Supplement to Annals of Long-Term Care: Clinical Care and Aging and Clinical Geriatrics

This educational activity is sponsored by the American Geriatrics Society

Needs Statement
According to The Centers for Disease Control and Prevention, approximately 20% of the U.S. population will develop herpes zoster (HZ), and this corresponds to more than a million new cases of the disease each year in the United States. Herpes zoster is a localized neurocutaneous infection that begins when the varicella zoster virus (VZV), which has been latent in cranial and spinal sensory ganglia following childhood chickenpox, reactivates and multiplies. After multiplying in the sensory ganglion, the virus travels down the sensory nerve to produce a vesicular rash in the corresponding dermatome. More than 1 in every 5 people who have had chicken pox as children will get herpes zoster. Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome that occurs as a complication of shingles, most commonly in older persons.

The incidence and severity of HZ, as well as the frequency and severity of its complications, increase markedly with age. More than half of all cases of HZ occur in persons over age 60. Even without complications, HZ can interfere with an elderly person’s ability to perform essential activities of daily living, resulting in a loss of independence that is emotionally devastating and often irreversible. The most common complication of HZ in elderly persons is PHN, the pain of which frequently results in disordered sleep, chronic fatigue, depression, and anxiety disorder.

Management of zoster-related pain should begin as soon as possible after the onset of symptoms. Combination therapy—including antiviral, antidepressant, corticosteroid, opioid, and topical agents—provides the most effective analgesia. However, antiviral therapy has a modest impact on the acute phase of HZ and does not appear to prevent the development of PHN.

On January 1, 2006, America’s oldest baby boomers reached the 60-year mark. As their ranks swell in the coming years, geriatricians and primary care physicians (PCPs) must be prepared to see a growing number of patients with HZ. They need data and clinical information that will help them better manage patients to improve outcomes.

Learning Objectives
After reading this supplement, participants should be able to:
• Explain the rationale for the use of a zoster vaccine to prevent herpes zoster and postherpetic neuralgia in older adults and the pharmacoeconomic implications of the vaccine.
• Describe how the zoster vaccine is being used in the United States and around the world.
• Discuss the most recent data on the impact of the varicella vaccine on chickenpox and herpes zoster.
• Discuss state-of-the-art thinking/practice regarding the treatment of acute herpes zoster pain and postherpetic neuralgia.

Accreditation Statement
The American Geriatrics Society (AGS) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The AGS designates this continuing medical education activity for a maximum
of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Target Audience
This continuing medical education offering is intended for internal medicine physicians, family practitioners, geriatricians, general practitioners, infectious disease specialists, pain specialists, neurologists, physician assistants, and nurses.

Method of Participation
Based on trials, this activity should take approximately 1 hour to complete.
To receive credit, participants must complete the CME Examination that appears at the end of this program, and fax or mail it to:

American Geriatrics Society
The Empire State Building
350 Fifth Avenue, Suite 801
New York, NY 10118
Fax: (212) 832-8646
Attn: Dennise McAlpin

A minimum score of 70% on the CME Examination is required for credit. A certificate of completion will be mailed within 4 weeks of receipt of the completed answer sheet.

Disclosure
As an accredited provider of Continuing Medical Education, the American Geriatrics Society continuously strives to ensure that the education activities planned and conducted by our faculty meet generally accepted ethical standards as codified by the ACCME, the Food and Drug Administration, and the American Medical Association’s Guide for Gifts to Physicians. To this end, we have implemented a process wherein everyone who is in a position to control the content of an education activity has disclosed to us all relevant financial relationships with any commercial interests as related to the content of their presentations and under which we work to resolve any real or apparent conflicts of interest.

Faculty conflicts of interest in this particular CME activity have been resolved by having the content independently peer reviewed before publication. James Pacala, MD, MS, served as the peer reviewer on behalf of the AGS Annual Meeting Program Committee. Peer Reviewer Disclosure: Dr. Pacala has no financial relationships with commercial interests.

All speakers were independently selected by the organizing committee for the 2007 Annual Scientific Meeting of the American Geriatrics Society, upon which this supplement is based. Those speakers who disclosed affiliations or financial interests with commercial interests involved with the products or services to which they may refer are listed below. We have also noted if a speaker indicates that s/he will be discussing a commercial product or an off-label or investigational use.

The following faculty (and/or their spouses/partners) have reported real or apparent conflicts of interest that have been resolved through a peer review content validation process:

Kenneth E. Schmader, MD
Dr. Schmader receives grant support and serves as a speaker for Merck & Co., Inc.
Rafael Harpaz, MD, MPH
Dr. Harpaz has no affiliation with or financial interest in any commercial interest that may have direct interest in the subject matter of his presentation.
Michael N. Oxman, MD
Dr. Oxman has no affiliation with or financial interest in any commercial interest that may have direct interest in the subject matter of his presentation.

Disclaimer
Program Release Date: September 15, 2007
Program Expiration Date: September 14, 2008

This educational activity is sponsored by the American Geriatrics Society.
This CME activity is supported by an educational grant from Merck & Co., Inc.

Update on the Burden and Treatment of Herpes Zoster Pain
Kenneth E. Schmader, MD

There are approximately 1 million new cases of herpes zoster (HZ, or “shingles”) in the United States each year, causing acute and chronic pain or postherpetic neuralgia (PHN). The incidence and severity of both HZ and PHN increase with increasing age and are greatest among older adults. Among all U.S. adults, there are approximately 1.2-4.8 cases per 1000 person-years, but among those at least 60 years of age, the incidence is between 7.2 and 11.8 cases per 1000 person-years.^1-4 With the older population growing in number, the incidence of HZ and PHN is likely to increase as well.⁴ The Centers for Disease Control and Prevention and the Group Health Cooperative performed a collaborative study of the age-specific incidence rates of HZ. They collected data from 1992 through 2002. The investigators observed that despite a decrease in the incidence of varicella disease (chickenpox) following introduction of the varicella vaccine, the incidence of HZ had not decreased, and it was higher with each decade of age, with the greatest incidence among those at least 80 years old.⁵

In addition to increasing age, suppression of the cellular immune system is a primary risk factor for HZ. Immunosuppressed patients, such as those infected with the human immunodeficiency virus, those undergoing exogenous immunosuppression for organ transplantation, or those with certain diseases, such as leukemia and lymphoma, are at high risk for HZ.⁴

HZ results from reactivation of the varicella zoster virus (VZV), which is a double-stranded DNA herpes virus. The virus establishes latency in dorsal sensory ganglia. With time and aging, the virus periodically reactivates, but it is generally contained by the cellular immune system. With immunosenescence, however, the cellular containment can fail and the virus can reactivate successfully in the sensory nerve. It also affects the dorsal root ganglion and the root, and even the ventral horn of the spinal cord. When VZV reaches the skin, obvious manifestations such as a characteristic rash develop (Figure 1).^4,6

Impact of Herpes Zoster
The most important effect of HZ is pain, both acute and chronic. It has become apparent that the effects of acute pain can be as devastating as those of chronic pain. Katz and colleagues⁷ performed a prospective study of the impact of acute HZ pain on health-related quality of life among 110 patients with HZ, about 73% of whom were at least 50 years of age. Although 4% of patients denied any HZ pain, 42% described their worst pain as “horrible” or “excruciating.” The investigators observed that a greater burden of acute HZ pain was associated with poorer physical and social functioning and increased emotional distress, particularly depression.⁷ Coplan et al⁸ performed a prospective, observational study enrolling patients at least 60 years of age to evaluate the Zoster Brief Pain Inventory. They found that HZ pain interference was greatest for enjoyment of life, sleep, general activities, leisure activities, getting out of the house, and shopping. The magnitude of interference increased with increasing intensity of pain and discomfort. Patients with high levels of pain had difficulty with all activities of daily living.⁸

HZ can affect the eyes, and patients with ophthalmic HZ frequently report excruciating pain that resembles an “ice pick behind the eye.” Acute inflammation in the trigeminal nerve makes this pain particularly excruciating. For many patients, including up to 70% of those at least 60 years of age, the damage over time causes changes in the peripheral and central nervous systems. Pain that persists long after the rash has healed is called PHN.⁴ The dorsal root ganglion undergoes a great deal of destruction and fibrosis, resulting in extensive cell death and scarring.⁹ This can even extend to the dorsal horn of the spinal cord. Like acute HZ pain, PHN can have an adverse impact on several domains of health and quality of life in elderly patients. Physically, PHN can cause chronic fatigue, anorexia, weight loss, physical inactivity, and insomnia. As with acute HZ pain, PHN can interfere with activities of daily living, including dressing, bathing, eating, moving in general, traveling, cooking, doing housework, and shopping. In the psychological domain, PHN is likely to cause depression, anxiety, and difficulty with concentration. Patients with PHN are also prone to avoiding social gatherings and to minimizing their social role.⁴

Treating Herpes Zoster and Postherpetic Neuralgia
The primary goal of treatment for HZ is reducing pain. Several general pain management principles are applicable to acute pain of HZ. They include using standardized pain measures, scheduled analgesia, anticipatory guidance regarding and treatment of adverse effects of analgesics, and consistent and frequent follow-up to adjust dosages or change medications. Optimally, pain management should be a daily activity for a patient having ongoing, severe pain. Because it is difficult to attain consistent, tight pain control, it is important to stay on top of the pain to whatever extent possible.

A group of experts in the field recently published a set of guidelines for management of acute pain caused by HZ.⁹ Antivirals are the first line of treatment for HZ. Analgesics, particularly opioid analgesics for moderate-to-severe pain, can reduce pain acutely. Some patients, however, will still have significant pain with these two interventions. Supplemental treatments available in that case include corticosteroids, anticonvulsants, tricyclic antidepressants, and anesthetic nerve block.

Antivirals
Antiviral therapy, especially if begun early in the course of the disease, has been shown to reduce acute pain. Additionally, although it does not prevent PHN, it is useful in reducing the duration of chronic pain. Antivirals used commonly to treat HZ include acyclovir, famciclovir, and valacyclovir. Famciclovir and valacyclovir are generally preferred over acyclovir because the bioavailability of these agents is much greater and patients need to take them only 3 times per day.¹⁰ For the clinician practicing within a restricted formulary who must use acyclovir initially, the good news is that there are no data to suggest that any one of these agents is superior to the others in terms of alleviating pain—only in bioavailability and ease of use.

Table I reflects data from several major trials of the effect of antiviral therapy on both acute and chronic pain of HZ after rash onset among patients at least 50 years of age.¹¹ The data are both encouraging and disappointing in that, although antiviral treatment is clearly superior to no treatment and is effective in reducing the duration of chronic pain, a large proportion of patients who receive treatment, even early in the disease course, continue to have pain.^11-14 Thus, antivirals are a good step forward, but they are not sufficient by themselves for resolving the pain of HZ, and they most often must be supplemented with other therapies.

Analgesia
Opioid analgesics are considered the gold standard for treating both inflammatory and neuropathic pain. Previously, there was a great deal of aversion to using opioids in neuropathic pain. Recently, however, a very good database has grown to support the utility of opioids in treating neuropathic pain. Opioids are known to be effective in reducing acute pain, but their ability—or lack of ability—to prevent PHN is as yet unknown. It is generally apparent almost immediately whether a patient is responding to opioids, and the risk of abuse by older adults without histories of substance abuse is low. Unfortunately, however, many patients, particularly frail elders, have difficulty tolerating opioids. Even if they are having moderate-to-severe pain, they often experience the side effects that are typical of opioid medications.⁹ This presents a quandary regarding what to use for these patients.

Several very good, evidence-based, randomized clinical trials have shown that corticosteroids do not prevent PHN. Additionally, these agents can have adverse side effects, particularly in frail elderly persons. Therefore, their routine use for treatment of acute pain in HZ cannot be advocated. That being said, patients who took corticosteroids in clinical trials felt better early in the course of the studies and reported decreased pain. Corticosteroid therapy may be worth considering for patients whose pain has not been relieved by antiviral therapy and/or treatment with opioid or nonopioid analgesics. These include patients with very severe pain, particularly cranial polyneuritis.⁹ Patients with painful Bell’s palsy may have HZ, and those individuals probably should receive antivirals and corticosteroids to reduce the swelling in the neural foramina.

The U.S. Food and Drug Administration (FDA) has approved gabapentin and pregabalin for the treatment of PHN. They are better tolerated than other anticonvulsants, which are not approved for treating PHN. Pregabalin may be preferable because its dosage can be titrated more quickly than can that of gabapentin.⁹ Using these drugs to treat acute HZ pain is off-label prescribing, but clinicians around the United States have been prescribing them early in acute HZ episodes. There are no clinical trials showing that these agents reduce acute HZ pain or prevent PHN. In a proof-of-concept study at the University of California at San Francisco, patients with acute HZ were given either placebo or a 900-mg dose of gabapentin, and their pain response was measured over a 24-hour period. The gabapentin clearly reduced HZ pain15; however, such a high dose may not be safe for elderly patients. The downside of the anticonvulsants are the somnolence and dizziness that patients can experience with these agents; also, ataxia and peripheral edema can be significant. Some patients who experience these side effects will begin to tolerate the effects if they persist with the dosing regimen, but others cannot tolerate them, becoming too dizzy and somnolent, and must discontinue treatment.¹⁶

As with anticonvulsants, there is no evidence that tricyclic antidepressants reduce acute pain. A placebo-controlled study by Bowsher¹⁷ in the United Kingdom assessed whether amitriptyline prescribed during the acute HZ phase would reduce PHN in patients more than 60 years of age. Although this was a small trial with key methodological flaws, the results suggested efficacy for amitriptyline.¹⁷ However, tricyclic antidepressants are clearly effective for reducing neuropathic pain. Data supporting the efficacy of tricyclic antidepressants for PHN are more plentiful than for other analgesic approaches. In fact, these agents are the standard of care for nonopioid analgesia in various formulary systems, including the National Health Service in England and the Veterans Affairs Healthcare System in the United States. Tricyclic antidepressants should be prescribed with caution, however, as they can have anticholinergic side effects and cardiac toxicity for some patients. Amitriptyline has the highest side-effect profile of the three commonly used tricyclics and is contraindicated
for elderly patients.¹⁸

Although there is a paucity of clinical trials of anesthetic nerve blocks in PHN, there are data suggesting that it does have a modest effect in reducing acute HZ pain.⁹ For patients who cannot tolerate opioids, or for whom other treatments have failed, nerve blocks can be very effective in reducing acute pain. Unfortunately, it appears that they do not prevent PHN. The Prevention by epidural Injection of postherpetic Neuralgia in the Elderly (PINE) study, performed in the Netherlands, compared antiviral therapy and oral analgesics plus usual care (n = 297) with a regimen comprising antiviral agents, oral analgesics, and a single epidural injection of bupivacaine and methylprednisolone (n = 301).¹⁹ Within the first few weeks, there was greater reduction in acute pain among patients who received epidural injections. After approximately 2 months, however, the disparity narrowed, and the injection did not prevent PHN.¹⁹ In a Japanese study, patients were admitted to the hospital and received continuous epidural infusions for several days. That did reduce acute pain and did seem to prevent PHN²⁰; however, no such study has been performed in the United States, and continuous infusion is not feasible in most situations.⁹

The lidocaine patch 5% is not indicated for acute HZ pain but is effective for PHN. It is very easy to use and has an excellent safety profile, and it is generally apparent within 2 weeks whether the patch is effective. Some patients develop skin rashes, but systemic absorption is minimal.¹⁸

Table II summarizes the advantages and disadvantages of agents used to treat PHN that have been shown to be effective in at least two trials each.^16,18

Another strategy for treating PHN is combination therapy. Rather than monotherapy, given in a sequential fashion, combining agents may augment a partial response to a single drug, provide the simultaneous efficacy of different mechanisms of action, or provide more rapid onset of relief than would the use of a single drug whose onset of action is slow. The disadvantages of combination therapy are the potential for increased adverse effects of unclear origin and increased expense.¹⁸

A Canadian study compared the effects of morphine, gabapentin, and their combination with one another and with placebo for neuropathic pain.²¹ This was a randomized, double-blind, 4-period crossover trial enrolling patients with diabetic neuropathy (n = 35) or PHN (n = 22). When the investigators analyzed the data after all of the crossover periods, there was some reduction of pain in that in the natural course of PHN, pain may decrease somewhat without treatment. Pain was reduced more by either drug alone than with placebo and more by the combination than with either drug alone (Figure 2).²¹ The adverse event rate was higher in the combination group than with either drug alone. This study supports the hypothesis that combination therapy probably is useful, but at the risk of increased adverse effects.²¹

Nonpharmacologic Therapy
There are a number of nonpharmacologic treatments for PHN, but none have been well proven. Patients whose pain is not controlled adequately with combinations of antiviral drugs and either analgesics or corticosteroids might benefit from referral to a pain specialist or pain management center. Patient education and psychological counseling also play important roles in pain management; additionally, mental and physical activity can help patients cope with their pain.^4,18 Other nonpharmacologic approaches to PHN that are sometimes quite useful include percutaneous or transcutaneous electrical nerve stimulation, acupuncture, and trigger point injections.

Older patients who have developed a myofascial component to their pain may present a particularly difficult management challenge. It may be that the virus crosses over and affects the ventral horn, which might cause paresis or irritation of a muscle. In fact, some patients with PHN have very tight muscle bands, with trigger points that are not the same as allodynia, and it is likely that these patients have some myofascial pathology. In a small case series at the University of Pittsburgh in Pennsylvania, five patients with pain lasting from 4 months to 7 years were found to have myofascial pathology, diagnosed based on the presence of taut bands and trigger points in the affected myotome. These patients were treated with nonpharmacologic modalities such as trigger point injections, percutaneous electrical nerve stimulation, dry needling, and physical therapy. All of the patients reported improvement, and four of them were able to discontinue or reduce their opioid therapy.²² Therefore, it may be useful to look beyond the neuropathic component of patients’ pain and explore the possibility of a myofascial component as well.

Conclusion
With the drugs that have shown efficacy in at least two well-controlled trials, namely opioids, tricyclic antidepressants, anticonvulsants, and the lidocaine patch 5%, clinically meaningful reductions in pain—between 30% and 50%—have occurred in 30-60% of patients. Thus, the good news is that we have more in our armamentarium to treat PHN and chronic HZ pain, and some patients do well on these medications. Clearly, however, the remainder of patients do not attain relief or cannot tolerate pharmacologic agents, and these patients’ pain is more difficult to treat. Immunotherapy also has a potential role in reduction of HZ pain and is addressed in the following articles. More research is needed to provide additional tools for use against the potentially devastating pain of PHN.

References
1. Gnann J, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med 2002;347:340-346.
2. Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 2004;4:26-33.
3. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.
4. Schmader K. Herpes zoster in older adults. Clin Infect Dis 2001;32:1481-1486. Epub 2001 Apr 17.
5. Jumaan AO, Yu O, Jackson LA, et al. Incidence of herpes zoster, before and after varicella-vaccination-associated decreases in the incidence of varicella, 1992-2002. J Infect Dis 2005;191:2002-2007. Epub 2005 May 12.
6. Grose C, Ye M, Padilla J. Pathogenesis of primary infection. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus. Cambridge, UK: Cambridge University Press; 2000:105-122.
7. Katz J, Cooper EM, Walther RR, et al. Acute pain in herpes zoster and its impact on health-related quality of life. Clin Infect Dis 2004;39:342-348. Epub 2004 Jul 19.
8. Coplan PM, Schmader K, Nikas A, et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the Brief Pain Inventory. J Pain 2004;5:344-356.
9. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(suppl 1):S1-S26.
10. Kost RG, Straus SE. Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32-42.
11. Dworkin RH, Schmader KE. Epidemiology and natural history of herpes zoster and postherpetic neuralgia. In:Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York: Elsevier Press; 2001:39-64.
12. Beutner KR, Friedman DJ, Forszpaniak C, et al. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39:1546-1553.
13. Dworkin RH, Boon RJ, Griffin DR, Phung D. Postherpetic neuralgia: Impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 1998;178(suppl 1):S76-S80.
14. Wood MJ, Kay R,Dworkin RH, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo-controlled trials. Clin Infect Dis 1996;22:341-347.
15. Berry JD, Petersen KL. A single dose of gabapentin reduces acute pain and allodynia in patients with herpes zoster. Neurology 2005;65:444-447.
16. Dubinsky RM, Kabbani H, El-Chami Z, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: Treatment of postherpetic neuralgia. An evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004;63:959-965.
17. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: A randomized, double-blind, placebo-controlled trial. Pain Symptom Manage 1997;13:327-331.
18. Dworkin RH, Schmader KE.Treatment and prevention of postherpetic neuralgia. Clin Infect Dis 2003;36:877-882. Epub 2003 Mar 13.
19. van Wijck AJ, Opstelten W, Moons KG, et al.The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: A randomised controlled trial. Lancet 2006;367:219-224.
20. Manabe H, Dan K, Hirata K, et al. Optimum pain relief with continuous epidural infusion of local anesthetics shortens the duration of zoster-associated pain. Clin J Pain 2004;20:302-308.
21. Gilron I, Bailey JM,Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352:1324-1334.
22. Weiner DK, Schmader KE. Postherpetic pain: more than sensory neuralgia? Pain Med 2006;7:243-250.


The Epidemiology of Herpes Zoster in the Varicella Vaccine Era
Rafael Harpaz, MD, MPH

Following the initial varicella zoster virus (VZV) infection, which causes chickenpox, VZV establishes permanent latency in dorsal root ganglia along the entire neuraxis.Years to decades later,VZV reactivates.The VZV virions reappear and spread to the skin through peripheral nerves to cause herpes zoster (HZ), a crop of blisters in a dermatomal distribution that is generally accompanied by pain.

Risk Factors for Herpes Zoster and Postherpetic Neuralgia
The lifetime risk of developing HZ is approximately 30%, and repeated episodes of HZ do occur. Age is an important risk factor for HZ and plays the dominant role influencing the incidence of HZ in the population. This observation was most elegantly made by Dr. R. Edgar Hope-Simpson, who had a large medical practice in the United Kingdom and charted the incidence of HZ among his patients by age. Although he observed a substantial amount of HZ among children, the incidence really started to increase among patients over 50 years of age.¹ Virtually all studies of the epidemiology of HZ have made the same observation regarding the impact of age on incidence of HZ.

Immunosuppression, though uncommon in the population, also has an important impact on the incidence of HZ due to the magnitude of its association with HZ. Patients who undergo bone marrow transplantation, those infected with human immunodeficiency virus, and those with hematologic malignancies all have risks of HZ that are many times higher than other persons of the same age.^2-11

There are other putative risk factors for HZ for which the data are inconsistent, unconfirmed, or of lower magnitude. Most studies show that there is a higher risk of HZ among females than among males. The risk among blacks has been observed to be less than half of that among whites, in both the United States and the United Kingdom.^12-14 The risk also appears to be lower by approximately 44% among people from regions where varicella occurs at older ages.¹⁴ Thomas et al¹⁵ found that the risk of HZ in an area with local trauma was increased 12-fold in the 30 days following trauma. Data from two studies showed that there is an approximately 40% increase in HZ risk following stressful life events.^13,16 Residence near waste-disposal sites¹⁷ and cigarette smoking13,14 may be risk factors, and there appear to be genetic factors that predispose for HZ as well. Of note, children who are infected during gestation or infancy have a very high rate of pediatric HZ.^18-20 Finally, evidence exists that exposure to varicella reduces the risk of HZ, most likely by boosting the VZV-specific immunity system.^21-24 However, these risk factors notwithstanding, it is not known why some immunocompetent persons develop HZ and others do not.

A population-based study in Olmsted County, Minnesota, concluded that the proportion of persons with HZ who go on to develop postherpetic neuralgia (PHN) is 10% if PHN is defined as 90 days of pain after resolution of the rash, and 18% if PHN is defined as 30 days of pain after rash resolution.²⁵ This would translate to about 100,000-200,000 new cases of PHN in the United States per year. Among persons experiencing HZ, the key risk factors for progression to PHN is age (Figure 1).¹ In his patient population, Hope-Simpson found very few patients under 60 years of age with HZ that progressed to PHN, but the risk of such progression increased dramatically in older patients with HZ. Other risk factors for HZ progression to PHN include female gender and ophthalmic HZ. Although immunosuppression increases the risk of HZ, the risk for progression to PHN is not as great.

The Varicella Vaccine
The varicella vaccine is composed of a live attenuated Oka/Merck strain of VZV, or Oka VZV. First evaluated in Japan, the vaccine was subsequently studied in the United States in immunocompromised children for whom chickenpox can often be life-threatening. In the United States, the varicella vaccine was first licensed in 1995, with licensure as part of a combination measles/mumps/rubella/varicella vaccine in 2005. Recommendations for routine vaccination were first issued in 1996 by the Advisory Committee on Immunization Practices (ACIP), and they were updated in 1999 and 2005. In 2006, a booster dose of varicella vaccination was recommended. Requirements for vaccination upon entry to daycare, elementary school, and/or middle school have been adopted in 46 states and the District of Columbia (CDC, unpublished data, 2006). The National Immunization Survey is a large, ongoing survey of immunization in families with children between 19 and 35 months of age; results of this survey show that from 1997 to 2005, coverage with varicella vaccine increased from 26% to almost 90% (Figure 2).²⁶

While varicella was not nationally notifiable until recently, data exist from several sources to strongly suggest that varicella circulation has declined substantially since licensure of varicella vaccine. Active surveillance for varicella is conducted in Antelope Valley, California, and in West Philadelphia, Pennsylvania. Each of these sites has several hundred thousand people living in its catchment area. In both sites, varicella incidence has declined by about 90% in the past 10 years.27 Another surveillance system looked at three states that have reported varicella rates consistently since the pre-vaccine era: Texas, Michigan, and West Virginia. The reductions in cases in these three states between 1995 and 2005 were 64%, 88%, and 80%, respectively (CDC, unpublished data, 2006). Administrative data from insurance companies show that the number of outpatient visits for varicella decreased by approximately 60% between 1994 and 2002.²⁸

There are three ways in which the varicella vaccine program could modify the epidemiology of HZ. The first is due to the fact that the vaccine is itself capable of reactivating and causing clinical HZ. The second is due to the impact of the vaccine on the age distribution of varicella. The third is due to reduced VZV circulation caused by the varicella vaccine, and the consequent reduction in VZV exposure that persons with a history of varicella experience since the vaccine became available.We will examine each of these mechanisms in more detail.

The live attenuated varicella vaccine itself presents a risk for HZ. Oka VZV establishes a latent infection, which has been demonstrated in animal models, and Oka-strain HZ has been detected in varicella vaccine recipients. During early clinical trials evaluating varicella vaccine in immunocompromised children, the risk of HZ among vaccine recipients was about one-third of that in matched immunocompromised children who had previously experienced chickenpox.²⁹ In healthy children, the risk of HZ following varicella vaccination was somewhat lower, perhaps 10% that in age-matched children who had had chickenpox.³⁰ Of note, the HZ tended to be less painful among the vaccine recipients as well. There are few data regarding risk of HZ in healthy adults that had received the varicella vaccine. One study followed 363 vaccinated healthcare workers for up to 26 years, for a median of 4 years, and there were no cases of Oka HZ.³¹ It is unknown, however, what happens to people who were vaccinated during early childhood when they reach the age of 60 and 70, when the risk of HZ is increased. Both children and adults may develop mild varicella after being vaccinated, and there have been reports of vaccine recipients who experienced wild-type HZ after having been vaccinated.³¹

Because of the reduced incidence of varicella and reduced risk of VZV exposure since initiation of the varicella vaccination program, the age of acquisition of new VZV infection is likely delayed as compared to the pre-vaccine era. Since primary infection with VZV during gestation and infancy are strong risk factors for pediatric HZ, it is thus likely that shifts of varicella to older children and adults have altered the age distribution of HZ as well. Less exposure to VZV would, of course, increase the proportion of people who escape VZV infection altogether, so they grow to adulthood without ever having had chickenpox or receiving vaccine. These people are at no risk for reactivation because they have no latent virus, but they are at risk for delayed adult varicella, which can be quite severe and even life-threatening.

In the near term, the third manner in which the varicella vaccine program could modify the epidemiology of HZ may be most important, since it might impact on the more than 99% of U.S.-raised adults who are now latently infected with wild-type VZV, and thereby at risk for HZ.²¹ As noted, the varicella vaccine has lowered the incidence of varicella and opportunities for exposure to VZV. There is evidence that VZV exposure boosts VZV-specific immunity (termed “external boosting”) and that such boosting might lower the risk of HZ. Such a process is biologically plausible; indeed, the efficacy of the newly licensed HZ vaccine provides direct evidence that boosting of VZV-specific immunity by exogenous VZV can prevent HZ.³² There is also epidemiologic evidence from a well-designed casecontrol study conducted in the United Kingdom that HZ risk is reduced among people with five or more exposures to varicella.24 The risk of HZ has also been found to be reduced in persons with increased likelihood of varicella exposure, such as persons living or working with children.^14,22,23,33 The same principle has been observed to apply to children with leukemia who are exposed to siblings who have chickenpox—the children with leukemia were at lower risk for HZ than they would have been absent such exposure.³⁴

It should be noted that these studies regarding the impact of varicella exposure on HZ risk had caveats or flaws, or their results were not substantiated by other studies. For example, living with children may be a marker for a protective health factor rather than a marker for exposure to VZV. In addition, a large case-control study recently conducted in the United States found no association between varicella exposure and reduced risk of HZ.35 Also, most studies find that women are at higher age-specific risk for HZ than are men, even though women typically have more exposure to children and varicella, which would seem to predict lower risk.¹⁴ Taken together, however, the lines of evidence discussed above make a possible case for VZV exposure conferring protection against HZ. Therefore, by reducing varicella incidence and, thus, exposure to VZV, the varicella vaccine may increase the risk of HZ in the short term.

Even if external boosting can in theory reduce the risk of HZ, it is not clear that the varicella vaccination program would adversely influence the epidemiology of HZ. For instance, evidence exists that VZV can reactivate subclinically and boost immunity to VZV.36-38 Might such “internal” boosting compensate when external boosting declines?

Also, protection against HZ may be conferred only at high levels of VZV exposure. In the UK case-control study, an effect was only noted with multiple exposures to varicella.²⁴ Are such levels relevant for the general population? In addition, is the duration of any protective effect sufficient to be important? Finally, if external boosting does reduce HZ risk, does this phenomenon affect the elderly who have fewer opportunities for exposure to varicella, have less robust immunity, and who are at greatest risk for the most serious consequences of HZ (ie, PHN)? Indeed, if reduced exposure to varicella does in fact increase HZ incidence, might it shift its age distribution to younger individuals at reduced risk of PHN? If so, could this paradoxically reduce the burden of HZ?

To address these questions, it is instructive to review results of studies that have tracked HZ incidence over time. These results are listed in the Table^25,32,39-50; they include periods of observation time both with and without varicella vaccine programs.While four of six studies performed after introduction of varicella vaccine show increases in the rate of HZ, eight of ten studies spanning observation time without varicella vaccine programs show increases in HZ rates as well. Rates appear to have been increasing in the United States and elsewhere in the absence of varicella vaccination, an increase that is age-specific and not due to simple aging of the population. These results suggest another unrecognized risk factor for HZ that is increasing in the population, and make interpretation of increases in HZ in the presence of vaccine difficult.

Conclusion
Varicella vaccination appears to reduce the incidence of HZ among vaccinated children and young adults. It would seem that this reduction in risk would persist as vaccine recipients reach older adulthood, but that remains to be proven. The varicella vaccine program should be reducing the number of primary varicella infections occurring during gestation or infancy, which should in turn reduce the incidence of pediatric HZ, but this is likely to be a rare occurrence in any event. The impact of the varicella vaccination program on the risk of HZ among the vast majority of adults with existing latent VZV infection is, in the near term, a more important question. While age-specific HZ rates appear to be increasing, it is not yet possible to attribute the role of the varicella vaccine program on this increase since increases in age-specific HZ rates have been occurring even in the absence of varicella vaccination. The reasons for this secular increase are not known, but this increase needs to be confirmed and its cause elucidated so that public health programs can fully monitor all effects of varicella vaccine and of the newly licensed HZ vaccine. In the long run, the impact of external boosting, if any, is likely to wane as the proportion of the general population with latent wild-type VZV infection declines.

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