Eye on ID

Herpes zoster: A potentially dangerous but preventable disease

Herpes zoster (HZ) continues to be a relevant public health issue because of its prevalence and potential complications. It is estimated that one out of three people in the United States will develop HZ in their lifetime. Varicella zoster virus, the cause of HZ, is one of eight herpes viruses that infect humans.

Varicella is followed by VZV latency

Similar to all other herpesviruses, primary infection leads to lifelong virus persistence. Primary infection with VZV causes varicella (chickenpox), which is highly contagious. Varicella was reviewed in a recent Eye on ID. VZV is most commonly transmitted from person to person via the airborne route and also can be transmitted by direct contact with infectious lesions. After the primary infection, the virus remains dormant in the dorsal root and cranial ganglia, where it establishes latency.

Muneerah Aleissa

VZV reactivates from latent infection to cause HZ

Similar to all herpesviruses, VZV can reactivate from its latent state. Because VZV latently persists in dorsal root or cranial ganglia, it may reactivate from these sites. In contrast to other herpesviruses in immunocompetent individuals, in whom reactivated disease is typically mild, reactivation of VZV may occur as a significant clinical syndrome, HZ. HZ manifests as a painful, localized, vesicular rash commonly known as shingles. The rash erupts as erythematous papules in a unilateral dermatomal distribution in one or adjacent dermatomes. Involvement of the thoracic or lumbar dermatomes is most common. Over a period of several days, grouped vesicles become the predominant manifestation, which then evolve to being pustular. Pain or dysesthesia in the dermatome may precede the rash by 1 to 3 days or longer. A few lesions can be seen outside the affected dermatome. In immunocompetent hosts, the lesions typically crust by 7 to 10 days and at that point are no longer considered infectious. In immunocompromised and older individuals, the lesions may be hemorrhagic. HZ can affect individuals of any age; however, it is seen more commonly as adults age, as the immune system wanes (particularly cellular immunity), usually in those aged older than 50 years. Those with immunocompromising conditions, such as HIV infection, or those on immunosuppressants or transplant patients or those with malignancies are more prone to develop HZ. Recurrent HZ can occur. One report found a 6.4% recurrence rate, usually in a different dermatome. Some individuals had two or three recurrences. HZ can occur with no rash (termed zoster sine herpete) but with all the other symptoms and complications.

Brandon Dionne

Postherpetic neuralgia

HZ is not a benign infection, and it can cause many potential complications. HZ is typically associated with pain in the dermatome involved, which can last for several months. However, a subset of individuals will have long-term pain, a complication termed postherpetic neuralgia, which is often defined as pain that persists for more than 3 months after the onset of the cutaneous lesions of HZ. The pain can be intense and debilitating and occurs in approximately 22% of cases. The incidence of postherpetic neuralgia differs by age group, increasing with age. Thus, older individuals are not only more prone to developing HZ, they are at increased risk for developing postherpetic neuralgia.

Kenneth M. Kaye

Ophthalmic zoster, Ramsay Hunt syndrome and other complications

Important complications can occur when zoster involves cranial nerves. Ophthalmic zoster, which involves the first branch of the trigeminal nerve, can be complicated by sight-threatening sequelae, including acute retinal necrosis, especially when lesions are present on the tip of the nose (Hutchinson’s sign). For this reason, involvement of an ophthalmologist is often recommended in these cases. The Ramsay Hunt syndrome, in which skin lesions occur in the external auditory canal, involves the 7th cranial nerve and can lead to Bell’s palsy. Ramsay Hunt syndrome can also involve the 8th cranial nerve, leading to hearing loss and vestibulitis, so care is often provided in consultation with an ear, nose and throat specialist.

In immunocompromised individuals, HZ can disseminate, with many lesions appearing outside the primary dermatome and with visceral involvement. Serious complications that can occur in immunocompromised individuals include pneumonia and hepatitis. Disseminated HZ can be associated with a high mortality rate.

Risk for stroke

Rarely, HZ, especially ophthalmic zoster, can be associated with stroke, leading to contralateral hemiparesis. This syndrome is believed to be due to direct VZV infection of cerebral arteries and typically occurs with a latent period of weeks to months following onset of the rash. Angiography can be helpful in making the diagnosis. Other neurologic complications include aseptic meningitis, myelitis and motor neuropathies.

Diagnosis

Donald Kaye

Diagnosis is usually clinical, based on recognition of the dermatomal rash. However, HZ may occasionally present with atypical lesions, especially in immunocompromised individuals. In cases in which there is clinical uncertainty, confirmatory laboratory testing can be helpful. PCR testing of lesions is highly sensitive (95%) and rapid (1 day). Direct fluorescent antibody can also be used and is rapid, but it is less sensitive than PCR. Viral culture can be performed but provides a slow turnaround because of the slow growth of the virus in vitro.

Management

Oral famciclovir, valacyclovir and acyclovir are approved by the FDA for the treatment of HZ in immunocompetent patients presenting within 72 hours of lesion onset (see Table 1). These agents inhibit viral DNA polymerase and reduce viral replication, which limits damage to the sensory neurons, thereby reducing the duration of pain. Although therapy should be initiated ideally within 72 hours of symptom onset, therapy after 72 hours can be considered, especially in the setting of ongoing lesion formation, complications, advanced age or severe pain. Thus, antiviral therapy should be considered for acute HZ treatment regardless of the time of presentation. Famciclovir and valacyclovir are preferred by many ID specialists because of the simpler dosing schedules and better pharmacokinetic characteristics. IV acyclovir should be administered in immunocompromised and other patients with severe HZ manifestations, such as cutaneous or visceral dissemination or those with central nervous system involvement. Treatment duration is usually 7 days; however, in the setting of severe complications, such as retinitis, treatment is often extended for longer periods of time. There was initial interest in glucocorticoids as a means of decreasing complications, especially postherpetic neuralgia. However, a meta-analysis that compared the use of acyclovir alone with acyclovir plus a glucocorticoid did not demonstrate any added benefit of glucocorticoids in terms of reduction in postherpetic neuralgia. Patients with active lesions should be counseled to keep the rash covered and to wash their hands in order to reduce transmission of VZV.

Prevention

Vaccination against VZV is the mainstay of prevention of HZ infection. Those who receive varicella vaccination as children are protected from acquiring the primary infection, and they also appear to be at lower risk for HZ, likely as a result of the attenuated nature of the vaccine virus strain. In fact, a recent study showed that the incidence rate of HZ was 78% lower in children vaccinated with the varicella vaccine compared with unvaccinated children.

In 2006, a live-attenuated vaccine (Zostavax, ZVL) was approved to prevent HZ (see Table 2). The vaccine boosts VZV-specific cell-mediated immunity, limiting latent viral reactivation and replication, and therefore it can prevent HZ infection or reduce its severity. The efficacy of ZVL was evaluated in a large phase 3 trial, which demonstrated a 51% reduction in the risk of HZ and 67% reduction in postherpetic neuralgia. The vaccine efficacy for the prevention of zoster was highest for those aged 60 to 69 years and declined with increasing age. There is a discrepancy between the recommendations of the CDC and the Advisory Committee on Immunization Practices compared with the FDA. The CDC and ACIP recommend that patients receive ZVL at age 60 years or older, even though it is FDA-approved for those aged 50 years or older. ZVL’s main drawback is that its effectiveness decreases with time and age. In adults vaccinated at age 60 years or older, vaccine efficacy wanes rapidly the first year after vaccination, and protection by 6 years after vaccination is less than 35%. Another limitation is that it cannot be used in patients with immunocompromising conditions because it is a live-attenuated virus.

In 2017, the FDA approved a recombinant, subunit zoster vaccine (Shingrix, RZV) for the prevention of shingles in adults aged 50 years or older (see Table 2). It is superior to ZVL and should replace it as protection against HZ because of its greater efficacy and longer lasting protection. Its efficacy was evaluated in two large phase 3 trials — ZOE-50 and ZOE-70. The mean follow-up periods in the two studies lasted over 3 years. The ZOE-50 trial evaluated the safety and efficacy of RZV in adults aged 50 years and older and demonstrated that two doses of RZV was associated with 97.2% lower risk for HZ compared with placebo. The ZOE-70 trial evaluated the safety and efficacy of RZV in adults aged 70 years and older and determined that two doses were associated with an 89.8% lower risk for HZ compared with placebo. The most common side effects of RZV include injection site reactions, headache, fatigue and some gastrointestinal upset. One limitation of RZV is that instead of a single dose, it requires two doses given 2 to 6 months apart. If more than 6 months have elapsed since the first dose of RZV, the second dose should be administered as soon as possible, and there is no need to restart the vaccine series. Additionally, since ZVL efficacy declines rapidly with age, ACIP recommends that people who were previously vaccinated with ZVL also receive the new recombinant zoster vaccine. RZV is preferred over ZVL because of its greater and longer lasting efficacy. The minimum interval between ZVL and administering RZV is 2 months. Because it is a recombinant, subunit vaccine and therefore not live, RZV is expected to be safe to use in immunocompromised individuals, and in fact it has been shown to be safe and efficacious in early trials with immune-suppressed individuals. It is important to note that there is currently a shortage of RZV largely due to an unprecedented demand for the vaccine.

Although antiviral therapy and vaccination are important in the treatment and prevention of zoster, respectively, recent evidence suggests that they may not reduce the risk for stroke immediately after an episode of HZ. Yang and colleagues conducted a self-controlled case series study of 35,186 patients who were aged at least 66 years and diagnosed with HZ and stroke between 2007 and 2015. Patients were classified into four categories (no treatment [60.9%], vaccination with ZVL [11.8%], antiviral treatment only [22.2%] and both antiviral treatment and vaccination [5.2%]), and the researchers assessed their risk for stroke. The results of this study — presented at the 2019 International Stroke Conference — found that the risk for stroke increased after HZ, and that neither previous vaccination nor antiviral therapy reduced that risk. The risk for acute stroke was higher within 14 days of HZ (incident rate ratio [IRR] = 1.48), and it remained elevated at 1 month (IRR = 1.31) before declining at 3 to 6 months after HZ (IRR = 1.07). These trends were consistent in all four categories. However, other work has suggested a protective effect of antivirals against stroke. Prevention of HZ through vaccination will likely be the most effective way to prevent the complication of stroke, and it will be interesting to see if the RZV vaccine will prove to have such benefits.

In summary, HZ is a major health burden that can affect individuals of any age. HZ is characterized by a painful vesicular rash with a well-defined unilateral dermatomal distribution. The most common complication associated with HZ is postherpetic neuralgia. Treatment with antiviral drugs is recommended within 72 hours of rash onset and has been shown to reduce the severity of lesions and acute pain. Whether treatment reduces other complications of HZ is less well defined. Routine vaccination of individuals against HZ has been shown to be effective in terms of reducing the incidence of HZ and postherpetic neuralgia. It is possible that with the widespread, continued use of the varicella vaccine to prevent wild-type VZV infection, HZ may become a rare disease in the future.

Disclosures: Aleissa, Dionne, Kaye and Kaye report no relevant financial disclosures.

Herpes zoster (HZ) continues to be a relevant public health issue because of its prevalence and potential complications. It is estimated that one out of three people in the United States will develop HZ in their lifetime. Varicella zoster virus, the cause of HZ, is one of eight herpes viruses that infect humans.

Varicella is followed by VZV latency

Similar to all other herpesviruses, primary infection leads to lifelong virus persistence. Primary infection with VZV causes varicella (chickenpox), which is highly contagious. Varicella was reviewed in a recent Eye on ID. VZV is most commonly transmitted from person to person via the airborne route and also can be transmitted by direct contact with infectious lesions. After the primary infection, the virus remains dormant in the dorsal root and cranial ganglia, where it establishes latency.

Muneerah Aleissa

VZV reactivates from latent infection to cause HZ

Similar to all herpesviruses, VZV can reactivate from its latent state. Because VZV latently persists in dorsal root or cranial ganglia, it may reactivate from these sites. In contrast to other herpesviruses in immunocompetent individuals, in whom reactivated disease is typically mild, reactivation of VZV may occur as a significant clinical syndrome, HZ. HZ manifests as a painful, localized, vesicular rash commonly known as shingles. The rash erupts as erythematous papules in a unilateral dermatomal distribution in one or adjacent dermatomes. Involvement of the thoracic or lumbar dermatomes is most common. Over a period of several days, grouped vesicles become the predominant manifestation, which then evolve to being pustular. Pain or dysesthesia in the dermatome may precede the rash by 1 to 3 days or longer. A few lesions can be seen outside the affected dermatome. In immunocompetent hosts, the lesions typically crust by 7 to 10 days and at that point are no longer considered infectious. In immunocompromised and older individuals, the lesions may be hemorrhagic. HZ can affect individuals of any age; however, it is seen more commonly as adults age, as the immune system wanes (particularly cellular immunity), usually in those aged older than 50 years. Those with immunocompromising conditions, such as HIV infection, or those on immunosuppressants or transplant patients or those with malignancies are more prone to develop HZ. Recurrent HZ can occur. One report found a 6.4% recurrence rate, usually in a different dermatome. Some individuals had two or three recurrences. HZ can occur with no rash (termed zoster sine herpete) but with all the other symptoms and complications.

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Brandon Dionne

Postherpetic neuralgia

HZ is not a benign infection, and it can cause many potential complications. HZ is typically associated with pain in the dermatome involved, which can last for several months. However, a subset of individuals will have long-term pain, a complication termed postherpetic neuralgia, which is often defined as pain that persists for more than 3 months after the onset of the cutaneous lesions of HZ. The pain can be intense and debilitating and occurs in approximately 22% of cases. The incidence of postherpetic neuralgia differs by age group, increasing with age. Thus, older individuals are not only more prone to developing HZ, they are at increased risk for developing postherpetic neuralgia.

Kenneth M. Kaye

Ophthalmic zoster, Ramsay Hunt syndrome and other complications

Important complications can occur when zoster involves cranial nerves. Ophthalmic zoster, which involves the first branch of the trigeminal nerve, can be complicated by sight-threatening sequelae, including acute retinal necrosis, especially when lesions are present on the tip of the nose (Hutchinson’s sign). For this reason, involvement of an ophthalmologist is often recommended in these cases. The Ramsay Hunt syndrome, in which skin lesions occur in the external auditory canal, involves the 7th cranial nerve and can lead to Bell’s palsy. Ramsay Hunt syndrome can also involve the 8th cranial nerve, leading to hearing loss and vestibulitis, so care is often provided in consultation with an ear, nose and throat specialist.

In immunocompromised individuals, HZ can disseminate, with many lesions appearing outside the primary dermatome and with visceral involvement. Serious complications that can occur in immunocompromised individuals include pneumonia and hepatitis. Disseminated HZ can be associated with a high mortality rate.

Risk for stroke

Rarely, HZ, especially ophthalmic zoster, can be associated with stroke, leading to contralateral hemiparesis. This syndrome is believed to be due to direct VZV infection of cerebral arteries and typically occurs with a latent period of weeks to months following onset of the rash. Angiography can be helpful in making the diagnosis. Other neurologic complications include aseptic meningitis, myelitis and motor neuropathies.

Diagnosis

Donald Kaye

Diagnosis is usually clinical, based on recognition of the dermatomal rash. However, HZ may occasionally present with atypical lesions, especially in immunocompromised individuals. In cases in which there is clinical uncertainty, confirmatory laboratory testing can be helpful. PCR testing of lesions is highly sensitive (95%) and rapid (1 day). Direct fluorescent antibody can also be used and is rapid, but it is less sensitive than PCR. Viral culture can be performed but provides a slow turnaround because of the slow growth of the virus in vitro.

PAGE BREAK

Management

Oral famciclovir, valacyclovir and acyclovir are approved by the FDA for the treatment of HZ in immunocompetent patients presenting within 72 hours of lesion onset (see Table 1). These agents inhibit viral DNA polymerase and reduce viral replication, which limits damage to the sensory neurons, thereby reducing the duration of pain. Although therapy should be initiated ideally within 72 hours of symptom onset, therapy after 72 hours can be considered, especially in the setting of ongoing lesion formation, complications, advanced age or severe pain. Thus, antiviral therapy should be considered for acute HZ treatment regardless of the time of presentation. Famciclovir and valacyclovir are preferred by many ID specialists because of the simpler dosing schedules and better pharmacokinetic characteristics. IV acyclovir should be administered in immunocompromised and other patients with severe HZ manifestations, such as cutaneous or visceral dissemination or those with central nervous system involvement. Treatment duration is usually 7 days; however, in the setting of severe complications, such as retinitis, treatment is often extended for longer periods of time. There was initial interest in glucocorticoids as a means of decreasing complications, especially postherpetic neuralgia. However, a meta-analysis that compared the use of acyclovir alone with acyclovir plus a glucocorticoid did not demonstrate any added benefit of glucocorticoids in terms of reduction in postherpetic neuralgia. Patients with active lesions should be counseled to keep the rash covered and to wash their hands in order to reduce transmission of VZV.

Prevention

Vaccination against VZV is the mainstay of prevention of HZ infection. Those who receive varicella vaccination as children are protected from acquiring the primary infection, and they also appear to be at lower risk for HZ, likely as a result of the attenuated nature of the vaccine virus strain. In fact, a recent study showed that the incidence rate of HZ was 78% lower in children vaccinated with the varicella vaccine compared with unvaccinated children.

In 2006, a live-attenuated vaccine (Zostavax, ZVL) was approved to prevent HZ (see Table 2). The vaccine boosts VZV-specific cell-mediated immunity, limiting latent viral reactivation and replication, and therefore it can prevent HZ infection or reduce its severity. The efficacy of ZVL was evaluated in a large phase 3 trial, which demonstrated a 51% reduction in the risk of HZ and 67% reduction in postherpetic neuralgia. The vaccine efficacy for the prevention of zoster was highest for those aged 60 to 69 years and declined with increasing age. There is a discrepancy between the recommendations of the CDC and the Advisory Committee on Immunization Practices compared with the FDA. The CDC and ACIP recommend that patients receive ZVL at age 60 years or older, even though it is FDA-approved for those aged 50 years or older. ZVL’s main drawback is that its effectiveness decreases with time and age. In adults vaccinated at age 60 years or older, vaccine efficacy wanes rapidly the first year after vaccination, and protection by 6 years after vaccination is less than 35%. Another limitation is that it cannot be used in patients with immunocompromising conditions because it is a live-attenuated virus.

PAGE BREAK

In 2017, the FDA approved a recombinant, subunit zoster vaccine (Shingrix, RZV) for the prevention of shingles in adults aged 50 years or older (see Table 2). It is superior to ZVL and should replace it as protection against HZ because of its greater efficacy and longer lasting protection. Its efficacy was evaluated in two large phase 3 trials — ZOE-50 and ZOE-70. The mean follow-up periods in the two studies lasted over 3 years. The ZOE-50 trial evaluated the safety and efficacy of RZV in adults aged 50 years and older and demonstrated that two doses of RZV was associated with 97.2% lower risk for HZ compared with placebo. The ZOE-70 trial evaluated the safety and efficacy of RZV in adults aged 70 years and older and determined that two doses were associated with an 89.8% lower risk for HZ compared with placebo. The most common side effects of RZV include injection site reactions, headache, fatigue and some gastrointestinal upset. One limitation of RZV is that instead of a single dose, it requires two doses given 2 to 6 months apart. If more than 6 months have elapsed since the first dose of RZV, the second dose should be administered as soon as possible, and there is no need to restart the vaccine series. Additionally, since ZVL efficacy declines rapidly with age, ACIP recommends that people who were previously vaccinated with ZVL also receive the new recombinant zoster vaccine. RZV is preferred over ZVL because of its greater and longer lasting efficacy. The minimum interval between ZVL and administering RZV is 2 months. Because it is a recombinant, subunit vaccine and therefore not live, RZV is expected to be safe to use in immunocompromised individuals, and in fact it has been shown to be safe and efficacious in early trials with immune-suppressed individuals. It is important to note that there is currently a shortage of RZV largely due to an unprecedented demand for the vaccine.

Although antiviral therapy and vaccination are important in the treatment and prevention of zoster, respectively, recent evidence suggests that they may not reduce the risk for stroke immediately after an episode of HZ. Yang and colleagues conducted a self-controlled case series study of 35,186 patients who were aged at least 66 years and diagnosed with HZ and stroke between 2007 and 2015. Patients were classified into four categories (no treatment [60.9%], vaccination with ZVL [11.8%], antiviral treatment only [22.2%] and both antiviral treatment and vaccination [5.2%]), and the researchers assessed their risk for stroke. The results of this study — presented at the 2019 International Stroke Conference — found that the risk for stroke increased after HZ, and that neither previous vaccination nor antiviral therapy reduced that risk. The risk for acute stroke was higher within 14 days of HZ (incident rate ratio [IRR] = 1.48), and it remained elevated at 1 month (IRR = 1.31) before declining at 3 to 6 months after HZ (IRR = 1.07). These trends were consistent in all four categories. However, other work has suggested a protective effect of antivirals against stroke. Prevention of HZ through vaccination will likely be the most effective way to prevent the complication of stroke, and it will be interesting to see if the RZV vaccine will prove to have such benefits.

In summary, HZ is a major health burden that can affect individuals of any age. HZ is characterized by a painful vesicular rash with a well-defined unilateral dermatomal distribution. The most common complication associated with HZ is postherpetic neuralgia. Treatment with antiviral drugs is recommended within 72 hours of rash onset and has been shown to reduce the severity of lesions and acute pain. Whether treatment reduces other complications of HZ is less well defined. Routine vaccination of individuals against HZ has been shown to be effective in terms of reducing the incidence of HZ and postherpetic neuralgia. It is possible that with the widespread, continued use of the varicella vaccine to prevent wild-type VZV infection, HZ may become a rare disease in the future.

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Disclosures: Aleissa, Dionne, Kaye and Kaye report no relevant financial disclosures.