VZV Disease
Comprehensive insights into disease, diagnosis, management, & pathogenesis
Other VZV disease
VZV can infect multiple organs and arteries producing multisystem disease with or without an associated rash.
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Other herpesvirus disease
Emerging reports show an association of other herpesviruses with neurological disease, including burning mouth, chronic fatigue, dementia, and multiple sclerosis.
Herpes Zoster
Herpes zoster (also known as shingles) is caused by varicella zoster virus (VZV). When VZV initially infects an individual, the virus spreads through the bloodstream and typically causes a widespread, fluid-filled rash called varicella (chickenpox). Some individuals get infected but never develop a rash. After primary infection, the virus becomes dormant/latent in neurons throughout your body (within cranial nerve, dorsal root, autonomic and enteric ganglia). When virus is dormant, it does not produce infectious particles and is "hidden" from the immune system for decades. When the individual's immune system weakens, then virus will flare up from one or more of these neurons and surf along the nerve fibers to the skin to cause one or more fluid-filled painful blisters in a dermatomal distribution on one side of the body (herpes zoster, shingles).Â
FAQs
Is shingles contagious?
The majority of adults have protective antibodies against VZV and will not get rash by being around a person with shingles. However, individuals who have not received the chickenpox vaccine (such as newborns), have never had chickenpox, or have negative VZV IgG antibodies are at risk of getting chickenpox when exposed to someone with shingles.
Who is at risk?
Anyone who has had chickenpox, received the chickenpox vaccine, or has positive VZV IgG antibody titers is at risk for VZV reactivation causing shingles, particularly those with weakened immune systems due to:Â
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Age-related immune decline
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HIV/AIDS
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Recent infections that suppress the immune system, such as COVID
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Cancer
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Stress
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Corticosteroids (e.g. prednisone)
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Other medications/therapies that weaken the immune system such as those used to (1) treat autoimmune disease/multiple sclerosis, (2) prevent transplant rejection, or (3) treat cancer (chemotherapeutic agents, radiation)
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Physical trauma like head injuries, biopsies, and surgery
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Even prolonged spaceflight can trigger shingles!
How is shingles diagnosed?
Diagnosis can be made by clinical presentation alone. Think shingles when the rash is one-sided following a dermatome (stripe pattern) and does not cross the midline. The rash appears as one or more blisters filled with clear fluid that eventually rupture then dry up. Pain, sensitivity to touch, or itching may occur at a specific site before the rash appears (preherpetic neuralgia). These abnormal sensations can persist for weeks after the rash has resolved. If the pain persists more than 3 months or longer after shingles, it is called postherpetic neuralgia.
​Sometimes, your health care provider may be unsure if the rash is shingles. The following tests can help confirm the diagnosis.
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Positive serum VZV IgMÂ
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Four-fold increase in serum VZV IgG titers when compared to baseline titersÂ
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Positive VZV DNA in rash swab, rash scraping/biopsy, or whole blood
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Positive VZV antigen in skin biopsy
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If other causes of rash are excluded and tests are indeterminate, a trial of antivirals (valacylovir, famciclovir, acyclovir) can be considered by your health care provider based on history and exam (unilateral, dermatomal-distribution rash). If rash improves with antivirals, then it was most likely due to VZV.
How is shingles treated?
Treatment should be decided by your health care provider who is aware of medical conditions that may affect treatment. In a healthy individual without kidney problems or other contraindications, valacyclovir (Valtrex) 1 gram tablet three times daily or famciclovir (Famvir) 500 mg tablets three times daily for 7 days is typically prescribed (per FDA); treatment may be prescribed for 14 days for specific cases (rash and pain not resolving, disseminated rash, immunosuppressed). Sometimes, prednisone is also given along with the treatment dose of antivirals to reduce virus-associated inflammation (e.g. prednisone 60 mg daily for days 1-5 of antiviral treatment; caution with steroids alone - without antivirals, can trigger shingles). In addition, pain meds are frequently given such as amitriptyline (Elavil), gabapentin (Neurontin) or pregabalin (Lyrica). The treatment of nerve pain associated with shingles and selection of the appropriate medication, given side effects and an individual's medical history, warrants an depth discussion with your health care provider.
Does rash have to look like fluid-filled blisters?
No. The shingles rash does not always look like fluid-filled blisters. It can look similar to mosquito bites or present as small, raised, red bumps without clear fluid...but always on one side of the body (left or right) following a dermatome. Sometimes, there is shingles WITHOUT a rash, just the burning pain along a dermatome on one side of the body; this is called zoster sine herpete (shingles without rash, "internal shingles") if other causes of radicular pain have been excluded.
Can shingles recur?
Yes, shingles can recur. It is an indicator of immunity gone awry, so it is important to evaluate possible causes with your health care provider. Recurrence may be due to medications (e.g. prednisone, rituximab, methotrexate), therapies (e.g. chemotherapy and radiation for cancer), or an immune deficiency (e.g. low antibody levels). If there is no obvious cause, a thorough evaluation of immune cell numbers and function by an immunologist is essential to guide management. For instance, if you have low IgG antibodies, you may need monthly antibody infusions/injections (IVIG/subcutaneous IG) to boost immunity if preventive antivirals do not stop recurrence. In rare instances, recurrent shingles may be caused by an undetected cancer that is weakening the immune system; thus, if no causes of recurrent shingles is found, a cancer work-up should be discussed with your health care provider.
Is shingles dangerous?
If you have shingles, you are infectious. The majority of individuals already harbor latent virus and have protective antibodies; however, newborns or children who did not receive the chickenpox (varicella) vaccine, individuals who never had chickenpox, or individuals with negative VZV IgG antibody titers are at risk for infection.
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If shingles is on the face, it is essential to follow up with an ophthalmologist immediately to check for VZV infection of the eye which can cause vision loss.
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Importantly, shingles has been associated with an increased risk of stroke and cardiovascular events, particularly nearest the time you had the rash, if rash was by the forehead-eye region (herpes zoster ophthalmicus), or if rash develops before 40 years of age. If you have stroke symptoms (such as one-sided facial droop or weakness, slurred speech, difficulty thinking, new unusual headache, sudden onset dizziness) or have heart symptoms (irregular heartbeats, chest pain, shortness of breath), seek medical care immediately. Recent epidemiological and basic research studies have also associated shingles with an increased risk of dementia by increasing brain inflammation, amyloid deposition, and cerebrovascular disease, thereby accelerating dementia progression.
What is herpes zoster ophthalmicus and Ramsay Hunt syndrome?
These are both forms of shingles characterized by where rash appears and other associated features.Â
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Herpes zoster ophthalmicus (HZO): shingles appears on one side of the face on the forehead and around the eye (V1 ophthalmic branch of the trigeminal nerve). HZO can be associated with vision loss if virus infects the cornea (VZV keratitis), particularly if Hutchinson sign is present (rash on the side, tip, or root of nose). An ophthalmology exam should be done immediately to evaluate for eye involvement.
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Ramsay Hunt syndrome (RHS, herpes zoster oticus): shingles appears in the ear canal or outer ear on one side of the face with associated facial weakness. Note that RHS can initially present as a red, painful ear, often mistaken for a bacterial cellulitis; the inner ear canal needs to be visualized for rash or the diagnosis of RHS considered if antibiotics do not resolve the ear symptoms. Early treatment is important including antiviral therapy (often 2 weeks or longer), ophthalmology evaluation (checking for VZV infection in eye, drops for dry eyes, taping lid closed when sleeping), physical therapy with facial exercises, and establishment of care with an ENT specializing in this disease for possible Botox or surgical interventions if weakness is severe and not improving or if there is aberrant nerve regeneration (such as left eye closing when left side of mouth raises up).
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Should I get vaccinated?
There is a shingles vaccine (Shingrix, GSK); the original vaccine study (ZOE-50) showed vaccine efficacy for preventing shingles was between 96.6% and 97.9% for all age groups (50 years and older). However, the decision to vaccinate should be made between you and your health care provider taking into account specific medical conditions (e.g. adverse reactions to vaccine components or prior dose, pregnancy, acute illness, pregnancy, recent shingles, immune suppression, active autoimmune disease), therapies, and personal beliefs/concerns. In general, the CDC recommends 2 doses of recombinant zoster vaccine (RZV) to prevent shingles and related complications in: (1) adults aged ≥50 years; and (2) adults aged ≥19 years who are or will be immunodeficient or immunosuppressed. For more information on CDC recommendations for the shingles vaccine, clinical considerations, side effects, and contraindications, go to https://www.cdc.gov/shingles/hcp/vaccine-considerations/index.html.
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It is important to note that while Shingrix prevents shingles, its most important use is prevention of postherpetic neuralgia, a terrible chronic pain condition that is often difficult to treat. Approximately 60% to 75% of individuals with shingles aged 60 to 70+ will develop postherpetic neuralgia.
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A frequent question I encounter is "should I get vaccinated if I had shingles or continue to have recurrent shingles"? No, do not get Shingrix if VZV disease is active. When disease is quiet, you and your healthcare provider can then discuss when to vaccinate if you choose. Of note, for shingles associated with eye involvement, the decision and timing to vaccinate needs to be discussed with the ophthalmologist because a 2024 study reported that individuals with herpes zoster ophthalmicus (HZO) who are vaccinated 3 months or more following the initial HZO diagnosis had a higher likelihood of disease recurrence and should be monitored closely.
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Where can I learn more about shingles?
This article entitled "The Protean Neurological Manifestations of Varicella-Zoster Virus Infection" was published in 2007, but has a very nice section on herpes zoster/shingles manifestations (including diaphragm paralysis with shortness of breath and spontaneous tooth exfoliation) with references on pages 490-491.
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For recent peer-reviewed publications, conduct searches on https://pubmed.ncbi.nlm.nih.gov/.
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For ongoing clinical trials, conduct searched on https://clinicaltrials.gov/.
Postherpetic neuralgia
Shingles is typically accompanied by pain and/or abnormal sensations at the site of rash that resolves over several weeks. If the pain persists for 3 months or longer, it is called postherpetic neuralgia (PHN). Individuals describe the one sided pain as burning, aching, and/or itching with unexpected lightning bolts of severe pain that can occur spontaneously or are triggered by light touch. Depending on the location of PHN, an individual may have difficulty showering, brushing their hair, or wearing certain clothes. The relentless pain is exhausting and depressing.Â
PHN is notoriously difficult to treat and is one of the leading causes of suicide in older adults with chronic pain. It is essential to work with your health care provider for pain management; your provider may refer you to a neurologist or pain specialist for additional help.
FAQs
What causes PHN?
The exact cause(s) of PHN is not well-characterized and may differ between individuals. Autopsy studies of some individuals show that the sensory neurons associated with VZV reactivation and shingles are damaged and are now incorrectly sending pain signals to the brain. Other studies show that some individuals may still have active virus replicating in the sensory neurons, triggering inflammation and nerve irritation; the concept of active replicating virus perpetuating the PHN pain is supported by studies and case reports showing that antiviral treatment decreases PHN pain. A new study shows that small extracellular vesicles in the circulation may prevent the nerves from healing after shingles.
How is PHN managed?
Successful pain management is the goal so that you are not consumed by 24/7 pain, affecting your social interactions, ability to do normal activities (e.g. exercising, driving, housework), and quality of life. It can be depressing and disheartening when pain controls your life. Medical management needs to be tailored, based on concurrent medical conditions and individual's side effects. Common therapies include amitriptyline (Elavil, contraindicated if you have urinary retention or heart disease), gabapentin (Neurontin, caution in congestive heart failure since it causes fluid retention, caution with dizziness), pregabalin (Lyrica, caution with dizziness), lidocaine patches, nerve blocks (and nerve ablation if block was successful), nerve stimulators, and in severe, intractable cases, chronic opioid therapy (buprenorphine is the preferred 1st line opioid therapy because of lower risk of overdose and milder side effect profile than other opioids).Â
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Many of the oral medications have signficant side effects so it is essential to discuss benefits and risks with your health care provider when selecting the best therapies. The general approach is to "start low and go slow". For instance, in my older patients, I typically start gabapentin at a 100 mg daily dose, increasing by 100 mg every few days rather than the 300 mg start dose in a younger individual to avoid side effects of dizziness and foggy brain. With opioids, it is essential to understand the side effects of respiratory depression, sedation, and cognitive issues, as well as the need to taper off rather than stopping suddenly. For traditional opioids, the CDC has established guidelines on prescribing and risk mitigation strategies.
VZV Vasculopathy
VZV vasculopathies are vascular abnormalities (including ischemia, hemorrhage, and aneurysm formation) due to VZV reactivation. VZV vasculopathy can affect arteries in the brain, causing stroke (intracranial VZV vasculopathy), or extracranial arteries, causing heart attacks, vision loss, gut ischemia, and temporal arteritis (extracranial VZV vasculopathy). It is important to note that VZV vasculopathy can occur without associated rash or months after the rash has resolved. Herpes zoster (shingles) increases the risk of vascular events up to one year after rash, with risk decreasing over time. The risk of stroke is highest if shingles rash appears on the face or the individual is <40 years old.​  Â
FAQs
What causes VZV vasculopathy?
Mechanisms by which VZV can produce cerebrovascular disease include: (1) reactivation of VZV from      Â
trigeminal ganglia or head and neck autonomic ganglia followed by spread of the virus to specific arteries
in the brain (figure above); a robust inflammatory response ensues that weaken the arteries wall
(aneurysm, ischemic/hemorrhagic stroke), and/or; (2) production of pathogenic exosomes (extracellular vesicles)
that circulate and increase the risk of blood clots (ischemic stroke).
Similar mechanisms occur for extracranial VZV vasculopathy with reactivation of virus from trigeminal, dorsal root, and
autonomic ganglia followed by spread of virus to systemic arteries (direct infection) or with production of exosomes that trigger blood clots.
When should I suspect VZV vasculopathy?
To recognize/diagnose/manage VZV vasculopathy, it is essential to work with your health care provider. If there
is no obvious cause of stroke (such as atrial fibrillation, known vascular malformations, atherosclerosis), it is
important to consider intracranial VZVÂ vasculopathy because it is treatable. VZV vasculopathy is also highly suspect if shingles
is present at time of stroke or occurred in the past year. A previous study of multiple VZV vasculopathy cases shows
that the time from shingles to stroke was ~4 months and there was a significant delay in diagnosis (~4 months).
Importantly, one-third of individuals with VZV vasculopathy have no associated rash, making diagnosis challenging.
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Multiple case reports and pathological studies studies show that a subset of giant cell arteritis is due to a VZV temporal arteritis, as demonstrated by the presence of VZV antigen/DNA in temporal artery biopsies and further supported by unbiased RNA sequencing of these arteries demonstrating enrichment of virus infection pathways. While rare immunohistochemistry studies did not have similar findings, likely due to differences in analytic technique and lower number of temporal arteries examined from inaccurate statistical analyses, VZV temporal arteritis should still be considered in individuals with presumed GCA. VZV temporal arteritis is also highly suspect if there was associated herpes zoster ophthalmicus on the same side as the temporal arteritis.
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Extracranial VZV vasculopathy is more challenging to recognize. It is often a diagnosis of exclusion. However, for example, if shingles appears in the abdominal region, followed by organ ischemia in the same dermatomes with imaging evidence of vasculitis/aneurysm, then extracranial VZV vasculopathy should be considered.
How is VZV vasculopathy diagnosed?
Intracranial VZV vasculopathy is diagnosed by a lumbar puncture and examination of cerebrospinal fluid (CSF) for intrathecal synthesis of anti-VZV antibodies and or VZV DNA by PCR. Detection of intrathecal antibody synthesis is more sensitive that PCR testing because VZV is highly cell-associated; unlike in HSV-1 central nervous system infection, VZV is not secreted as free virions into CSF.
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There are no clear guidelines on diagnosing extracranial VZV vasculopathy. Suspect intracranial VZV vasculopathy if there was shingles in the region in the past year, if there are vascular imaging abnormalities, and if other causes have been ruled out (compressive lesion on spine imaging, other causes of vasculitides).
How is VZV vasculopathy treated?
Treatment should be decided by your health care provider who is aware of medical conditions that may affect treatment. In a healthy individual without kidney problems or other contraindications, confirmed VZV vasculopathy is treated with intravenous (IV) acyclovir 10 mg/kg, along with IV fluids to reduce risk of kidney toxicity, for 14 days. In cases of recurrent or persistent VZV vasculopathy, another round of intravenous acyclovir 10-15 mg/kg for 21 days can be considered. Because VZV reactivation increases stroke risk for up to a year, after IV acyclovir therapy is complete, the individual can be maintained on preventive dosing of antiviral medications. Sometimes, prednisone is also given along with the treatment dose of intravenous antivirals to reduce virus-associated inflammation. The benefit of antiplatelet agents (e.g. aspirin, clopidogrel, ticagrelor) has not been systematically studied; however, given a recent study showing that VZV reactivation, manifesting as shingles, increases platelet aggregation, the benefits and risks of antiplatelet agents can be determined for decision-making.
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For intracranial VZV vasculopathy cases that continue to progress in a life-threatening manner despite IV acyclovir, IV foscarnet can be considered; however, foscarnet has significant side effects of kidney toxicity, electrolyte imbalance, and gastrointestinal upset.
What is the prognosis for VZV vasculopathy?
For first episode VZV vasculopathy, about two-third of individuals stabilize or improve with IV acyclovir therapy. There is no clear data for outcomes of recurrent cases. For recurrent cases of stroke due to VZV vasculopathy, a thorough work-up for causes of recurrence is needed (immune deficits, cancer, immune suppressive therapies); then, if possible, these causes need to be addressed.
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In children with VZV vasculopathy following varicella (chickenpox), disease is usually monophasic and the child recovers. If there is recurrence, then immune cell numbers and function, including screening for inborn errors of immunity, need to be completed if no other cause is found.
Where can I learn more about VZV vasculopathy?
This comprehensive review, entitled "VZV vasculopathy", was published in 2018.
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For recent peer-reviewed publications, conduct searches on https://pubmed.ncbi.nlm.nih.gov/.
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For ongoing clinical trials, conduct searched on https://clinicaltrials.gov/.
Zoster Sine Herpete
Zoster sine herpete (shingles without rash, "internal shingles") presents as dermatomal distribution pain without rash. It is difficult to diagnose and individuals go from doctor to doctor - getting multiple imaging studies, blood tests, and even nerve conduction studies without a final diagnosis. Oftentimes, it is the affected individual themselves that come across the medical condition of zoster sine herpete through their internet searches, only to be told that shingles without rash does not exist. Zoster sine herpete is a true medical entity, and there is even a billable and specific ICD-10-CM code covering this diagnosis, B02.9.
FAQs
What causes zoster sine herpete?
Zoster sine herpete occurs when VZV reactivates from one or more sensory ganglia, remains replicating in the ganglia, and induces inflammation (VZV ganglionitis), ultimately resulting in pain. Unlike herpes zoster (shingles), virus does not travel to the skin to produce blisters but just stays isolated in the sensory ganglia causing nerve dysfunction and pain.Â
How is zoster sine herpete diagnosed?
Diagnosis is challenging because it is based on history and exam, and often is a diagnosis of exclusion. Burning pain (lasting days to years) is present on one side of the body, in a dermatomal distribution, with no rash present. Often, contact with the area causes worse pain, and there may be intermittent shocks of severe unexpected pain that occurs. Imaging studies of the affected area shows no compressive lesions on the sensory nerves; sometimes there may be nerve/ganglia enhancement indicating inflammation. Nerve conduction studies are normal. No other medical conditions account for the pain, such as prior injury to the area. Interestingly, in some cases, an individual has a history of burning pain with rash (herpes zoster, shingles) in the same area that completely resolved; then months to years later, they experience the exact same burning pain in the region without a rash. This type of prior history with diagnosed shingles at the same site of burning pain without rash is highly suggestive of zoster sine herpete.
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Because zoster sine herpete is a frequently missed diagnosis, there is a dearth of studies on the best test for diagnosis and treatment. During an acute flare, the detection of VZV DNA in blood, positive VZV IgM in serum, and/or intrathecal synthesis of anti-VZV antibodies support the diagnosis. However, negative tests do not rule out diagnosis because detection of VZV DNA and VZV IgM may be negative in chronic disease; further, there has been so systematic study to determine how sensitive detection of intrathecal anti-VZV antibodies are and what would be the "gold standard" for comparison beyond detection of VZV DNA and/or antigen in the sensory ganglia after death. This 2014 article describes a man with shingles followed by zoster sine herpete at the same site; after death, trigeminal ganglia was analyzed and was positive for VZV antigen that is only present on reactivation, supporting the notion that zoster sine herpete is due to a VZV ganglionitis.
How is zoster sine herpete treated?
Zoster sine herpete is treated with oral antivirals, similar to the treatment of acute shingles. However, there are no large studies on the best dose and duration of treatment, especially when pain does not resolve after 2 weeks. Aside from antivirals, pain must also be addressed in a manner similar to the treatment of postherpetic neuralgia.
Where can I learn more about zoster sine herpete?
This article entitled "Neurological Disease Produced by Varicella Zoster Virus Reactivation Without Rash" was published in 2010 and has a section on zoster sine herpete (page 2) and also describes other VZV disease without rash.
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For recent peer-reviewed publications, conduct searches on https://pubmed.ncbi.nlm.nih.gov/.
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