A 70-Year-Old Woman With Shingles: Title and subTitle BreakReview of Herpes Zoster

DR LIBMAN: Ms A is a 70-year-old woman who presented to the emergency department with shingles. The patient was in her usual state of health until 3 days before presentation, when she developed sharp stabbing pain in her right ear associated with itching. One and a half days before presentation, she developed numbness and tingling over her right jaw, which subsequently spread to her cheek. At about the same time, she noted a painful rash in the region. She denied fever, headache, loss of vision, diplopia, difficulty hearing, tinnitus, vertigo, dysarthria, dysphagia, numbness or weakness of her torso or extremities, bladder or bowel dysfunction, or cognitive impairment. Ms A had chickenpox as a child but no prior documented episodes of shingles.

Ms A's medical history is noteworthy for hypertension, esophageal reflux disease, asthma, osteoporosis, and depression. In addition, she has a remote history of atrioventricular nodal reentry tachycardia (in 2007), for which she initially received medical therapy and, more recently, an ablation procedure; and breast cancer (in 1993), for which she received lumpectomy, lymph node dissection, and radiation therapy. Ms A's mother had diabetes mellitus, her father had colon cancer, and her son and cousins have sleep apnea.

Ms A's medications include albuterol, 90 μg, 2 puffs inhaled twice a day; alendronate, 70 mg by mouth once a week; fluticasone, 220 μg, 2 puffs inhaled twice a day; fluticasone, 50 μg, 1 spray in each nostril twice a day; omeprazole, 20 mg by mouth once a day; salmeterol, 50 μg, 1 puff inhaled twice a day; sertraline, 25 mg by mouth once a day; triamterene/hydrochlorothiazide, 37.5 mg/25 mg by mouth once a day; and verapamil, 360 mg by mouth once a day. She has a history of allergies or adverse reactions to cefaclor, ciprofloxacin, codeine, iodine, penicillins, and sulfonamides.

Ms A is married and lives with her husband. She has 5 grown children. She is employed as an administrative assistant. She occasionally has wine with dinner but has no history of smoking or drug use.

On examination, Ms A's blood pressure was 124/68 mm Hg, her pulse was 64/min and regular, and her respirations were unlabored. She was afebrile. She had several vesicles on an erythematous base in the right external auditory canal (Figure), on the right mandible, and under the right lip. There were no mouth lesions. Her neurologic examination was noteworthy for decreased sensation to light touch with paresthesia and dysesthesia over right V2 and V3; results of examination of her other cranial nerves, motor and sensory function, deep tendon reflexes, cerebellar function, and mental status were normal. The remainder of her general examination was unremarkable.

Ms A's laboratory studies showed normal complete blood cell count, glucose, and renal function measurements. Her electrocardiogram showed normal sinus rhythm with no diagnostic abnormalities. A computed tomography (CT) scan of the head without contrast was noteworthy for a 2 × 4-mm hypodense region in the left frontal white matter, likely representing an old lacunar infarct.

Ms A was diagnosed as having facial shingles and began taking valacyclovir, 1000 mg by mouth 3 times a day. She was seen for follow-up 3 days later in the neurology clinic, at which time she reported new pain on the right side of her scalp, her right forehead, and inside the right side of her mouth. In addition to the findings described previously, her physical examination was noteworthy for a single vesicular lesion inside the right side of her mouth and decreased sensation to light touch involving V1. She was advised to continue to take valacyclovir for a total duration of 14 days (longer than standard therapy of 7 days) and began taking gabapentin, 300 mg at bedtime, for pain control. She was seen again 1 week later in the neurology clinic, at which time she continued to report right facial pain, which was especially bad with chewing. Her physical examination showed no new abnormalities. It was recommended that she gradually increase the gabapentin dosage to 600 mg by mouth 3 times a day as tolerated.

I first noticed the pain at the hairdresser. It was very tender on the back of my head. From there, my right ear started to itch and I had drainage from both ears. Eventually I couldn't stand the itchiness anymore so I went to the doctor and they found some sores inside my right ear. In addition, I had pain near my eyes and my vision was blurred. I thought I needed stronger glasses, but even now, I’m still having difficulty seeing and reading well.

I developed swelling and numbness on the right side of my face. It started at my ear and went all the way to my teeth and jaw. My teeth felt like they were recovering from [local anesthetic] and they were so sensitive, I couldn't even brush my teeth. I also had difficulty swallowing and drinking on the right side of my mouth and was unable to use a straw.

My right side was affected more than my left. Sometimes my right hand would be numb—particularly in the night—and though both legs were weak, my right leg was significantly weaker than my left. For the first time, I had trouble walking and going up stairs. Sometimes I felt so exhausted, I wanted to cry. I can't even explain it. I just felt drained.

I went to the emergency department because of the earache I had developed and because the pain was so strong, I couldn't stand it. As I walked into the hospital, I started to break out into these little sores and they immediately put me in isolation. The emergency department doctor and a neurologist did a routine examination, took my blood pressure, and ordered a CT scan. They determined that it was shingles and decided to treat me with [valacyclovir]. They also offered me painkillers, but I really didn't want to take that. I took [extended-release acetaminophen], which seemed to work.

I had taken the [valacyclovir]for 10 days when my whole right side became numb, sometimes with shooting pains. My right ear was extremely itchy and the pain was so sharp that I felt like a pencil was shooting in my ear. Consequently, they put me on [gabapentin]. I started taking two 300-mg pills each night and was supposed to slowly increase my dosage over the next 5 weeks until I reached 1800 mg. I’m afraid to take such high doses because the [gabapentin] makes me feel very groggy.

Eventually the skin lesions erupted and became scabby. As they healed, they slowly dried and went away. By my second visit to the neurologist, the swelling had gone down and I had a dull feeling in the back of my head and in my face, cheeks, and jaw. The doctors told me that if I stopped the [gabapentin], the pain would probably come back. When I asked them about the numbness, they said that sometimes it never goes away.

My perception of shingles was that only old people got it—of course, I probably am old and don't know it—but I was really surprised. I know people who have really bad cases where their whole body is affected and I sometimes feel really guilty because they are so bad.

What are the epidemiology and pathophysiology of shingles? How should shingles be diagnosed and treated? What is Ramsay-Hunt syndrome? What are the other complications of facial shingles? How should postherpetic neuralgia (PHN) be managed? Can it be prevented? What are the indications for varicella and shingles vaccine preparations? What would you recommend for Ms A?

DR WHITLEY: Ms A presented to the emergency department with a prodrome of pain followed by a vesicular rash, which is characteristic of shingles.

Varicella-zoster virus (VZV) is a herpes virus that causes 2 distinct clinical syndromes. Varicella (chickenpox), the primary infection, is a common, extremely contagious, and usually benign illness that occurs in epidemics. Before the licensure of the pediatric varicella vaccine in the United States, approximately 96% of persons living in the United States experienced chickenpox by age 20 years. With primary infection, VZV establishes latency in the dorsal root ganglia.¹ Quiz Ref IDReactivation of latent VZV results in herpes zoster (shingles), a common disorder in older individuals.^{1 - 2} The immune responses that limit reactivation of VZV from the sensory ganglia are poorly understood; however, a decline in VZV-specific cell-mediated immune (CMI) responses that accompanies advancing age appears to be important.^{2 - 3} Decreased CMI responses can be induced by immunosuppressive illnesses or medical treatments. Patients with neoplastic diseases, especially lymphoproliferative malignancies; hematopoietic and organ transplant recipients; and human immunodeficiency virus–infected persons are at increased risk of developing shingles.

Herpes zoster occurs equally in men and women, and there is no seasonal variation. The incidence of herpes zoster is estimated to be 1.5 to 4 cases per 1000 persons annually,^{4 - 6} with about 1 million cases occurring each year in the United States.^{6 - 8} An increase in the incidence of shingles is noted at 55 to 60 years of age. Individuals older than 75 years have an incidence of herpes zoster greater than 10 cases per 1000 person-years.⁹ Approximately 30% of individuals develop herpes zoster over their lifetime^{10 - 12} ; however, second episodes of shingles in immunocompetent persons are uncommon.^{4 - 5 ,12 - 13}

Quiz Ref IDThe onset of shingles is characterized by a prodrome that can consist of any of several constitutional symptoms including headache, photophobia, malaise, and localized dermatomal pain prior to the appearance of vesicles by as many as 5 days. Fever is uncommon. Of note, photophobia and headache are more common with involvement of facial dermatomes.¹⁴ As the disease evolves, patients report localized abnormal skin sensations ranging from mild itching or tingling to severe pain. Skin manifestations begin with an erythematous maculopapular rash followed by the appearance of clustered vesicles. These lesions are usually 3 to 5 mm in diameter and can coalesce to form larger lesions. New vesicles form over a period of 3 to 5 days and then evolve through stages of pustulation and scabbing. Complete healing often requires 2 to 4 weeks and can result in skin scarring and permanent pigmentation changes. The cutaneous eruption of shingles is unilateral and does not cross the midline. Simultaneous involvement of multiple noncontiguous dermatomes almost never occurs in immunocompetent hosts. A syndrome known as zoster sine herpetica has been described as dermatomal pain attributed to herpes zoster but in the absence of vesicles.¹⁵

Acute pain occurs in at least 95% of patients older than 50 years who develop shingles. Of those presenting with pain, at least 40% consider it severe.¹⁵ One month after the onset of cutaneous manifestations, 60% to 70% of patients older than 50 years have persistent pain.¹⁶ Postherpetic neuralgia, defined as pain persisting at 120 days after disease onset, is the most debilitating complication of shingles.^{17 - 19} The incidence and, likely, the duration of PHN correlate directly with patient age.^{5 ,20} Quiz Ref IDIn patients older than 60 years, the prevalence of pain at 6 months has been reported to be 13% to 40%, occasionally persisting for years.^{21 - 22} Within the affected dermatome, patients with PHN may experience a variety of sensory abnormalities, including paresthesias, dysesthesias, and allodynia (eg, pain in response to a normally nonpainful stimulus; ie, light touch), in addition to neuropathic pain. Approximately 400 000 new cases of PHN occur annually in the United States.^{6 ,10 ,23 - 31}

While pain is considered the most significant complication of herpes zoster, other complications include encephalitis, myelitis, cranial nerve palsies, and peripheral nerve palsies.¹⁵ Secondary bacterial infections of the skin, including methicillin-resistant Staphylococcus aureus infection, have become increasingly common in recent years.¹⁴ Other complications include granulomatous arteritis and herpes gangrenosum. Ophthalmic zoster, requiring prompt medical intervention to avoid visual loss, occurs in 15% of patients.³² Acute retinal necrosis is a complication that occurs most commonly in immunocompromised patients.³³ Although Ms A receives fluticasone, it is unlikely that this medication contributed to immunosuppression.

Ms A presented with a rash involving her ear. This unusual manifestation of herpes zoster involves pain and vesicles in the external auditory canal and a loss in sense of taste in the anterior two-thirds of the tongue, occurring in less than 1% of all patients with herpes zoster.¹⁴ Ipsilateral facial palsy is common and usually resolves with therapy. The geniculate ganglion of the sensory branch of the facial nerve is involved. This condition, known as Ramsay-Hunt syndrome, involves the facial and auditory nerves. There are few data on long-term outcomes.

The rash of herpes zoster is sufficiently distinctive that a diagnosis based on clinical findings is usually accurate. However, the location or appearance of the cutaneous lesions may be atypical, especially in immunocompromised patients. For individuals with recurrent localized vesicles, especially involving the mouth or genital regions, herpes simplex virus should be considered in the differential diagnosis.⁸

If laboratory confirmation is required, several approaches are available, though no single laboratory approach is preferred. Isolation of VZV in cell culture is difficult because of the lability of the virus in transport from the patient to the diagnostic virology laboratory. Direct fluorescent antigen assay (DFA), a more sensitive test, uses a modified Tzank technique, in which cells are scraped from the base of the lesions with a scalpel blade or beveled edge of a large-gauge needle, smeared on a glass slide, and stained using fluorescein-conjugated monoclonal antibodies. When DFA was compared with viral culture in 92 human immunodeficiency virus–seropositive patients with herpes zoster, the DFA was positive in 92% compared with culture in only 65%.³⁴ Polymerase chain reaction has been used to detect VZV DNA in the lesions and is the most sensitive technique currently available. Although sensitivity and specificity data are limited, both exceed 90%.^{8 ,35}

Quiz Ref IDThe goals for medical management of herpes zoster are to accelerate the resolution of cutaneous disease, limit the severity and duration of pain, and reduce the risk of complications. Currently, 3 drugs—acyclovir, valacyclovir, and famciclovir—are licensed by the US Food and Drug Administration (FDA) for systemic therapy of herpes zoster (Table).¹⁴ In Europe, brivudine (bromovinyl deoxyuridine) is also licensed. However, because of its potential for life-threatening interactions with 5-fluorouracil, approval in the United States is unlikely.⁴¹ The Table summarizes relevant trials and a meta-analysis of antiviral agents used to treat herpes zoster.

Acyclovir was the first medication licensed for the treatment of herpes zoster. Randomized, placebo-controlled trials evaluated oral acyclovir therapy at a dose of 800 mg 5 times daily, initiated within 72 hours of lesion onset. Acyclovir therapy accelerated the cessation of new lesion formation and cutaneous healing.^{42 - 44} A meta-analysis demonstrated that acyclovir was superior to placebo for resolution of moderate to severe zoster-associated pain, defined as a continuum of pain measured from initial onset until resolution (Table).³⁶ In addition, the median duration of time to the first pain-free period was modestly reduced from 32 days to 28 days and absence of pain from 67 days to 28 days, for placebo and acyclovir recipients, respectively. Acyclovir's utility is limited by relatively poor bioavailability and, as a consequence, the need to take the medication 5 times daily.

Valacyclovir, the prodrug of acyclovir, produces significantly higher (5-fold) serum acyclovir levels when administered as 1 g orally 3 times daily. In a randomized trial of patients older than 50 years, valacyclovir and acyclovir were equivalent for accelerating the events of cutaneous healing when initiated within 72 hours of lesion onset. However, valacyclovir was superior to acyclovir in accelerating the resolution of zoster-associated pain (median duration of pain, 38 days vs 51 days; P = .001).³⁷ No benefit was reported for the prevention of PHN. A Cochrane review of antiviral treatment for preventing PHN reported no benefit of valacyclovir at 4 or 6 months after rash onset.⁴⁵

Famciclovir, the prodrug of penciclovir, was evaluated in a placebo-controlled trial conducted in 419 immunocompetent patients within 72 hours of onset of herpes zoster.³⁸ Therapy (500 mg every 8 hours for 7 days) was superior to placebo in reducing the duration of viral shedding, limiting the duration of new lesion formation by 1 day, and accelerating the events of total cutaneous healing by 1 to 2 days. In a subset of patients older than 50 years, the median duration of PHN was reduced from 163 days to 63 days (P = .004) in the placebo and famciclovir treatment groups, respectively.³⁸ Some authorities have concluded that famciclovir has no effect on PHN.⁴⁵

Valacyclovir and famciclovir were compared for the treatment of herpes zoster in immunocompetent patients in a randomized, controlled clinical trial that initiated treatment within 72 hours of lesion onset. The drugs were therapeutically equivalent both for cutaneous healing and pain resolution.⁴⁰ Because of the superior pharmacokinetic profiles and ease of administration (3 times per day instead of 5 times per day), valacyclovir and famciclovir are preferred over acyclovir for the treatment of herpes zoster. While each of the 3 drugs has been associated with increased creatinine levels in poorly hydrated patients, all have been found to be safe and well-tolerated.^{37 - 38 ,45} The cost of a course of generic acyclovir, valacyclovir, and famciclovir for the treatment of herpes zoster averages $45.57, $247.01, and $245.27, respectively, with some variation by pharmacy.^{46 - 47} Valacyclovir should become available generically late in 2009.

The role of corticosteroid therapy in the management of herpes zoster at presentation has been evaluated in 2 large controlled clinical trials. One study compared acyclovir with and without prednisolone in individuals older than 18 years.⁴⁸ No placebo population was included. A second study enrolled patients older than 50 years in a 2 × 2 factorial trial, including placebo groups. In both studies, patients receiving corticosteroids had a modest but significant acceleration in cutaneous healing (hazard ratio, 2.07; 95% confidence interval, 1.26-3.38)⁴⁹ and acceleration in cessation of acute neuritis (hazard ratio, 3.02; 95% CI, 1.42-6.41).⁴⁹ However, neither study demonstrated an effect on the incidence or duration of PHN. The addition of corticosteroids for the management of herpes zoster in selected older individuals did result in the improvement of quality-of-life measurements such as reduction in time to uninterrupted sleep, time to return to usual activities, and analgesic use.⁴⁹ The risk reduction for each of these factors varied between 2 and 3.3. These findings should not be ignored when considering corticosteroid therapy. The optimal dose and duration of corticosteroid therapy in the setting of herpes zoster has not been defined, but a reasonable approach may be to initiate prednisone, 60 mg/d, and taper the dose over 10 to 14 days. Corticosteroid therapy can have significant adverse effects and should not be used in patients who are at increased risk of toxic effects, such as those with diabetes mellitus, gastritis, significant hypertension, or osteoporosis.^{47 - 48} In my opinion, in the absence of these clinical entities, the benefits outweigh risks. The use of corticosteroid therapy for herpes zoster without concomitant antiviral therapy is not recommended.

Ms A appropriately was prescribed valacyclovir at the time of presentation to the emergency department. While controversial, the use of corticosteroid therapy might have been considered because of the severity of her pain.

Medical management, including administration of narcotic analgesics, of PHN is complex.^{24 ,50 - 51} A clinical trial of oxycodone for patients with PHN resulted in a significant reduction of pain from 67% to 11% in placebo and treated recipients, respectively.⁵² Long-acting opioid preparations (oral or transdermal) are preferable to short-acting analgesics for pain management. Additionally, several randomized, controlled clinical trials have shown that tricyclic antidepressants, either as a single agent or in combination with other drugs, can be effective in reducing the pain of PHN.^{53 - 54} Because tricyclic antidepressants are frequently associated with sedation and anticholinergic adverse effects, treatment should begin with a low dose at bedtime and gradually increased as tolerated. Historically, phenytoin and carbamazepine were used based on limited clinical trial data, but these drugs have been replaced by gabapentin and pregabalin. Gabapentin has been shown to significantly reduce PHN (on a 0-10 Likert pain scale the pain score decreased from 6.3 to 4.2 with gabapentin vs 6.5 to 6.0 with placebo).^{25 ,55} It is initiated at a dosage of 300 mg 3 times per day and increased as tolerated; adverse effects such as somnolence, dizziness, and ataxia, which occur in up to 30% of patients, may limit the ability to escalate the dose in some patients.^{56 - 57} The adverse effects of narcotics, tricyclic antidepressants, and gabapentin can be additive, especially in elderly patients.²⁵ Pregabalin, with improved pharmacokinetics over gabapentin, has been shown to reduce PHN by 30%.⁵⁸ Many physicians will attempt to wean patients from these medications when abnormal sensations are resolved or at 6 months after disease onset.⁵⁹ The wholesale costs of gabapentin and pregabalin at standard doses are $60 and $80 per week, respectively.

Other approaches to management of chronic pain include topical application of capsaicin⁶⁰ and lidocaine patches.^{61 - 62} These are not the most practical approaches for pain management and are not frequently used. Once-weekly intrathecal administration of methylprednisolone acetate has also been reported to reduce pain in a study of 227 patients; however, additional studies must validate this approach.⁶³ Prevention of PHN is a major concern because antiviral drugs alone do not reliably prevent this complication.⁴² The use of pain medications along with antiviral drugs at the time of presentation of herpes zoster is one strategy that is under investigation.

In March 1995, the FDA licensed the Oka varicella vaccine for administration to children aged 19 to 35 months. By 2003, more than 85% of children had received it. The number of varicella cases in the sentinel surveillance projects decreased from 4000 in 1995 to less than 500 in 2004.^{64 - 65} With universal vaccine deployment, mortality in the United States from varicella in immunocompetent persons has decreased sharply, from approximately 100 deaths annually to 10 or fewer.⁶⁵ Overall, vaccination has resulted in a decrease in the total number of cases of varicella by 3.4 million and hospitalizations by 9600, resulting in a medical cost savings estimated to be $62.8 million.^{66 - 67} Because of sporadic varicella outbreaks, the Advisory Committee on Immunization Practices recently recommended administration of a second dose of vaccine at the time of school entry⁶⁸ because of the failure to seroconvert (24% of vaccinees) and the loss of vaccine-induced immunity to VZV over time.^{69 - 71} The universal vaccination of children with 2 doses of the Oka vaccine strain may change the epidemiology of herpes zoster in adults. If immunity wanes following a second dose, reactivation of herpes zoster may be anticipated in the community because of the lack of exposure of adults to circulating VZV. This hypothesis was suggested more than 40 years ago by Hope-Simpson,¹² who reported a higher incidence of shingles in adults who had no young children in residence. However, this hypothesis remains controversial, and additional prospective data are needed to further clarify the true risks.^{72 - 73}

While the Oka vaccine was licensed to prevent varicella, it was also evaluated in adults to prevent shingles, but a higher titer of live attenuated virus was required to elicit significant and durable increases in CMI responses.⁷⁴ Therefore, a live attenuated VZV vaccine (Zostavax; Merck & Co, Whitehouse Station, New Jersey) was developed specifically for protection against herpes zoster. The herpes zoster vaccine contains, on average, 19 400 plaque-forming units per dose,⁷⁵ whereas the chickenpox vaccines contain either approximately 9800 plaque-forming units per dose (quadrivalent measles, mumps, rubella, and varicella vaccine)⁷⁶ or 1350 plaque-forming units per dose (monovalent varicella vaccine [Varivax; Merck & Co]).⁷⁷ A herpes zoster vaccine, to be effective, should boost an older person's CMI responses and, therefore, mimic immunologic benefit of exposure of VZV-immune adults to chickenpox.⁷⁸ Indeed, several dose-ranging studies of vaccine defined a boost in waning CMI in older individuals.^{74 ,79 - 80}

The Shingles Prevention Study evaluated the high-titer, live attenuated herpes zoster vaccine⁸ in nearly 40 000 participants older than 60 years with a mean follow-up of 3 years. Benefit was defined in 3 specific areas. First, the incidence of herpes zoster was 50% lower in the vaccine group than in placebo recipients (5.4 cases per 1000 person-years vs 11.1 cases per 1000 person-years [P < .001]). From a safety standpoint, among participants who developed herpes zoster during the study, vaccine virus was not detected by polymerase chain reaction. Quiz Ref IDSecond, the incidence of PHN was 67% lower among vaccine recipients (0.5 cases per 1000 person-years vs 1.4 cases per 1000 person-years [P < .001]). In addition, the median duration of pain among individuals in whom herpes zoster developed was statistically significantly shorter in the vaccine group, albeit of marginal clinical value (21 vs 24 days [P = .003]). Third, vaccination significantly decreased the burden of illness overall for patients who developed herpes zoster (as assessed by area under the burden-of-illness curve analysis [P = .008]). When outcomes were analyzed according to 2 age groups, the vaccine was more effective at preventing herpes zoster in younger elderly (60-69 years) compared with older elderly (≥70 years) patients. However, it prevented PHN and burden of illness to a similar extent in both groups.

In 2006, the FDA licensed the herpes zoster vaccine for the prevention of herpes zoster in persons aged 60 years or older.^{8 ,75} This vaccine is not indicated for the treatment of PHN or herpes zoster. The herpes zoster vaccine is contraindicated in persons with a history of anaphylaxis to gelatin, neomycin, or any other vaccine component. Similarly, it is not licensed for use in immunocompromised individuals.

The cost of the vaccine varies; however, in analyses performed by the Centers for Disease Control and Prevention, the cost was estimated at $700. The estimated cost per quality-adjusted life-year ranges from $14 877 to $34 852, a range that is considered acceptable for vaccine administration. Approximately 17 individuals would need to be vaccinated to prevent 1 case of herpes zoster, and 31 would need to be vaccinated to prevent 1 case of PHN.⁶ The cost of management per case of herpes zoster is estimated to be $3300 and the cost of management for PHN is estimated at $6405.⁶

Administration of the herpes zoster vaccine appears safe and free of significant complications. Varicella-like rashes have been noted at the injection site (0.1% vs 0.04% in vaccine vs placebo recipients, respectively [P = .07]).⁸ Erythema, localized tenderness, and pruritus were also significantly more common at the injection site for vaccine recipients; 1 or more adverse events at the injection site occurred in 48% (vs 17% in placebo).⁸ Myocardial infarctions were more frequent in vaccine recipients (0.6% vs 0.4%), but this difference was not significant.⁷⁵ Whether these are attributable to the vaccine remains to be established.

Several questions require study, including the need to continue to monitor long-term outcomes, particularly the duration of immunologic responsiveness of vaccine recipients, additional cost-benefit analyses, the value of the vaccine for persons aged 50 to 59 years, its use in immunocompromised persons, and the efficacy of the vaccine in persons who have had a previous episode of herpes zoster and the effect of the chickenpox and shingles vaccines on the changing epidemiology of VZV infections.⁷²

At this juncture, Ms A would not benefit from continued antiviral therapy. Because of her age and pain at presentation, the likelihood of her developing PHN exceeded 75%.¹ She and her physician may want to consider adding an analgesic to the gabapentin,⁸¹ in addition to the plan of increasing the gabapentin dose over the next several weeks to allow acclimation to the sedating effects of the medication. This approach likely will help control her pain but will require careful titration. Of note, the Advisory Committee on Immunization Practices recommends administration of herpes zoster vaccine to those who have had shingles but does not specify at what interval it should be given after infection.⁶⁸

QUESTION: Can you comment about the 72-hour window for antiviral drug administration?

DR WHITLEY: The clinical trials of acyclovir, valacyclovir, and famciclovir all required that patients be treated within 72 hours of disease onset.^{36 - 38 ,43 - 44} Thus, this is the window that was used by the FDA for licensure. Personally (and this is off label), if a patient continues to form new lesions after 72 hours at the time of presentation, I think that therapy may still be of benefit.

QUESTION: Are there instances where the vaccine virus has been associated with herpes zoster? Presumably it disseminates and will be a source of zoster in the future. Could you please comment on this observation?

DR WHITLEY: Cases of herpes zoster attributed to the vaccine have been reported, but they are uncommon. In the Shingles Prevention Study there were no cases attributed to the vaccine.⁸ However, cases have been reported in immunocompromised children who participated in the very early varicella vaccine trials.⁸² But the incidence of shingles in children with acute lymphoblastic leukemia who received vaccine was lower than that in placebo recipients.⁸³

QUESTION: For health care providers who see patients with herpes zoster, do we get the same kind of boost in immunity that pediatricians get?

DR WHITLEY: Yes, health care providers who are exposed to patients with VZV infections have periodic boosts in their CMI responses. As such, the incidence of shingles is decreased.

QUESTION: You mentioned briefly about the use of corticosteroids, an old therapy, for the treatment of shingles. The question is, does it have any role now? And if so, how do we select patients who would benefit from it, what dose do we use, and how long do we use it?

DR WHITLEY: The concomitant administration of prednisone and an antiviral drug will significantly improve such quality-of-life parameters as return to usual activity, ability to sleep at night, and cessation of analgesic use.⁴⁹ However, steroids, because of potential complications, should be restricted to those who have severe pain at presentation and are not at significant risk of toxic effects. Patients with significant hypertension, osteoporosis, and diabetes mellitus should be excluded from this therapeutic approach regardless of their degree of pain.⁴⁹