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Herpes zoster in 2007: Treatment and prevention

Early, aggressive treatment of shingles and appropriate use of the shingles vaccine are essential to the effective management of this painful condition.

Fred J. Friel, MPAS, PA-C

Fred Friel practices at a family medicine/urgent care clinic in Boise, Idaho, and is senior physician assistant in the Idaho Army National Guard. He has indicated no relationships to disclose relating to the content of this article.

Herpes zoster—also called shingles—is a painful rash arising from reactivation of the varicella-zoster virus (VZV; human herpesvirus 3) in the dorsal nerve root ganglia. The risk for shingles increases with age, reflecting an age-related diminished immune response to the virus.

It is essential for physician assistants to be familiar with the diagnosis and treatment of this disease. Not only do an estimated 1 million cases of shingles occur in the United States each year, the population of older Americans is increasing, and more people are living longer with disease-induced or treatment-induced immunosuppression.^1,2 These realities suggest that the already large number of shingles cases will only increase. Furthermore, the threat of postherpetic neuralgia (PHN)—the lingering, debilitating pain along cutaneous nerves that can persist well after shingles lesions have healed—makes it even more important for clinicians
to recognize the clinical signs of shingles. Patients must be treated effectively, appropriately, and as early as possible to diminish the morbidity of this illness.

EPIDEMIOLOGY

More than 90% of adults in the United States have serologic evidence of VZV infection and are at risk for shingles as their immune function declines.³ The Shingles Prevention Study found that the incidence and severity of shingles increase markedly with age; more than half of all shingles sufferers are older than 60 years.^4,5 Even when complications do not develop, shingles can interfere with an elderly person’s ability to carry on activities of daily living, resulting in short-term or even long-term loss of independence. Worse yet, the most common complication from shingles, PHN, can cause chronic pain, poor sleep, chronic fatigue, anxiety, and severe depression.² Other zoster complications include herpes ophthalmicus, myocarditis, paresis, myelopathy, vasculopathy, pneumonia, and encephalitis.^1-3

Incidence rates for shingles have been reported at 2.5 to 5 per 1,000 people at age 60 years and increase to 3 to 6.8 per 1,000 people by age 70 years.^1,4 The Shingles Prevention Study, a randomized, double-blind, placebo-controlled trial of an investigational live attenuated varicella zoster vaccine,^4,5 reported that the annual incidence was 11 per 1,000 people in the placebo group.⁵ This incidence rate is given a study enrollment of 38,546 subjects.⁵ Of these, 20,747 subjects were aged 60 to 69 years.⁵ In the older than 70 years cohort, 17,799 were enrolled.⁵ The subjects were spread over 22 study sites throughout the United States.⁵

DIAGNOSIS

Clinical presentation Before the rash appears, shingles can be confusing. However, there are some clues that should alert providers and thus enable them to begin early treatment. The prodrome of shingles includes headache, malaise, photophobia, and, rarely, fever, as well as a preherpetic neuralgia that includes an exquisitely painful hypersensitivity along the affected dermatome. This neuralgia includes a burning or itching sensation and/or a deep, bony pain that some patients verbalize as a fear that they have fallen out of bed while asleep and broken a rib or their spine. Some or all of these symptoms and signs can arise a few days before the skin eruption.

The rash typically begins with a red patch, hypersensitive to touch, with grouped vesicles arising out of initial papular lesions (see Figure 1). The patch typically will follow a unilateral, single dermatome; it seldom crosses more than one dermatome and rarely crosses the midline. Up to 10 days after the initial breakout, the rash and vesicles can continue to spread. The vesicles then go through the stages of pustulation, ulceration, and drying to a crust.^2,3 In immunocompetent patients, rashes crossing midline or dermatomal borders are of little prognostic importance.³ Multidermatomal, trigeminal, ocular, and other complications are more likely to occur in immunocompromised patients.⁶

Laboratory studies Although shingles can generally be diagnosed clinically, typical rash manifestations can sometimes confuse the process, and laboratory studies can be helpful in these cases. Viral cultures are certainly possible, but the VZV is very fragile and is relatively difficult to
culture from swabs from the skin lesions. Direct immunofluorescence assays are more sensitive than viral cultures, should be less expensive, and offer quicker turnaround time. Both viral cultures and immunofluorescence assays can distinguish between herpes simplex virus and VZV. Polymerase chain reaction (PCR) studies detect varicella virus DNA and can help in the diagnosis as well.³

Postherpetic neuralgia PHN has been defined a number of ways, with distinctions proposed between acute herpetic neuralgia (pain within 30 days of rash), subacute herpetic neuralgia (pain 30-120 days after onset of rash), and PHN (pain lasting at least 120 days after rash onset).^2,3,7 Well-
established risk factors for PHN are older age, female sex, presence of a prodrome to the shingles outbreak, greater rash severity, and greater pain with acute herpetic neuralgia. Patients with all these risk factors may have as much as a 50% to 75% risk of pain persisting 6 months after rash onset.^7,8

Jung and associates, examining baseline and follow-up data in a 2003 study of 965 herpes zoster patients, found that those with subacute herpetic neuralgia that did not progress to PHN were considerably younger and had less severe acute pain than did those who did develop PHN.⁸ Curiously enough, in one analysis, younger patients with larger rash and significant subacute pain were less likely to experience PHN.⁸ The authors proposed that subacute herpetic neuralgia that does not progress to PHN reflects peripheral nerve damage and inflammation caused by a particularly severe or widespread rash.⁸

Early and aggressive treatment for shingles is key to decreasing the likelihood of PHN. By inhibiting the replication of VZV, treatment decreases the spread of the rash, improves healing times, and decreases the length of time patients suffer acute pain.

TREATMENT

The primary antiviral medications used against shingles are acyclovir, famciclovir, and valacyclovir, and early initiation of antiviral treatment is key to a good outcome (see Table 1). Randomized controlled trials and meta-analyses have shown that treatment with acyclovir decreases the likelihood of long-term pain. In one meta-analysis, the summary odds ratio for the incidence of “any pain” in the distribution of rash at 6 months in adults treated with acyclovir was 0.54 (95% confidence interval, 0.36-0.81).⁹ Acyclovir also decreases viral shedding, hastens rash resolution, and decreases all pain end points.^2,7

The two prodrugs, famciclovir and valacyclovir, may be more effective than acyclovir because of their bioavailability profiles and more convenient dosing. Both are taken 3 times rather than 5 times daily. In one study, valacyclovir significantly shortened the median time to the resolution of zoster-related pain compared to acyclovir.¹⁰ In immunocompetent patients, valacyclovir and famciclovir appear to be therapeutically equivalent.^2,3,7

Oral acyclovir, valacyclovir, and famciclovir are all considered effective in less severely immunocompromised patients, such as those with solid tumor malignancy or patients receiving corticosteroid therapy.⁶ In severely immunocompromised patients, such as those with leukemia or receiving bone marrow transplants, intravenous acyclovir is an effective therapy for herpes zoster.^6,11

All these medications should be started within 72 hours of the onset of rash, and all should be continued for at least 7 days.^2,3,7,12 Beginning antiviral therapy at the prodrome stage, rather than waiting for the rash to develop, may be reasonable. Although the diagnosis of shingles is not clear until the rash appears or confirmed until PCR results are returned, an argument for treating early and aggressively can be made. Furthermore, these drugs are well-tolerated in patients with adequate renal function, and they have few side effects (headache and nausea primarily).

Herpes ophthalmicus When the VZV reactivates in the trigeminal nerve, the typical manifestations are unilateral pain and rash in the forehead, periocular region, and nose. Some patients with herpes ophthalmicus may have ophthalmic findings only. Ophthalmic involvement is not correlated by age of patient or severity of disease. Any patient with symptoms suggestive of herpes ophthalmicus should be referred to an ophthalmologist within 24 hours. Prompt referral plus antiviral therapy are the cornerstones of treatment. Without treatment, some 50% of first division of trigeminal nerve shingles will progress to herpes ophthalmicus and the ocular complications associated with it (keratopathy, episcleritis, iritis, or stromal keratitis).¹³

Corticosteroids Experts disagree regarding the use, efficacy, and safety of concomitant corticosteroid and antiviral use in the treatment of shingles. All agree that corticosteroids alone should not be used, but some believe that combination treatment can hasten the resolution of rash and pain in immunocompetent patients.⁷

Herpetic neuralgia Patients should be instructed to keep the rash clean, dry, and covered. They should be educated as to the risk of secondary bacterial infection. Because the rash is vesicular, patients should use a sterile, nonocculsive, nonadherent dressing. This will diminish the likelihood of secondary infection and give the patient some relief from irritation from clothing.

Neurologic pain can be severe. Providers should not underestimate this pain and should recall that minimizing neuralgia in the acute setting may decrease the likelihood of PHN. Consider use of short-acting narcotic analgesics early on. For more intractable pain, longer-acting scheduled narcotics may be needed, and transdermal analgesics may be appropriate. Consider longer-acting, controlled-release opioids for intractable pain in conjunction with shorter-acting narcotics for breakthrough pain. Remember to counsel patients on the side effects of these agents, particularly constipation and nausea.^2,3,7

Postherpetic neuralgia Despite treatment, some patients with shingles will experience long-term pain. In those older than 50 years, some 20% continue to report pain 6 months after the onset of shingles even with antiviral treatment.⁷ Early, aggressive treatment is believed to decrease the likelihood of continuing pain. Combination therapy will likely be required, including the use of short-acting and long-acting controlled-release narcotics. Tricyclic antidepressants such as amitriptyline or desipramine taken in conjunction with gabapentin or carbamazepine have proven effective^2,3,7 (see Table 2). Consider these medications early in treatment, particularly during the acute phase, and remember that the side effects are additive, particularly in the elderly. Monitor patients closely. Describe the side effects, and explain what to watch for and what to do to ease them if they occur (stool softeners for constipation, increased fluids and lozenges for dry mouth, etc).

Local analgesic patches such as 5% lidocaine, or capsaicin cream can provide some relief for patients. Intrathecal methylprednisolone has been proven very effective for severe, intractable PHN. When injected once weekly for 4 weeks, the medication resulted in a significant reduction of pain.¹⁴

THE SHINGLES VACCINE

As noted in a recent editorial in the Annals of Internal Medicine, studies have suggested that herpes zoster can be prevented in adults with a live, attenuated varicella vaccine.¹ The Shingles Prevention Study, a large, multicenter, randomized, double-blind, placebo-controlled clinical trial, investigated a zoster vaccine.^4,5 The study enrolled 38,546 adults aged 60 years or older who were randomly assigned to receive one 0.5-mL SC injection of placebo or vaccine from 1 of 12 lots.⁵ Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for 6 months. The primary end point was the burden of disease due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of PHN.^4,5Study participants were followed monthly for a mean of 3.13 years, and more than 95% of participants completed follow-up.⁵ Herpes zoster was confirmed in 957 cases, 315 in the vaccine group and 642 in the placebo group.⁵ The vaccine reduced the incidence of herpes zoster by 51.3% and the incidence of PHN by 66.5%.⁵

On May 26, 2006, the FDA approved the zoster vaccine (Zostavax) for the prevention of herpes zoster and PHN. According to the product labeling, the vaccine is indicated for persons aged 60 years and older. It is not indicated for the treatment of zoster or PHN, nor should it be used that way. Contraindications include a history of anaphylactoid reactions to gelatin, neomycin, or any other component to the vaccine. Persons with a history of primary or acquired immunodeficiency states, those receiving immunosuppressive therapy, and pregnant women also should not receive the vaccine. (Note that the vaccine should not be administered to women of childbearing age.)

The shingles vaccine promises to decrease the burden of disease associated with herpes zoster and PHN considerably. All providers should familiarize themselves with the costs, risks, and benefits of the vaccine and should consider it for their older patients.

HERPES ZOSTER AS AN OPPORTUNISTIC INFECTION

The clinical manifestations of herpes zoster in HIV-seropositive patients are typically similar to those in immunocompetent patients. However, zoster in HIV-infected patients does have some unique characteristics, such as more frequent occurrences and, less commonly, extensive cutaneous dissemination and visceral involvement. Progressive outer retinal necrosis is a VZV-related occurrence that typically occurs in persons infected with HIV-1 whose CD4+ counts have dropped below 50 cells/μL.¹⁵ This manifestation of shingles is often associated with a typical sensory dermatomal rash but is also characterized by “multifocal retinal opacification with little or no ocular inflammation and rapid visual loss.”¹⁵

The diagnostic workup for shingles is similar whether the patient is HIV-positive or HIV-negative. If the lesions appear atypical, however, and the diagnosis is in question, swabs of fresh lesions or a tissue sample can be submitted for viral culture or antigen detection.¹⁵

Treatment for a typical dermatomal shingles rash in the HIV-positive patient is famciclovir or valacyclovir for 7 to 10 days. If cutaneous lesions are extensive or clinical evidence of visceral involvement is observed, treatment with intravenous acyclovir should be initiated and continued until all cutaneous lesions have resolved. Progressive outer retinal necrosis rapidly progresses and leads to “profound loss of vision.”¹⁵ Because of this rapid progression, high-dose IV acyclovir in combination with foscarnet is recommended.¹⁵ Adjunctive corticosteroids should not be used in HIV-positive patients because of their immunosuppressive effects.¹⁵

Treatment failure should be considered if lesions are not improving after 10 days of therapy. A lesion culture should be obtained, and if virus is isolated, susceptibility testing is needed to confirm antiviral drug resistance. For patients with acyclovir-resistant VZV infections, treatment with IV foscarnet is recommended.¹⁵

CONCLUSION

Early recognition and aggressive treatment of herpes zoster can minimize the severity and long-term effects of the illness. Predictors of PHN are older age, female sex, presence of a prodrome, greater rash severity, and greater pain with acute herpetic neuralgia. Antiviral therapy combined with analgesics is the cornerstone of treatment of this prevalent, debilitating illness. The current availability of the VZV vaccine could significantly lower the burden of disease associated with herpes zoster.

DRUGS MENTIONED

Acyclovir (Zovirax)
Amitriptyline
Capsaicin cream
Carbamazepine
Desipramine (Norpramin)
Famciclovir (Famvir)
Foscarnet (Foscavir)
Gabapentin (Gabarone, Neurontin)
Lidocaine transdermal (Lidoderm)
Methylprednisolone
Valacyclovir (Valtrex Caplets)

REFERENCES

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	12.	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. Ann Intern Med. 1995;123(2):89-96.
	13.	Shaikh S, Ta CN. Evaluation and management of herpes zoster ophthalmicus. Am Fam Physician. 2002;66(9):1723-1730, 1732.
	14.	Kikuchi A, Kotani N, Sato T, et al. Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med. 1999;24(4):287-293.
	15.	Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among hiv-infected adults and adolescents. Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. AIDSinfo Web site. http://www. aidsinfo.nih.gov/ContentFiles/TreatmentofOI_AA.pdf. Accessed October 2, 2007.