromal pain, severe pain during an attack, severe rash, and immunosuppression. Finally, varicella may lead to infection in the fetus during pregnancy and complications in the newborn, but chronic infection or reactivation, known as herpes zoster, is not associated with fetal infection.

Evaluation

Herpes zoster is clinically diagnosed based on burning pain, characteristic morphology, and typical distribution. Herpes simplex virus can occasionally produce a rash in a pattern called zosteriform herpes simplex.[10][11][12]

Dermatoscopy of herpes zoster consistently shows the following: 

• An erythematous background, indicating increased vascularity, is the most common finding and is seen in 100% of cases.
• Round, cloudy-white polyglobular structures representing grouped vesicles are observed in 53% to 80% of patients.
• Central brown dots are present in 50% to 80% of cases and likely correlate with the crusted centers of vesicular lesions (see Image. Dermoscopic Vesicles in Herpes Zoster).
• The distinctive halo sign appears due to the contrast between the yellowish or brownish crusted centers of vesicles and the surrounding erythematous background, creating an annular pattern around each element of the rash (see Image. Dermoscopic Halo Sign in Herpes Zoster).

Dermatoscopy plays a significant role in the early diagnosis of herpes zoster, enabling diagnosis approximately 1.62 days earlier than clinical evaluation alone. These dermoscopic features assist clinicians in differentiating herpes zoster from other similar dermatologic conditions and enable earlier initiation of treatment.[13]

 Tests for varicella-zoster virus include the following:

• The Tzanck smear of vesicular fluid shows multinucleated giant cells. The Tzanck smear has lower sensitivity and specificity than direct fluorescent antibody testing or polymerase chain reaction (PCR).
• Varicella-zoster virus–specific IgM antibody in blood is detected during active infection with chickenpox or shingles but not when the virus is dormant.
• Direct fluorescent antibody testing of vesicular fluid or corneal fluid can be done when eye involvement is present.
• PCR testing can be performed on vesicular fluid, corneal lesions, or blood in patients with ocular involvement or disseminated infection.

Molecular biology tests based on in vitro nucleic acid amplification (PCR tests) are currently considered the most reliable. The nested PCR test has high sensitivity but is susceptible to contamination, which can lead to false-positive results. The latest real-time PCR tests are rapid, easy to perform, associated with a lower risk of contamination, and more sensitive than viral cultures.

Treatment / Management

Antiviral therapy hastens lesion resolution, reduces acute pain, and helps prevent postherpetic neuralgia, especially in older adults. The standard therapy for herpes zoster is acyclovir and its prodrug valacyclovir. Acyclovir and valacyclovir are processed to nucleoside analogues that specifically block viral DNA replication in affected cells. Oral bioavailability of acyclovir is 10% to 30%. Approximately 15% is metabolized in the liver, whereas 85% of acyclovir is excreted unchanged by the kidney through glomerular filtration and tubular secretion. Acute crystalline nephropathy is a reversible form of acute kidney injury caused by intratubular precipitation of acyclovir crystals and obstruction; histology may show crystals in the distal tubules with patchy interstitial infiltration, without tubular necrosis.[14](B3)

Mutations in the viral thymidine kinase or DNA polymerase confer acyclovir resistance. For patients with acyclovir-resistant herpes zoster, famciclovir is an alternative. Valganciclovir is a valine ester prodrug of ganciclovir that can be administered orally, and recent findings showed activity against varicella-zoster virus.

Doses:

• Acyclovir: 800 mg, 5 times daily for 5 days
• Valacyclovir: 1 g 3 times daily for 5 days
• Famciclovir: 500 mg 3 times daily for 7 days

In immunocompromised patients, intravenous acyclovir is administered at 10 mg/kg every 8 hours for 7 days. Ideal body weight should be used for patients with obesity. Intravenous infusion is preferred over 1 hour, using a diluted 5% dextrose in water solution or 0.9% sodium chloride, to a final concentration of 7 mg/mL or less at a constant rate to prevent renal damage. Please see StatPearls' companion reference, "Acyclovir," for further information.

Topical antibiotic creams such as mupirocin or framycetin help prevent secondary bacterial infection, and analgesics help relieve pain. Occasionally, severe pain may require an opioid medication. Topical lidocaine and nerve blocks may also reduce pain.[10][15][16] (B3)

Pharmacologically, first-line systemic treatments consist of anticonvulsants such as gabapentin and pregabalin. Pregabalin, in particular, may provide faster pain relief than gabapentin, but both require careful dose titration and monitoring for adverse effects such as sedation and cognitive impairment. Tricyclic antidepressants such as amitriptyline and nortriptyline are also commonly used because of their analgesic properties; nortriptyline tends to be better tolerated. Opioids such as tramadol are considered third-line because of concerns about adverse effects and dependency. These systemic agents often require combination therapy to optimize pain control while minimizing adverse events.[17][18](B2)

Topical therapies include 5% lidocaine and 8% capsaicin patches. Lidocaine patches provide localized pain relief with minimal systemic effects, making them suitable for older adults and patients with comorbidities. Capsaicin patches, derived from chili peppers, desensitize peripheral nociceptors, with higher-concentration patches offering prolonged analgesia after a 30- to 90-min application under medical supervision.

Interventional pain treatment techniques such as the modified Jaipur block (local anesthetics combined with corticosteroids), spinal cord stimulation, and dorsal root entry zone lesioning have gained attention. These techniques are particularly helpful in refractory cases or for patients with severe neuropathic pain. The modified Jaipur block is a local subcutaneous infiltration of 2% lidocaine, 0.5% bupivacaine, and methylprednisolone. The involved dermatomes are identified, scarred areas are avoided, and areas of maximum pain are identified. At these sites, 2 mL is injected subcutaneously, with a maximum of 8-10 injections per sitting. In the original Jaipur block, the corticosteroid traditionally used was dexamethasone.[17] Additionally, nonpharmacological approaches are emerging adjunctive therapies, including frequency-specific microcurrent therapy that reduces burning and stabbing pain in patients with postherpetic neuralgia unresponsive to medications. Transcutaneous electrical nerve stimulation combined with other agents such as methylcobalamin has also demonstrated beneficial effects.(B2)

Prevention remains essential, with herpes zoster vaccination significantly lowering the incidence and severity of both herpes zoster and postherpetic neuralgia in immunocompetent older adults. The recombinant zoster vaccine (Shingrix; GlaxoSmithKline) is a subunit vaccine containing an adjuvant that the Advisory Committee on Immunization Practices recommended for use in adults 50 years or older in 2017. In October 2021, the Advisory Committee on Immunization Practices approved the recombinant zoster vaccine for preventing herpes zoster in adults 19 years or older who are or will be at an increased risk of herpes zoster due to immunodeficiency or immunosuppression caused by known diseases or therapy.[19](A1)

Differential Diagnosis

Cutaneous lesions of herpes zoster should be differentiated from herpes simplex, dermatitis herpetiformis, impetigo, contact dermatitis, candidiasis, drug reactions, and insect bites. Preceding pain without the development of skin lesions in herpes zoster should be differentiated from cholecystitis and biliary colic, renal colic, trigeminal neuralgia, and dental infection. Herpes zoster typically involves only 1 side of the oral cavity, distinguishing it from other oral blistering conditions. In the mouth, herpes zoster initially presents as vesicles that break down quickly, leaving ulcers that heal within 10 to 14 days. The prodromal pain before the rash may be confused with a toothache, leading to unnecessary dental treatment.

The differential diagnosis includes:

• Cellulitis
• Chickenpox
• Cnidaria envenomation
• Contact stomatitis
• Dermatologic manifestations of herpes simplex infection
• Ecthyma
• Erysipelas
• Erysipeloid
• Folliculitis
• Human cowpox infections
• Irritant contact dermatitis
• Insect bites
• Paederus dermatitis [20]
• Lichen striatus
• Mucosal candidiasis

Prognosis

Herpes zoster usually resolves within 10 to 15 days in healthy individuals and has an excellent prognosis in younger patients. However, older adults and immunocompromised individuals face significantly higher risks of complications, including severe pain and potentially life-threatening disseminated infections. The principal morbidity is postherpetic neuralgia, which can persist for months and profoundly affect quality of life. Vaccination with the recombinant zoster vaccine can reduce the incidence and severity of herpes zoster. Ultimately, outcomes are most favorable with early diagnosis and prompt initiation of antiviral therapy.

Complications

Complications include:

• Postherpetic neuralgia
• Bacterial infection
• Ocular complications, including chronic ocular inflammation, vision loss, and debilitating pain
• Ramsay Hunt syndrome
• Meningoencephalitis
• Motor paralysis
• Pneumonitis
• Hepatitis
• Aseptic meningitis
• Peripheral motor neuropathy
• Guillain-Barré syndrome
• Transverse myelitis
• Cardiac arrhythmias
• Urinary retention and hematuria