Approach Considerations
Episodes of herpes zoster (shingles) are generally self-limited and resolve without intervention; they tend to be more benign and mild in children than in adults. An enormous number and variety of therapeutic approaches have been proposed over the years, most of which are probably ineffective. [79] Some effective therapies do exist, however, and these can reduce the extent and duration of symptoms, and possibly the risk of chronic sequelae (eg, postherpetic neuralgia [PHN]) as well.
Therapeutic choices generally depend on the host’s immune state and on the presentation of zoster. Conservative therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs); wet dressings with 5% aluminum acetate (Burow solution), applied for 30-60 minutes 4-6 times daily; and lotions (such as calamine).
Treatment is of greatest benefit in those patient populations at risk for prolonged or severe symptoms, specifically, immunocompromised people and persons older than 50 years. The benefit of treating younger and healthier populations is unclear.
Uncomplicated zoster does not require inpatient care. Hospital admission should be considered for patients with any of the following:
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Severe symptoms
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Immunosuppression
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Atypical presentations (eg, myelitis)
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Involvement of more than 2 dermatomes
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Significant facial bacterial superinfection
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Disseminated herpes zoster
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Ophthalmic involvement
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Meningoencephalopathic involvement
Patients with disseminated disease or severe immunosuppression or who are unresponsive to therapy should be transferred to a higher level of care. If consultation is required but not available at the initial facility, patients should be transferred to a tertiary care medical center.
Medications used include steroids, analgesics, anticonvulsants, and antiviral agents. Surgical care is not generally indicated, though it may be required to treat certain complications (eg, necrotizing fasciitis). Rhizotomy (surgical separation of pain fibers) may be considered in cases of extreme, intractable pain.
Varicella-zoster virus (VZV) vaccine is used for preventive purposes. Varicella-zoster immune globulin (VZIG) is used to prevent or modify clinical illness in susceptible persons who are exposed to varicella or zoster.
Topical Treatments
There are a variety of topic treatments, including topical acyclovir 5% cream, lidocaine, and capsaicin. [80, 81] The latter, applied at least 5 times a day, depletes neurotransmitters at involved nerve endings. Topical lidocaine can also be used to treat patients with PHN. [82] For acute HZO, a good approach is wet-to-dry dressings with sterile saline solution or Burow solution (a pharmacologic preparation made of 5% aluminum acetate dissolved in water), which should be applied to the affected skin for 30-60 minutes 4-6 times daily. A modified form of Burow solution is commercially sold as Domeboro powder packets, which need to be dissolved in water. The acyclovir cream is often applied 5 times a day for 4 days. Calamine lotion, a mixture of zinc oxide with about 0.5% iron (III) oxide, may be used as an antipruritic agent. It is also used as a mild antiseptic to prevent infections that can be caused by scratching the affected area, as well as an astringent for weeping or oozing blisters. There is, however, no proof that calamine lotion has any real therapeutic effect on rashes and itching. Topical ozone therapy may be beneficial in diminishing pain and shortening the course, with few if any adverse effects. [83]
Pharmacologic Therapy for Herpes Zoster
The goals of therapy are as follows:
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To shorten the clinical course
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To provide analgesia
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To prevent complications
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To decrease the incidence of PHN
Corticosteroids
Whether steroids are essential or even helpful for zoster remains subject to debate. Many practitioners have long used oral prednisone and similar medications to reduce acute pain. [84] Some have also hoped to decrease the incidence of PHN, presumably by reducing inflammation in dorsal root ganglia and involved sensory nerves. Whereas some studies have provided evidence that the early use of steroids may decrease the incidence of PHN, others have failed to show benefit. Additional study is needed.
A substantial dose (40-60 mg every morning) typically is administered as early as possible in the course of the disease and is continued for 1 week, followed by a rapid taper over 1-2 weeks. Dissemination of viral particles beyond dermatomal limits always has been a theoretical concern, but clinically, it almost never is observed in individuals with intact immune systems. Typical risks inherent in the use of systemic steroids, such as adrenocortical suppression and femoral osteonecrosis, must be kept in mind.
Two controlled studies evaluated the addition of oral corticosteroids to acyclovir therapy. [85, 86] In comparison with antiviral agents alone, the combined regimen was were found to accelerate the resolution of acute neuritis and to yield a clear improvement in quality-of-life measures. The use of oral steroids had no effect on the development or duration of PHN.
A study involving a single epidural injection of steroids and local anesthetics given in conjunction with a standard regimen of oral antivirals and analgesics was found to yield a modest improvement in zoster-associated pain for 1 month as compared with treatment without steroids. [87] No effect in preventing PHN was noted.
In view of the potential adverse effects of and contraindications to corticosteroid use, it has been suggested that these agents should be limited to cases of moderate to severe zoster pain or cases in which significant neurologic symptoms (eg, facial paralysis) or central nervous system (CNS) involvement is present and the use of corticosteroids is not otherwise contraindicated. [1]
The optimal duration of steroid therapy is not known. It seems reasonable that if such therapy is prescribed, it should be administered concurrently with antiviral therapy. The duration of steroid use should not extend beyond the period of antiviral therapy. Steroids should not be given alone (without antiviral therapy).
Agents for pain control
The majority of patients with acute herpes zoster experience pain, and this pain is usually the most debilitating symptom of the disease. Accordingly, efforts should be made to reduce patients’ pain and suffering, even if opioid therapy is required. Failure to do so is problematic, especially in view of emerging evidence that providing adequate pain control on an acute basis may reduce the incidence of PHN.
Primary medications for acute zoster-associated pain include the following:
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Narcotic and nonnarcotic analgesics (both systemic and topical)
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Neuroactive agents (eg, tricyclic antidepressants [TCAs])
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Anticonvulsant agents
The efficacy of these treatments for general neuropathic pain has been well established, but only a few of them have been evaluated specifically for acute zoster-associated pain in controlled studies.
The oral narcotic oxycodone and the oral anticonvulsant gabapentin, as well as the topical analgesics aspirin and lidocaine, proved capable of reducing acute zoster-associated pain in double-blind, placebo-controlled studies. [88, 89, 7, 90, 91] On the other hand, the oral anticonvulsant pregabalin had no statistically significant effect in relieving acute zoster pain in a small double-blind, placebo-controlled study. However, other controlled studies showed this medication to be effective in treating the pain of PHN. [92]
Corticosteroids (see above) and antiviral agents (see below) have also been shown to accelerate the resolution of zoster-associated pain. [42, 1, 93, 94, 95, 96, 85, 97]
Nonpharmacologic therapies that may be considered for acute zoster-associated pain include sympathetic, intrathecal, and epidural nerve blocks and percutaneous electrical nerve stimulation. Although well-controlled studies are few, meta-analyses and clinical trials suggest that these treatments are effective in treating acute zoster-associated pain. [4, 98, 99]
Antiviral agents
Many studies have found acyclovir and its derivatives (valacyclovir, famciclovir, penciclovir, and desciclovir, which is not available in the United States) to be safe and effective in treating active disease and preventing PHN. Their mechanism of action involves preventing VZV replication through inhibition of viral DNA polymerase. [43, 100] Valacyclovir and famciclovir are not approved by the US Food and Drug Administration (FDA) for treatment of herpes zoster in children; acyclovir is more commonly used.
Antiviral therapy may decrease the length of time for new vesicle formation, the number of days to attain complete crusting, and the days of acute discomfort. Usually, the earlier antiviral medications are started, the more effective they are in shortening the duration of zoster and in preventing or decreasing the severity of PHN. Ideally, therapy should be initiated within 72 hours of symptom onset.
Controlled studies of antiviral use have only evaluated the efficacy of initiation of therapy within 48-72 hours of rash onset, demonstrating no loss of effectiveness when medications are started at any point during that period. [100] Several observational studies found antiviral therapy to be capable of reducing zoster pain even when started beyond the traditional 72-hour therapeutic window. [101, 102] Thus, antiviral therapy should be considered for acute zoster treatment regimens, regardless of the time of presentation.
Clinical trials showed that oral acyclovir, famciclovir, and valacyclovir reduce viral shedding and accelerate resolution of symptoms (eg, pain) in uncomplicated herpes zoster. Some studies suggested that valacyclovir and famciclovir may be superior to acyclovir in resolving pain and accelerating cutaneous healing. In addition, both agents have greater bioavailability than acyclovir and thus require less frequent dosing. [42, 1, 93, 94, 95, 96] Moreover, acyclovir-resistant viral strains are emerging, suggesting a potentially increased role for newer agents.
The duration of antiviral treatment in studies has ranged from 7 to 21 days. For immunocompetent patients, a 7- to 10-day course of acyclovir or a 7-day course of one of the newer agents is probably appropriate; longer courses may be needed in immunocompromised patients.
The evidence of benefit notwithstanding, there remains some debate about the use of antivirals in this setting. For example, a study by Kubeyinje concluded that acyclovir did not decrease acute pain duration or the incidence of complications in healthy young adults with typical herpes zoster. [103] However, these results cannot be extrapolated to the elderly, who are at greater risk of PHN.
Treatment of Complicated Herpes Zoster
Immunocompromised states
Individuals with altered cell-mediated immunity, due either to an immunosuppressive condition (eg, HIV infection or cancer) or to a treatment (eg, extended corticosteroid use), are at increased risk. Furthermore, presentations in the immunocompromised population can be complicated by disseminated disease and visceral organ involvement. [1, 104] Unsurprisingly, the risk of developing multiple myeloma, leukemia, and lymphoma is increased in patients with herpes zoster. [105]
Antiviral therapy has been demonstrated to halt progression and dissemination of acute herpes zoster in immunocompromised patients, even when initiated more than 72 hours after rash onset. [106] Accordingly, such therapy is recommended for all immunocompromised patients who present before the full crusting of all lesions.
IV acyclovir remains the drug of choice for the following populations of immunocompromised patients:
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Patients with evidence of disseminated disease or visceral organ involvement
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Patients with ophthalmic involvement
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Patients with advanced HIV/AIDS who harbor active opportunistic infections or exhibit prominent wasting
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Transplant recipients who have just undergone transplantation or are being treated for rejection
Patients without such risk factors can be treated with oral antiviral agents. Data on adjunctive therapy with corticosteroids are insufficient to permit a recommendation recommended. Antiviral therapy should be continued until all lesions have resolved. [106]
Herpes zoster ophthalmicus
A study by Morgan and King showed that the eye was the most common site of zoster involvement in patients requiring hospital admission. [107] Pain was the main complaint.
Two trials comparing oral acyclovir with famciclovir or valacyclovir in patients with herpes zoster ophthalmicus (HZO) found outcomes to be comparable with any of the regimens. [108, 109] Patients with diagnosed or suspected HZO should receive antiviral therapy and should be promptly referred to an ophthalmologist.
Management of Postherpetic Neuralgia
If a patient complains of severe pain at any point at or beyond the appearance of crusted vesicles, the clinician should strongly suspect that PHN has developed. Once established, the pain is notoriously difficult to alleviate with traditional analgesics, including narcotics. Consequently, treatment of PHN is complex; a multifaceted, patient-specific approach is important.
It should be noted that whereas acute zoster pain and PHN are believed to result from different pathophysiologic mechanisms, it is clinically and experimentally impossible to determine precisely when the 2 types of pain cross over. Accordingly, some workers use the term zoster-associated pain to describe both acute and chronic pain as a continuum.
The only consistently successful method of treating PHN is to prevent it via prompt treatment of acute zoster and its associated pain. Initiation of antiviral therapy as early as possible in the course of acute zoster, and definitely within 72 hours of onset, has been shown to be effective in alleviating acute pain and preventing PHN in most patients (though treating already-established PHN with antivirals appears not to be beneficial [110] ). Consultation with pain specialists may also be required. [5, 111, 112, 113]
Once PHN has developed, various treatments are available, including the following:
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Neuroactive agents (eg, TCAs) [6]
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Anticonvulsant agents (eg, gabapentin [7] and pregabalin)
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Narcotic and nonnarcotic analgesics, both systemic (eg, opioids) and topical
Two placebo-controlled studies that evaluated gastroretentive gabapentin in 357 patients with PHN found that more of the patients in the gabapentin group felt better and exhibited a response to treatment. [114] The reduction in PHN pain with gabapentin was noted as early as day 2 of therapy and lasted for at least 10 weeks.
Topical capsaicin can be helpful; its active ingredient depletes neurotransmitters at involved nerve endings. However, the cream must be applied at least 5 times daily, and pain may increase upon application for the first few days as accumulated neurotransmitters are released. Once neurotransmitter reserves have been depleted, any resultant pain relief is temporary.
Topical lidocaine is occasionally used to treat patients with PHN, though the data are insufficient to allow it to be recommended as a first-line agent for PHN with allodynia. [115] In one small study, administration of lidocaine 4% ophthalmic eyedrops produced a significant reduction in eye and forehead pain. [82]
The use of oral or epidural corticosteroids in conjunction with antiviral therapy has been found to be beneficial in treating moderate-to-severe acute zoster but to have no effect on the development or duration of PHN. [85, 97, 87] Intrathecal administration of corticosteroids has also been attempted [116] but is not currently recommended.
Combination therapies have shown promise for relieving PHN, but clinical evidence to support such approaches is limited. [117]
Pavan-Langston has proposed the following protocol for treatment of PHN [118] :
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TCAs – Nortriptyline, amitriptyline, or desipramine 25 mg; adjust up to 75 mg at bedtime; continue for several weeks if necessary
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Topical treatment with either capsaicin ointment (once or 4 times daily) or lidocaine patches
Although anesthesia-based interventions such as local anesthetic blocking of sympathetic nerves or stellate ganglion blockade may produce transient relief, their effectiveness in reducing the protracted pain of PHN remains to be determined. Transcutaneous electric nerve stimulation (TENS) and, if necessary, neurosurgery (eg, thermocoagulation of substantia gelatinosa Rolandi) have been found to be helpful in exceptional cases.
Diet and Activity
No specific dietary changes are recommended.
Patients with shingles can perform activities as tolerated. Most are capable of self-restricting their activities on the basis of any limitations that may be imposed by pain; additional advice from physicians is rarely, if ever, necessary.
During the acute phase, patients are contagious should be counseled to avoid direct skin contact with immunocompromised persons, pregnant women, and individuals with no history of chickenpox infection. Infants and babies are especially vulnerable at the acute, contagious stage. If the patient is hospitalized, contact isolation measures should be considered.
Prevention
Varicella-zoster virus vaccine
It has been proposed that zoster occurs when varicella antibody titers and varicella-specific cellular immunity drop to a level at which they no longer are completely effective in preventing viral invasion. Evidence for this hypothesis includes observation that pediatricians, who presumably are reexposed to varicella virus routinely and thus maintain high levels of immunity, seldom develop zoster. It follows that there is a rationale for vaccination.
Since 1995, live attenuated VZV vaccine (Varivax) has been available in the United States and has been up to 99% effective in protecting susceptible children from varicella infection. The higher-potency live attenuated VZV vaccine introduced in 2006 (Zostavax) demonstrated a reduction in shingles in adults by 51.3% during 3 years of follow-up in one study. [122]
The routine use of the live attenuated varicella vaccine has led to a remarkable reduction in the incidence of primary varicella infection. Furthermore, vaccinated children have demonstrated lower rates of herpes zoster than those infected through natural exposure to VZV. [123, 124] However, the effect of childhood vaccination on the incidence of herpes zoster in adult populations remains to be fully elucidated.
Prevention or attenuation is particularly desirable in older patients because zoster is more frequent and is associated with more complications in older populations and because declining cell-mediated immunity in older age groups is associated with an increased risk of zoster. A zoster vaccine immunization program in older adults may be cost effective and has the potential to decrease the incidence or reduce its severity. [125, 126]
In February 2018, the Centers for Disease Control and Prevention (CDC) approved the 2018 adult immunization schedules. Changes to this year’s schedule regarding zoster vaccines includes the following [127, 128] :
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Administer two doses of recombinant zoster vaccine (RZV) (Shingrix) 2-6 months apart to adults aged 50 years or older regardless of past episodes of herpes zoster or receipt of zoster vaccine live (ZVL) (Zostavax)
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Administer two doses of RZV 2-6 months apart to adults who previously received ZVL at least 2 months after ZVL
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For adults aged 60 years or older, administer either RZV or ZVL (RZV is preferred)
In 2006, on the basis of the findings from the Shingles Prevention Study, [122] the US Food and Drug Administration (FDA) approved Zostavax for prevention of herpes zoster in people aged 60 years and older. This randomized, double-blind, placebo-controlled trial of the vaccine enrolled more than 38,000 adults older than 60 years. The vaccine reduced the incidence by 61.1% and the incidence of PHN by 66.5%.
Shortly thereafter, the CDC recommended that the zoster vaccine be given to all nonimmunocompromised, nonpregnant people aged 60 years of age and older, including those who have had a previous episode of zoster. [122]
In 2011, the FDA lowered the approved age for use of Zostavax to 50-59 years. Approval was based on a multicenter study, the Zostavax Efficacy and Safety Trial (ZEST), which was conducted in the United States and 4 other countries and included 22,439 subjects aged 50-59 years. [129] Participants were divided into 2 equal groups and randomly assigned to receive either Zostavax or placebo, then monitored for at least 1 year for development of shingles. Zostavax reduced the risk of developing zoster significantly (approximately 70%).
Persons with a reported history of zoster can be vaccinated. Repeated zoster has been confirmed in immunocompetent persons soon after a previous episode. Although the precise risk for and severity of zoster as a function of time after an earlier episode are unknown, some studies suggest it may be comparable to the risk in persons without a history of zoster. Furthermore, no laboratory evaluations exist to test for the previous occurrence of zoster, and any reported diagnosis or history might be erroneous.
The live attenuated VZV vaccine demonstrated a reduction in the incidence rate of herpes zoster, preventing both herpes zoster and postherpetic neuralgia. [130] More recently, the safety of this recombinant zoster vaccine has been judged as favorable, [130] even in those with immune-mediated inflammatory diseases. [131]
In October 2017, the FDA approved Shingrix (zoster vaccine recombinant, adjuvanted) for the prevention of shingles in adults aged 50 years and older. Approval is based on findings from a phase III clinical trial program assessing its efficacy, safety, and immunogenicity in 38,000 patients. Data from a pooled analysis of two clinical trials demonstrated efficacy against shingles greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of 4 years. [132, 133]
The first trial, ZOE-50, was a randomized, placebo-controlled study conducted in 18 countries in Europe, North America, Latin America, and Asia-Australia. The study evaluated the efficacy, immunogenicity, and safety of the HZ/su vaccine in adults aged 50 years or older. Participants were randomly assigned in a 1:1 ratio to receive either HZ/su vaccine (0.5 mL at month 0 and 2) or placebo. Two doses of HZ/su administered 2 months apart had a vaccine efficacy of 97.2%, compared with placebo, in reducing the risk of herpes zoster in adults aged 50 years or older. The vaccine efficacy was similar among the three age groups. [132]
The second trial, ZOE-70, studied the safety and efficacy of HZ/su in adults aged 70 years or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster was 89.8% and was similar in participants aged 70-79 years (90.0%) and participants aged 80 years or older (89.1%). In pooled analyses of data from participants aged 70 years or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% and vaccine efficacy against postherpetic neuralgia was 88.8%. [133]
The two vaccines, the discontinued zoster vaccine live (ZVL; Zostavax) and the currently available nonlive adjuvanted recombinant zoster vaccine (RZV; Shingrix), differ in efficacy and durable response. [134] Vaccination with RZV in immunocompetent adults aged 50 years or older is recommended, including those previously vaccinated with ZVL. The cost-effectiveness of vaccinating US adults aged 60 years and older, previously vaccinated with ZVL, was evaluated. Compared with revaccinating with ZVL, vaccination with RZV is highly desirable.
Other methods of prevention of initial infection include contact and respiratory isolation of infected patients until full crusting of lesions is achieved, as well as postexposure prophylaxis with VZIG in select populations.
Varicella-zoster immune globulin
The CDC recommends administration of VZIG to prevent or modify clinical illness in persons with exposure to varicella or herpes zoster who are susceptible or immunocompromised. It should be reserved for patients at risk for severe disease and complications, such as neonates and patients who are immunocompromised or pregnant. [135]
VZIG provides maximum benefit when administered as soon as possible after the presumed exposure, but it may be effective if administered as late as 96 hours after exposure. Protection after VZIG administration lasts for an average of approximately 3 weeks, according to the CDC.
Consultations
Consultation is rarely necessary in cases of uncomplicated zoster. Consultation with the appropriate specialist may be indicated when symptoms point toward meningitis (HZO), dental disease (zoster of the maxillary branch), ear infections or deafness (Ramsay Hunt syndrome), oropharyngeal infections, meningoencephalitis, or encephalomyelitis; when the patient is immunocompromised; when the rash is atypical; when motor complications are present; or when the urinary bladder, the lungs, or the gastrointestinal tract is involved.
Long-Term Monitoring
Typical cases of zoster may be treated in the outpatient setting and do not require extensive follow-up. Patients should be informed about the natural progression of herpes zoster and its potential complications. Initial evaluation should address the possibility of atypical manifestations. Pain relief should be a primary concern.
After initial treatment, further care consists solely of monitoring the patient and remaining alert for complications (eg, secondary infection, eye involvement, and meningeal or visceral involvement) and for sequelae such as PHN. Patients who develop PHN should be seen regularly and should receive emotional support in addition to medical therapy.
Since there is an increased risk of developing multiple myeloma, leukemia, and lymphoma, an appropriate screening with physical examination and laboratory test should be considered. [105]
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Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.
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Suspected zoster of the hand.
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Herpes zoster, unilateral, on trunk.
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Herpes zoster on lateral part of abdomen.
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Maculopapular rash due to herpes zoster in child with history of leukemia. Image courtesy of Centers for Disease Control and Prevention (CDC).
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Herpes zoster in ophthalmic (V1) distribution of trigeminal nerve. Note unilateral distribution of rash and how V1 distribution may extend to tip of nose. Though at risk for keratitis with zoster in this distribution, patient had normal ocular examination. Patient consented to picture distribution for educational use; written permission on file. Image courtesy of JS Huff.
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Herpes zoster on neck.
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What is herpes? Herpes is a virus causing sores most commonly around the mouth (oral herpes) and genitals (genital herpes).
