Challenging Clinical Cases in Adult Immunization

Focus on: Zoster

Introduction

Herpes zoster currently affects approximately 1 million people in the United States each year, with most cases occurring in the elderly. The aging of the American population and the increasing number of immunocompromised individuals will result in increasing numbers of individuals at risk. As an example, individuals who reach the age of 85 years have an approximately 50% chance of developing herpes zoster.

While most cases are self-limited, herpes zoster can be accompanied by significant morbidity and can significantly decrease the quality of life among elderly patients. These complications, especially postherpetic neuralgia, can occur despite early institution of antiviral therapy. Prolonged symptoms of postherpetic neuralgia can be incapacitating and, in some elderly patients, initiate a downhill spiral in their lives. The introduction of a vaccine with preventive efficacy against the development of herpes zoster is, as a consequence, a welcomed addition to the medical care system. 

The CDC’s Advisory Committee on Immunization Practices recommends that the herpes zoster vaccine be administered to all patients aged 60 and older, except for those with specified contraindications, such as immunodeficiency. 

In October 2009, Vindico Medical Education assembled a panel of experts to address the morbidity associated with zoster, the treatment options, and the safety and efficacy of the vaccine among older and immunocompromised patients. Our panel presented three cases and then discussed the supporting data and implications for clinical practice.

I thank the panel for sharing their experiences and for their assistance in the preparation of this monograph. Readers can expect to gain knowledge on the efficacy, safety, and logistics of the zoster vaccine that can be applied directly to practice.

Stanley C. Deresinski, MD
Course Chair

Increased Risk of Zoster in Older, Immunocompromised Adults

Stanley C. Deresinski, MD

Herpes zoster (zoster) is an illness that occurs by reactivation of the varicella zoster virus, which remains dormant in sensory dorsal root ganglia for decades after the initial infection that had caused chickenpox.¹ Zoster occurs most frequently in older and immunocompromised adults. Approximately 50% of people who live to age 85 will have experienced zoster.^2,3 There are at least 1 million cases of zoster in the United States each year. Given an aging population and the increased risk imposed by aging, these numbers will undoubtedly continue to increase.

The Centers for Disease Control and Prevention (CDC) recommends prompt treatment of herpes zoster with an antiviral agent— either acyclovir, valacyclovir, (an acyclovir prodrug), or famciclovir. These agents can, when indicated, be supplemented with corticosteroids and analgesics, tricyclic antidepressants, and other agents to control the pain.¹

Zoster can be an incapacitating illness during the acute process and is often associated with a variety of complications, including ocular and central nervous system infections. Development of postherpetic neuralgia (PHN), the most frequent complication, causes significant morbidity and diminished quality of life. Like zoster, the risk of PHN also increases with advancing age.⁴

The presence of rheumatoid arthritis increases the risk for zoster, with an incidence of approximately 10 cases per 1,000 patient-years reported among this group.^5,6 For this patient, the primary concerns are whether she will have another occurrence of zoster and how her underlying disease should affect decisions related to treatment and vaccination.

In a normal host, episodes of herpes zoster do not necessarily protect against future occurrences.⁴ The CDC Advisory Committee on Immunization Practices (ACIP) recommends vaccination of all people aged 60 years and older, regardless of past history of herpes zoster. Zostavax, the only currently commercially available vaccine protective against herpes zoster, has been approved by the FDA for use in this age group. The vaccine has been demonstrated to be safe and effective in people who do not have contraindications such as pregnancy, severe immunosuppression, or an allergy to vaccine components (Table). The immunogenicity of the vaccine is highest in patients in their 60s, with somewhat diminishing immunogenicity in older individuals, although it remains efficacious in all age groups studied.⁷

Although this patient is only 64 years of age, vaccine immunogenicity could potentially be diminished by her chronic underlying disease and methotrexate therapy. On the other hand, immunosuppressive therapy increases the risk of the development of herpes zoster. Further complicating the analysis is the fact that the available zoster vaccine consists of live attenuated varicella zoster virus, raising the question of safety in an immunocompromised patient. Additional factors to be considered are that she has a history of herpes zoster, she has rheumatoid arthritis, she is receiving methotrexate, and she is about to receive anti-TNF therapy.

The clinical trial demonstrated that the vaccine was most effective in reducing the incidence of zoster in the youngest age group studied (60–69 years),⁷ so this patient would be anticipated to have an excellent immunologic response to the vaccine, based on this factor.

Also to be considered is that she previously had suffered from a zoster episode. Although some have suggested that reactivation of the virus resulting from the waning cellular immunity may be an immunizing event that can boost immunity again,⁸ there are no clear data to support this hypothesis. In fact, current evidence suggests that development of zoster may not provide any protection against future episodes.⁴ While patients with a previous episode of zoster were excluded from the vaccine clinical trial⁷ and, as a result, we have no direct evidence of efficacy, it is currently recommended that such patients in the appropriate age group are candidates for zoster vaccination.

Caution is needed when considering use of the vaccine in severely immunocompromised patients. The CDC has recommended that the vaccine not be given to immunosuppressed patients, such as those being treated for rheumatologic diseases with methotrexate doses greater than 0.4 mg/kg/week, prednisone doses greater than 20 mg/day, or corticosteroid treatment for more than 2 weeks.¹

While therapy with low doses of methotrexate (<0.4 mg/kg/week), as is the dose used to treat this case patient, is not considered sufficiently immunosuppressive to raise concerns about zoster vaccine safety and is not a contraindication to its administration, therapy with TNF inhibitors and other potent immunosuppressive agents is another matter. A recent study found that patients who receive anti-TNF monoclonal antibodies are at increased risk of zoster.⁹ This is also the case for patients with Crohn’s disease.¹⁰ Ongoing studies are examining the risk-benefit ratio in these populations.

For immunocompromised individuals, the infection can be more severe and have a longer duration. One specific risk for these patients can be dissemination; cutaneous dissemination occurs in up to 37% of zoster patients not receiving antiviral therapy. Although a typical dermatomal distribution of the rash often antedates dissemination, the appearance of a varicelliform eruption may, in some cases, be the first manifestation. The risk of neurologic complications is also increased in patients who are immunocompromised. These complications can include myelitis, chronic encephalitis, ventriculitis, meningoencephalitis, and cranial palsies. Among patients infected with HIV, the clinical features can be less severe. HIV-infected patients may have atypical skin eruptions, alveolar bone necrosis, tooth exfoliation, and aggressive variant of acute retinal necrosis that can result in blindness.¹

For a patient scheduled for anti-TNF therapy, such as this patient with active rheumatoid arthritis, the anti-TNF treatment should be delayed for five half lives of the drug after administering the vaccine. For patients anticipating treatment with infliximab, which has a half life of 9.5 days, the therapy should be delayed more than 30 days. 

References

1. Harpaz R, Ortega-Sanchez IR, Seward JF, Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30.
2. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect. 2001;127:305-314.
3. Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32:1481-1486.
4. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82:1341-1349.
5. Antonelli MA, Moreland LW, Brick JE. Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. Am J Med. 1991;90:295-298.
6. Smitten AL, Choi HK, Hochberg MC, et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007;57:1431-1438.
7. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-2284.
8. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med. 1965;58:9-20.
9. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301:737-744.
10. Marehbian J, Arrighi HM, Hass S, Tian H, Sandborn WJ. Adverse events associated with common therapy regimens for moderate-to-severe Crohn's disease. Am J Gastroenterol. 2009;104:2524-2533.

Herpes Zoster Vaccine: Preventing Morbidity

Richard J. Whitley, MD

Efficacy of Herpes Zoster Vaccine

Several published articles have examined the efficacy of the herpes zoster vaccine to prevent morbidity and the incidence of shingles.^1,2

A randomized, double-blind, placebo-controlled trial of the then-investigational live attenuated zoster vaccine found that use of the vaccine reduced the incidence of herpes zoster by 51.3%(P<.001) (Figure).¹ More than 38,500 adults aged 60 and older (median age 69) were included in the 22-site trial. Nearly all participants were followed until completion of the study, a median of 3.2 years. All participants either had a history of varicella or had lived in the United States for at least 30 years.

During the study, there were 957 cases of herpes zoster; 315 among the group that received the zoster vaccine and 642 among the placebo group. Postherpetic neuralgia (PHN), defined as pain rated as 3 or more on a 10-point scale that persisted or appeared more than 90 days after the rash, occurred in 27 of the vaccine recipients and in 80 from the control group, a reduction in incidence of 66.5% (P<.001).

The burden of illness due to herpes zoster was the primary end point of the trial, defined as a measure of the total pain and discomfort by a severity-by-duration measure. If a participant had confirmed herpes zoster, they were asked to respond to questions on the Zoster Brief Pain Inventory. Their pain severity was calculated during the 182 days after the onset of rash. The vaccine was found to decrease the burden of illness due to herpes zoster by 61.1% (P<.001).

The vaccine was found to be safe. Reactions at the injection site were more frequent among vaccine recipients but were generally mild.¹

Coadministration of Zoster Vaccine with Other Vaccines

A common concern about any vaccine is whether it can be coadministered with other vaccines. Regarding the herpes zoster vaccine, there are data demonstrating that similar immune responses and safety profiles for the zoster and influenza vaccines are observed whether they are administered individually or simultaneously.³ Preliminary data regarding the coadministration of the zoster and pneumococcal polysaccharide vaccines suggested that antibody responses to herpes zoster were slightly compromised.⁴ The significance of this finding is questionable, however, as antibody response is not considered to correlate with protection against herpes zoster. Cell-mediated immunity appears to carry more of a role in protection against herpes zoster.

Risk of Transmission of Zoster Vaccine

Transmission of the virus strain used in the zoster vaccine has been documented following varicella vaccination (to prevent chickenpox—a different vaccine). However, this type of transmission is extremely rare and has only occurred when the vaccine recipient developed a varicella-like rash, and the development of a varicella-like rash appears to be less common with herpes zoster immunization than with varicella vaccination. Transmission of the varicella strain from recipients of the zoster vaccine has not been documented. Therefore, vaccine recipients having close household or occupational contact with persons at risk for severe varicella need not take any precautions after receiving the zoster vaccine, except in rare instances in which a varicella-like rash develops. If this occurs, standard contact precautions are adequate.⁵ The vaccine virus is attenuated and healthy contacts would likely develop a mild case of chickenpox.

Risk of Transmission of Herpes Zoster

Patients who present with acute zoster often have significant concerns about whether infection poses any risk to others. When lesions are present, infection can be transmitted, particularly to those who have not had chickenpox and are seronegative for varicella zoster virus. Children who have not received the chickenpox vaccine, usually under the age of 18 months, are vulnerable to infection; contact with these children should be avoided until the lesions heal. Contact with immunocompromised people of all ages should be also be avoided because of the risk of infection. Lesions should be covered; once scabbed, they are no longer infectious. Zoster does not lead to the reactivation of varicella zoster virus in another person. Transmission of zoster may lead to subclinical boosting of immune responses, but it does not result in chickenpox.

References

1. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-2284.
2. Kimberlin D, Whitley RJ. Varicella-zoster vaccine for the prevention of herpes zoster. New Engl J Med. 2007;356:1338-1343.
3. Kerzner B, Murray AV, Cheng E, et al. Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated influenza vaccine in adults aged 50 and older. J Am Geriatr Soc. 2007;55:1499-1507.
4. Macintyre R, Egerton T, McCaughney M, et al. Concomitant administration of zoster and pneumococcal vaccines in adults < 60 years old. Abstract presented at: 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC. #G-399d.
5. Harpaz R, Ortega-Sanchez IR, Seward JF, Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30.

Barriers to Zoster Immunization and Treatment of Herpes Zoster

Katherine E. Galluzzi, DO, CMD, FACOFP dist.

Herpes zoster can be viewed as a modern day scourge with far-reaching effects on the patients’ well-being and quality of life. Virtually all adults born and raised in the United States have had chickenpox and thus are at risk of developing zoster.  Physicians must try to accelerate the healing, limit the severity and duration of pain, and reduce the painful complications. The most effective means of reducing the burden of herpes zoster is prevention through vaccination. Unfortunately, there are a variety of significant barriers to immunization against this disease.

Barriers to Herpes Zoster Immunization

One significant barrier to immunization is that elderly patients often do not know that they need to be immunized. A recent Medicare Current Beneficiary Survey questioned people over age 65 about the immunizations recommended for them. The major reason for not receiving influenza or pneumococcal vaccines was that they were unaware that they need vaccination.¹ This is a more significant problem among some ethnic groups, according to a recent study by the Department of Veterans Affairs, which found that African-Americans and Hispanics over age 50 were less likely than their non-Hispanic, white-matched controls to have been immunized.² Other barriers to immunization against herpes zoster are fear of needles and the mistaken belief that the vaccine can cause the illness. For a brief period of time, there was a shortage of the vaccine so that some who desired vaccination faced delays in receiving it; however, this barrier has now been removed. Also, many elderly people find it difficult to determine whether they will be reimbursed for the cost of the vaccine. Therefore, it is essential for physicians to take the time to educate their elderly patients on the importance of being immunized against herpes zoster, the improbability of becoming ill from the vaccine, and their payment options.

Treatment of Herpes Zoster

Given the existing barriers to zoster immunization, physicians must be knowledgeable of the treatment options, should an unvaccinated patient become infected.

Antivirals are the commonly used therapy. The nucleoside analogs block viral replication³and promote rash healing.⁴Treatment options include 800 mg acyclovir 5 times per day for 7–10 days; ⁵  500 mg famciclovir every 8 hours for 7 days;⁶  and 1 g valacyclovir 3 times daily for 7 days.⁷

These agents have been found to effectively accelerate rash healing. Acute pain is resolved over 30 days. Antivirals are most effective when administered within 72 hours of rash onset, but their efficacy is unknown after 72 hours.⁸

Efficacy for pain resolution has been studied in several clinical trials, with famciclovir and valacyclovir associated with similar rates;⁹ a meta-analysis found that acyclovir was better than placebo for pain resolution.¹⁰ In one randomized controlled trial, valacyclovir was more effective than acyclovir for resolution of pain;¹¹ in another, famciclovir was equal to acyclovir for resolution of pain and rate of lesion healing;¹² and in another, famciclovir and acyclovir were equally effective for resolution of pain and lesion healing.¹³

Efficacy, tolerability, cost of the drug, dosing regimen and ease of administration, side-effect profile, and duration of therapy should all be considered before prescribing an antiviral.

Complications of Herpes Zoster

The complications of zoster cannot be trivialized. Patients with disseminated herpes zoster can require inpatient stays with IV antiviral therapy. Prolonged or permanent sequelae include pain, facial scarring, and loss of vision.¹⁴ Patients can develop neuropathies of the peripheral nervous system, as well as encephalitis, cerebellitis, and aseptic meningitis. Ramsay Hunt syndrome is a relatively common manifestation caused by geniculate ganglion infection and herpetic eruption on ipsilateral tympanic membrane or external ear canal. Symptoms of Ramsay Hunt include pain, vertigo, hearing loss, tinnitus, sound sensitivity, and loss of taste.

Herpes zoster can involve the eye, leading to zoster ophthalmicus in about 10%–25% of cases, as well as keratitis with subsequent corneal ulceration, uveitis, episcleritis, conjunctivitis, scleritis, retinitis, choroiditis, optic neuritis, lid retraction, ptosis, and glaucoma. Extraocular muscle palsies also occur. Other complications of herpes zoster are pneumonitis, hepatitis, and urinary retention.

Postherpetic neuralgia

The biggest burden of herpes zoster, particularly among elderly patients, is postherpetic neuralgia (PHN), defined as pain that persists after the onset of the rash.¹⁵ PHN may last for 30 days after the onset of the rash, or can last 6–9 months after the onset of the rash. PHN can also last for years. The risk of PHN increases with age.¹⁶ Women are more commonly affected than men.¹⁴

In PHN, the neuropathic pain results mainly from damage to sensory nerves. The symptoms are generally one of two types: a burning, raw, severe aching or tearing pain; or superimposed paroxysmal stabbing or electric shock-like pain. Patients report unpleasant skin sensitivity, with hyperalgesia, allodynia, and hypoesthesia.¹⁷  

PHN is difficult to treat. The therapy does not work for all patients and its effect can be modest. Any treatment decision must be individualized, with therapy introduced and modified sequentially to determine efficacy and tolerability. Doses should be titrated so that the benefits exceed the side effects, and all treatments should be introduced separately.

Treatment must also focus on the central nervous system derangement. Rather than the common analgesics, treatment can include antiepileptic agents, tricyclic antidepressants, and serotonin norepinephrinergics duloxetine and venlafaxine. Comorbid illness, the risk of drug interactions, and side effects must be considered when treating elderly patients with PHN.

Among the options for treatment: 

• Gabapentin has a reported 33% reduction in pain, and 63% of patients receiving pregabalin experienced clinically significant pain relief.^15,18 Adverse events can include somnolence, dizziness, and peripheral edema. 
• Tricyclic antidepressants give at least moderate pain relief in 47%–67% of patients.¹⁷ Adverse events include sedation, confusion, urinary retention, dry mouth, postural hypotension, and arrhythmia.
• Opioid analgesics have been reported to provide pain relief in 38%–58% of treated patients, with adverse events including constipation, nausea, loss of appetite, dizziness, and drowsiness.^19,20
• Lidocaine patch has a reported 60% efficacy, with at least moderate pain relief and no adverse events, with local reactions including erythema and skin rash.²¹
• Capsaicin cream can give moderate pain relief but can be accompanied by intolerable burning.

References

1. CDC. Reasons reported by Medicare beneficiaries for not receiving influenza and pneumococcal vaccinations-United States, 1996. MMWR. 1999;48:886–890.
2. Straits-Tröster KA, Kahwati LC, Kinsinger LS, Orelien J, Burdick MB, Yevich SJ. Racial/ethnic differences in influenza vaccination in the Veterans Affairs Healthcare System. Am J Prev Med. 2006;31:375–382.
3. Kost RG, Straus SE. Postherpetic neuralgia-pathogenesis, treatment, and prevention.N Engl J Med. 1996;335:32–42.
4. Gnann JW Jr, Whitley RJ. Clinical practice. Herpes zoster.N Engl J Med. 2002;347:340-346.
5. Zovirax [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2004. 
6.  Famvir [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2002.
7. Valtrex [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Mounsey AL, Matthew LG, Slawson DC. Herpes zoster and postherpetic neuralgia: prevention and management. Am Fam Physician. 2005;72:1075–1080.
9. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group.Ann Intern Med .1995;123:89–96.
10. Wood MJ, Shukla S, Fiddian AP, Crooks RJ. Treatment of acute herpes zoster: effect of early (< 48 h) versus late (48-72 h) therapy with acyclovir and valaciclovir on prolonged pain.J Infect Dis. 1998;178(suppl 1):S81–S84.
11. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults.Antimicrob Agents Chemother. 1995;
    39:1546–1553
12. Shen MC, Lin HH, Lee SS, Chen YS, Chiang PC, Liu YC. Double-blind, randomized, acyclovir-controlled, parallel-group trial comparing the safety and efficacy of famciclovir and acyclovir in patients with uncomplicated herpes zoster. J Microbiol Immunol Infect. 2004;37:75–81.
13. Shafran SD, Tyring SK, Ashton R, et al. Once, twice, or three times daily famciclovir compared with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, multicenter, double-blind clinical trial. J Clin Virol. 2004;29:248–253.
14. Harpaz R, Ortega-Sanchez IR, Seward JF, Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.
15. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67:241–251.
16. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82:1341–1349.
17. Pappagallo M, Haldey EJ. Pharmacological management of postherpetic neuralgia.CNS Drugs. 2003;17:771–780.
18. Rowbatham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837–1842.
19. Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837–1841.
20. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.Neurology. 2002;59:1015–1021.
21. . Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64:937–947.