Definition, Etiology, Pathogenesis Top
Herpes zoster (shingles) is a viral infection caused by the local reactivation of a latent varicella-zoster virus (VZV) after a prior primary infection. Herpes zoster is associated with characteristic cutaneous signs and symptoms.
1. Etiologic agent: VZV (see Varicella); the virus remains latent in the cells of dorsal root ganglia and cranial nerve ganglia following the primary VZV infection, and may reactivate under certain conditions (eg, in immunocompromised patients, with advanced age).
2. Reservoir and transmission: see Varicella.
3. Risk factors: Age >50 years (particularly >80 years), malignancy, immunosuppressive treatment including glucocorticoid use, HIV infection, and other factors leading to a significant impairment of cell-mediated immune response.
4. Incubation and contagious period: see Varicella; patients with herpes zoster are significantly less contagious than patients with varicella. Susceptible individuals who have a history of exposure to vesicular zoster lesions on uncovered areas of the skin are at risk for developing varicella.
Clinical Features Top
1. Prodromal phase (observed in 70%-80% of cases): Pain within a single dermatome, which may be constant or intermittent, frequent or sporadic, burning, piercing, pulsating, sometimes triggered mostly by touch. The clinical presentation may be dominated by pruritus, a tingling sensation, or other paresthesias. The pain occurs throughout the day and night. It usually precedes skin eruptions by 3 to 4 days and may persist for a week or longer after the lesions have resolved. Other symptoms may include low-grade or high-grade fever, malaise, and headache.
2. Rash: Polymorphic eruptions most commonly limited to 1 or 2 adjacent dermatomes (localized zoster), commonly appearing on the trunk along a thoracic dermatome (see below); usually, the rash does not cross the body’s midline. The rash evolves from erythematous macular lesions (transient and easy to overlook) to clustered papules. Over 1 to 2 days the papules turn into vesicles filled with a clear or turbid fluid, and then into pustules. After 4 to 5 days the vesicles rupture, leaving painful erosions and ulcerations, which crust in 7 to 10 days. Successive crops of lesions continue to appear over ~7 days. The crusts fall off within 3 to 4 weeks, frequently leaving scars and areas of hypo- and hyperpigmentation. Mucosal lesions (erosions and minor ulcerations) may also be observed. In the course of typical zoster, clustered lesions appear within the area innervated by 1 sensory nerve branch (a dermatome), unilaterally, most frequently on the trunk (dermatomes Th3 to L3) or on the head within the areas innervated by cranial nerves: V (in particular the first branch: V1), VII, and VIII. Involvement of the extremities is less frequent. The rash is accompanied by pain and pruritus (similar to the prodromal phase) as well as general symptoms (observed in <20% of patients): fever, headache, malaise, and fatigue.
3. Other manifestations: Paresis (in 5%-15% of patients), most frequently affecting the extremities as a result of motor nerve involvement. Paresis may manifest as Bell palsy (due to the involvement of the cranial nerve VII [peripheral facial nerve paresis]) or Ramsay Hunt syndrome (involvement of the geniculate ganglion and cranial nerve VII, which results in unilateral peripheral facial nerve paresis and auricular herpes zoster; it may be accompanied by disturbances of taste and of secretion of tears and saliva).
4. Distinct clinical presentations of herpes zoster:
1) Herpes zoster ophthalmicus: Eruptions are located along the trigeminal nerve (particularly V1), involving the skin of the forehead and eyelids as well as conjunctiva and cornea. The course may be severe and may lead to the development of corneal ulcerations. Untreated herpes zoster ophthalmicus may result in vision impairment (or even blindness) and ocular motor nerve paralysis.
2) Herpes zoster oticus: Lesions form along the peripheral nerves of the geniculate ganglion, involving the skin of the auricle and retroauricular area, external auditory canal, and tympanic membrane. The eruptions are accompanied by severe otalgia, tinnitus, impaired hearing, and vertigo (due to the involvement of cranial nerve VIII); this may also be accompanied by peripheral paralysis of cranial nerve VII (Ramsay Hunt syndrome).
3) Disseminated herpes zoster develops most commonly in patients who are immunocompromised (eg, as a result of hematologic or solid organ malignancy, or due to immunosuppressive medications). The rash involves 3 or more dermatomes and may even involve the entire body; it is similar to the course of varicella but painful. Patients may develop pneumonia, hepatitis, and encephalitis.
4) Recurrent herpes zoster (in ≤5% of patients) may indicate a malignancy or impaired cell-mediated immune response.
In typical cases herpes zoster is diagnosed in patients with a history of varicella and a typical clinical presentation.
Diagnostic tests are recommended in immunocompromised patients as well as in atypical or equivocal cases.
1. Prodromal pain (particularly if persistent): Other possible causes of pain affecting the same area.
2. Skin lesions: Herpes simplex (herpes simplex virus [HSV] infection), contact dermatitis, toxic dermatitis, and skin lesions resulting from multiple insect bites.
3. Disseminated herpes zoster: Varicella, disseminated HSV infection, allergic rash, papular urticaria, acne vulgaris.
4. Herpes zoster ophthalmicus: HSV infection, erysipelas.
1. In immunocompetent patients ≥50 years of age, patients with moderate or severe pain, or patients with skin eruptions that are of at least moderate severity or extend beyond the trunk, use oral acyclovir (INN aciclovir) 800 mg 5 times a day for 7 to 10 days, or oral valacyclovir (INN valaciclovir) 1000 mg every 8 hours for 7 days. Start treatment as soon as possible after the onset of rash (optimally within 24 hours).Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). For older adults: High Quality of Evidence (high confidence that we know true effects of intervention). For patients aged <50 years: Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to extrapolations of data (indirectness). Jackson JL, Gibbons R, Meyer G, Inouye L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia. A meta-analysis. Arch Intern Med. 1997 Apr 28;157(8):909-12. PubMed PMID: 9129551. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med. 1995 Jul 15;123(2):89-96. PubMed PMID: 7778840.
2. In immunocompromised patients, organ transplant recipients, patients with malignancy, or with disseminated herpes zoster, use IV acyclovir 10 mg/kg (500 mg/m2 body surface area) every 8 hours (guidance for IV administration of acyclovir: see Varicella). In patients whose condition improves (no new lesions, resolution of symptoms including pain), oral acyclovir may be continued until the improvement of immune function.
1. Treatment of pain:
1) In patients with mild or moderate pain, use acetaminophen (INN paracetamol) or nonsteroidal anti-inflammatory drugs; adding a weak opioid (eg, tramadol) may be also considered.
2) In patients with severe pain, consider a strong opioid (eg, fentanyl or transdermal buprenorphine). If this is not effective, consider adding one of the following: oral gabapentin (start from 300 mg at bedtime and titrate up to tid administration, up to a maximum of 3600 mg/d) or oral pregabalin (start from 75 mg at bedtime and titrate up to bid administration, up to a maximum of 600 mg/d); oral amitriptyline (start from 10 mg at bedtime and titrate up to a maximum of 150 mg/d); a glucocorticoid (only in combination with antiviral treatment; eg, oral prednisone 30 mg bid on days 1 to 7 followed by 15 mg bid on days 8 to 14 and then by 7.5 mg bid on days 15 to 21).
2. Topical agents (antiviral agents, antibiotics, and analgesics) in a form of powders or pastes are not recommended.
Complications are more frequent in patients with impaired cell-mediated immune response.
1. Local complications:
1) Postherpetic neuralgia (occurs in 20%-50% of patients, more frequently in the elderly): Pain persisting for >30 days from the onset of the infection or recurring after approximately 4 weeks; it may persist for months or even years. Postherpetic neuralgia is a common complication of herpes zoster ophthalmicus; this can be a disabling complication because of the severity of pain. Treatment of pain: see Symptomatic Treatment, above.
2) Postherpetic pruritus may persist for several months after the skin lesions have resolved; it is sometimes accompanied by neuralgia. Postherpetic pruritus is a neuropathic phenomenon.
3) Scarring, hyperpigmentation or hypopigmentation of the skin.
4) Complications of herpes zoster ophthalmicus include conjunctivitis, keratitis, uveitis, optic neuritis.
5) Bacterial superinfection of lesions due to Staphylococcus aureus or group A streptococcus.
2. Neurologic complications:
1) Aseptic meningitis: Characterized by a mild course; resolves spontaneously within 1 to 2 weeks. Asymptomatic cerebrospinal fluid abnormalities typical for aseptic meningitis are observed in as many as one-third of immunocompetent patients with herpes zoster.
2) Acute encephalitis (rare): Usually develops a few days after the onset of rash (less frequently, a few weeks before or after). Risk factors: immunocompromised patients, involvement of dermatomes innervated by cranial nerves, and disseminated herpes zoster. The risk of death is up to 25%, depending on the immune status.
3) Chronic encephalitis: Affects almost exclusively patients with impaired cell-mediated immune response, particularly with AIDS. Chronic encephalitis develops a few months after recovering from herpes zoster (in 30%-40% of patients, no prior skin manifestations are seen). The prognosis is poor, as the disease is progressive and fatal.
4) Stroke: A rare complication of herpes zoster ophthalmicus, which results from segmental inflammation, stenosis, or thrombosis of the proximal branch of the middle or anterior cerebral artery; it may also affect immunocompetent individuals, typically occurring ~7 weeks (sometimes up to 6 months) after herpes zoster. The mortality rates are 20% to 25%; permanent neurologic sequelae are seen.
5) Myelitis: A rare complication that develops predominantly in patients with impaired cell-mediated immune response (particularly with AIDS). Myelitis is usually a complication of herpes zoster affecting the thoracic dermatomes, but it may also occur in patients without prior skin manifestations. Signs and symptoms: motor paresis (in the case of involvement of the pyramidal tracts) of the segment affected by skin lesions and/or hypoesthesia of the dermatomes below the affected one (involvement of the sensory tracts). The symptoms appear ~12 days after the onset of rash. Severe forms of myelitis: hemisection of the spinal cord (Brown-Séquard syndrome) or complete transverse spinal cord injury. The prognosis is variable.
6) Retinitis: Acute retinal necrosis in immunocompetent patients; in patients with AIDS: retinitis, progressive outer retinal necrosis, or rapidly progressive herpetic retinal necrosis. Retinitis usually develops simultaneously or a few weeks or months after the onset of rash. The disease may progress to involve both eyes. Ophthalmoscopic examination reveals granular yellowish ischemic patches that are expanding and coalescent; retinal detachment may eventually develop. The rapid progression of the disease leads to confluent necrosis and blindness (in 75%-85% of patients).
7) Facial nerve palsy.
3. Disseminated herpes zoster, viremia, cutaneous dissemination: These are usually observed in patients with severe impairment of cell-mediated immune response; high risk of death in patients with visceral dissemination.
Prognosis is good in immunocompetent patients, although postherpetic neuralgia may persist for months. Immunocompromised patients and patients with complications of herpes zoster are at risk for permanent sequelae and death, depending on the course of the disease (see Complications, above).
1) Varicella vaccine is the key prevention method (see Vaccines: Varicella Zoster (Chickenpox and Shingles)).
2) Herpes zoster vaccine is indicated in persons >50 years of age.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Tricco AC, Zarin W, Cardoso R, et al. Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: systematic review and network meta-analysis. BMJ. 2018 Oct 25;363:k4029. doi: 10.1136/bmj.k4029. PubMed PMID: 30361202; PubMed Central PMCID: PMC6201212.
1. Isolation of patients (particularly from high-risk individuals): Immunocompromised patients as well as immunocompetent patients with disseminated herpes zoster should be isolated for the entire duration of the disease. Immunocompetent patients with localized herpes zoster should be isolated until all lesions have dried and crusted.
2. Covering the affected areas of the skin (eg, with clothing) reduces the risk of VZV infection in persons who have direct contact with a sick individual.