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With its burning grip, shingles can do lasting damage

When varicella zoster reawakens, it wreaks a surprising amount of havoc in the body

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9:00am, February 26, 2019
shingles illustration

BURNED  When the virus responsible for chicken pox reemerges — sometimes decades after that first infection — it can raise the risk of stroke, dementia and long-term pain.

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At age 37, Hope Hartman developed a painful, burning rash in her right ear, in the part “you would clean with a Q-tip,” the Denver resident says. The pain got so bad she went to a local emergency room, where the staff was flummoxed. Hartman was admitted to the hospital, where she started to lose sensation on the right side of her face.

During that 2013 health crisis, Hartman’s husband, Mike, sent a picture of the ear to his mom, a nurse. She said it looked like zoster, better known as shingles, which is caused by the varicella zoster virus. She “diagnosed it from an iPhone photo,” Hartman recalls.

Antiviral treatment didn’t fully clear the infection. For about two weeks after her release from the hospital, Hartman coped with severe pain, hearing loss and difficulty eating. Her right eye wouldn’t fully open or close. Following an appointment with neurologist Maria Nagel of the University of Colorado School of Medicine in Aurora, Hartman was admitted to the university’s hospital to get another antiviral drug intravenously. The pain subsided, and Hartman regained her hearing and the feeling in her face.

To spare others the same trauma of a delayed diagnosis, Hartman arranged for Nagel to give a talk on the virus at the local hospital where staff missed the signs of the illness, known as Ramsay Hunt syndrome. That’s the name for a shingles infection that strikes the facial nerve important to facial movement. As Hartman experienced, varicella zoster virus can cause a grab bag of symptoms that go beyond the typical torso rash.

Hartman’s young age didn’t help with the diagnosis. Shingles is more common in people 50 and older. But no one is risk-free. Varicella zoster virus lives in about 95 percent of the U.S. adult population, thanks to the virus’s first line of attack: chicken pox. The body eventually clears the itchy, red pox from the skin, but the virus remains, dormant in nerve cells. The rash kept scores of U.S. children home from school until about 1995 (when a vaccine became available).

Decades after its first assault, varicella zoster virus can mount a second attack from its hiding place within nerve cells, bringing pain, burning, numbness or itchiness to the skin, after which a blistery rash often blooms. The pain and rash are usually confined to the strip of skin connected to the infected nerve cells.

The torso is the most common site of this eruption; the belt of pain and rash wraps from front to back on half of the body. Indeed, the words zoster and shingles, from Greek and Latin, mean girdle or belt. As to the pain, the Norwegian word for shingles, helvetesild, means “hell’s fire.”

Less common, but just as painful, shingles can originate on one side of the face, in an ear or in and around an eye. And researchers now know that shingles can occur in the gut, which comes with no rash tip-off.

Age discriminator

Shingles can strike anyone infected with varicella zoster virus, but the risk really begins to climb with each year after age 50. Data here are for the U.S. population, but this trend also holds for populations worldwide.

U.S. shingles incidence by age group

Source: R.P. Insinga et al/Journal of General Internal Medicine 2005

The list of nasty complications from the infection has also grown beyond the debilitating pain that persists in some people for months or years. Recently, scientists have learned more about the virus’s ability to infect arteries, increasing the risk of stroke or causing headaches and vision problems. There are even hints of a connection between shingles in the eye and dementia.

Researchers are fighting back against the virus. In 2017, the U.S. Food and Drug Administration approved Shingrix, a vaccine to prevent shingles in people 50 and older that outperforms an earlier vaccine, Zostavax. (Yet supplies of the new vaccine aren’t keeping up with demand.) And in the lab, scientists recently uncovered a genetic message in the virus that may eventually provide a way to lock the virus in a permanent sleep.

A reawakening

A half century ago, a doctor in Cirencester, England, northwest of London, developed a hypothesis for how shingles arises, based on observations of 1,270 patients with either chicken pox or shingles in his practice from 1947 to 1962. By tracking those patients, R. Edgar Hope-Simpson demonstrated that shingles was not a new infection from outside of the body but a reawakening of the varicella zoster virus from within. He also noted that the occurrence of shingles rose with age and that patients whose immune systems were suppressed, due to leukemia or radiation therapy, for example, were also at higher risk.

Hope-Simpson shared his hypothesis in a 1964 lecture. He proposed that during chicken pox, the virus travels from the infected skin — along nerves that detect sensation in the skin — to hubs of nerve cell bodies outside of the central nervous system, called ganglia. Within a ganglion, the virus becomes dormant, remaining in the body for life. If the virus awakens and multiplies, copies of the virus travel back along nerves to the skin, and shingles, also called herpes zoster, flares up.

The British doctor’s hypothesis was largely on the mark. Today, scientists are expanding the virus’s list of effects. Because every organ in the body has a supply of nerves, Nagel says, “there’s a direct pathway, when [the] virus reactivates, to hit every single organ system.”

One recently discovered viral target is the gut. Anne Gershon, a pediatric virologist at Columbia University Vagelos College of Physicians and Surgeons in New York City, and colleagues found that the virus haunts the digestive organs’ local system of nerves, known as the enteric nervous system. In the gut, instead of a rash, the virus can cause abdominal pain, ulcers or other problems.

Gershon and colleagues — including her husband, Michael Gershon, also at Columbia and an expert on the enteric nervous system — detected varicella zoster virus in the saliva of six of 11 patients with unexplained abdominal pain for up to four months. The researchers reported those findings in 2015 in Clinical Infectious Diseases.

Double duty

Varicella zoster virus causes chicken pox, a body-wide rash (1), then hides within nerve cell hubs called ganglia (2). Years later, the virus may launch a second infection, shingles (3), in the torso, an eye, ear, or even the gut, depending on the location of the ganglia where the virus awakens. Shingles may lead to complications (4) that boost stroke and dementia risk.

1. Chicken pox2. Latency3. Shingles4. Complications
1. Chicken pox2. Latency
3. Shingles4. Complications
Images: E. Otwell

Source: Leigh Zerboni et al/Nature Reviews Microbiology 2014

It’s complicated

During shingles, the virus can also infect arteries. The immune system’s attempt to clear the infection from the vessels sparks inflammation, damaging artery walls. When this post-shingles complication, called varicella zoster virus vasculopathy, hits arteries in the brain, stroke risk goes up.

Numerous studies have shown the heightened stroke risk, to varying degrees and length of time. The first major look was a study of Taiwanese medical records published in 2009, which found a 31 percent increase in stroke risk for a year after shingles; when shingles had occurred in the eye, stroke risk rose further, roughly four times above normal. More recent studies out of the United Kingdom, Germany and the United States have found similar trends.

Antiviral drugs can reduce pain and itchiness and hasten the rash’s departure. The U.K. study, published in 2014 in Clinical Infectious Diseases, suggested that those same drugs reduced the risk of a post-shingles stroke. Yet, in cases of shingles that feature pain but no rash, the diagnosis may be missed and the infection left untreated.

The brain vessel damage that can occur with shingles is similar to what is often seen in dementia. So researchers in Taiwan wondered whether having shingles in the eye raises the risk of dementia. The team analyzed health insurance data and found that dementia risk was three times higher for people who’d had shingles in the eye, known as herpes zoster opthalmicus, compared with those who hadn’t had an episode. The group with shingles in the eye experienced 10.2 new cases of dementia per 1,000 people per year compared with 3.6 new cases per 1,000 in the group with no shingles, according to a 2017 report in PLOS ONE.

The reactivated virus may also be behind some cases of a painful inflammation of the arteries at the temples called giant cell arteritis. More common in older adults, the disorder causes severe headaches, jaw pain and vision problems, and can lead to blindness. Nagel and colleagues found the virus in 61 of 82 artery samples taken from the temples of patients with the disorder, the team reported in 2015 in Neurology

A potential sleeping pill

Varicella zoster virus can stir up a lot of trouble in the body, depending on where it awakens. But surprisingly, the virus appears to hide in very few nerve cells. In autopsy samples of ganglia from 18 people who had had chicken pox, researchers found dormant virus in only 34 of 2,226 nerve cells, or 1.5 percent. The dormant virus in the body “is like a needle [in] a huge haystack,” says neurovirologist Randall Cohrs of the University of Colorado School of Medicine in Aurora. “That needle can reactivate and wreak so much havoc.”

How this virus does what it does has vexed scientists for a long time. Humans are the only animals that can become infected by this virus, which makes studies in rats and other lab animals challenging. But varicella zoster shares certain features with herpes simplex type 1, a virus that also lies dormant in nerve cells. Herpes simplex causes cold sores and other health problems when it reactivates. Research has revealed a genetic message in the virus, called a latency associated transcript, that appears to keep the herpes simplex virus from becoming active.

Judith Breuer, a clinical virologist at University College London, and colleagues have now found a similar genetic message in varicella zoster virus, which they reported last year in Nature Communications. Using recently developed tools that allow researchers to zero in on very small amounts of genetic material, the researchers analyzed ganglia autopsy samples and pulled out a transcript “which had never before been seen,” Breuer says.

The transcript, which Breuer’s group dubbed the varicella zoster virus latency-associated transcript, or VLT, is a message that appears to stop a gene in the virus from turning on and launching an active infection.

This research offers “a new mechanism for how varicella zoster virus may establish and maintain latency,” says Jeffrey Cohen, chief of the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases in Bethesda, Md. And because the VLT seems to block a gene that’s crucial to an active infection, Cohen says, there may be ways to manipulate the VLT and prevent the virus from reawakening and causing shingles.

Shot to the system

Someday there may be drugs, based on VLT or other new findings, to keep the virus dormant. But for now, vaccines are the best protection.

Approved in 2006, Zostavax was the first vaccine to prevent shingles. Based on the chicken pox vaccine, Zostavax is a high-dose version of live, weakened virus, meant to boost the body’s immune response. In a clinical trial of Zostavax in people 60 and older, 315 cases of shingles occurred in a group of about 19,200 people who got the vaccine. In a placebo group of the same size, 642 people got shingles. The vaccine offered less protection for people 70 and older, those at highest risk for the disease.

“The older you get, the more likely you are to get zoster,” Anne Gershon says. “And the more likely your zoster is to produce postherpetic neuralgia,” the debilitating pain that can persist long after the rash retreats in anywhere from 5 to 30 percent of patients.

A better vaccine that stimulates the immune system with a protein from the virus, rather than with a live, weakened virus, became available in 2017. Called Shingrix, the vaccine was 97 percent effective at preventing shingles in adults 50 and older in a clinical trial that followed participants for an average of about three years, researchers reported in 2015 in the New England Journal of Medicine.

A better option

The Shingrix vaccine (blue line) reduced cases of shingles in people 70 and older compared with a placebo (red line). An earlier vaccine, Zostavax, did not work as well in older adults.

Shingrix vaccine effectiveness in people 70 and older

Shingrix made a very strong showing in people 70 and older as well; it was about 90 percent effective at stopping shingles and preventing postherpetic neuralgia, scientists reported in the same journal in 2016. So far, the vaccine appears to provide strong immune protection for nine years.

The vaccine may also reduce the risk of stroke and other complications of shingles. Shingrix was 94 percent effective at preventing post-shingles complications for those 50 and older (92 percent for those 70 and older) in an analysis of clinical trials, published in 2018 in Vaccine.

Unfortunately, a shortage of Shingrix in the United States that began in mid-2018 is expected to continue this year, leaving some adults in limbo as they try to complete the two-shot vaccine regimen. But GlaxoSmithKline, the maker of the vaccine, has pledged to increase the U.S. supply.

Meanwhile, a kind of population-wide experiment is happening, one that might answer this question: Will shingles largely go away? Those vaccinated with Shingrix will be protected against shingles and postherpetic neuralgia — not complete protection but pretty close.

The chicken pox vaccine leaves a live, weakened virus dormant within nerve cells, where it could later cause shingles. But there’s early evidence that the vaccine may offer some protection. In a study from 2005 to 2009 in children younger than 18 (who can get shingles, though rarely), researchers recorded 48 cases of shingles per 100,000 vaccinated children per year versus 230 cases per 100,000 per year in kids who did not get the vaccine. The study was reported in 2013 in the Journal of Infectious Diseases.

The United States is “facing the possibility that [it] will see very, very, very little varicella zoster virus disease,” Breuer says. Of course, that requires maintaining high vaccination rates. At the moment, that leaves out people like Hope Hartman, now 43. She had chicken pox before a vaccine was available, and she was (and still is) too young to get the vaccine to prevent shingles. Shingrix was tested only in people 50 and older and therefore approved only for that age group.

For Nora Fox, who lives in Parker, Colo., the shingles vaccines came too late. Fox’s shingles began as she was hanging fall decorations on her porch in September 2005, when she was 67. She felt what she thought was a bug bite under her right arm. That night, her pain grew, and in the following months and years, it did not go away. Now 81, Fox has postherpetic neuralgia. She describes the pain as a branding iron constantly held against her torso. “It feels like the devil.”

The pain, for which there is no reliable treatment, shapes Fox’s days. She feels best in the mornings, so that’s when she plans appointments and does aerobics at the pool. Her pain grows worse in the afternoon and evening. She uses ice packs and creams to try to cool down the skin. “When the pain gets too bad, it’s as though my shirt is on fire,” she says.

Fox has encouraged her friends to get vaccinated. But they see her in the morning when she feels her best. So she tells them, “You should come see me about 2 o’clock. You’d get it.”


This article appears in the March 2, 2019 issue of Science News with the headline, "Shingles' Sneak Attack: The painful rash is common, but there may be more damage to endure."

Citations

D. Depledge et al. A spliced latency-assocaited VZV transcript maps antisense to the viral transactivator gene 61. Nature Communications. Vol. 9, March 21, 2018. doi: 10.1038/s41467-018-03569-2

M. Kovac et al. Complications of herpes zoster in immunocompetent older adults: incidence in vaccine and placebo groups in two large phase 3 trials. Vaccine. Vol. 36, March 14, 2018, p. 1537. doi: 10.1016/j.vaccine.2018.02.029

M-C. Tsai M-C et al. Increased risk of dementia following herpes zoster ophthalmicus. PLoS ONE. Vol. 12, November, 22, 2017. doi: 10.1371/journal.pone.0188490

A. L. Cunningham et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. New England Journal of Medicine. Vol. 375, September 15, 2016, p. 1019. doi: 10.1056/NEJMoa1603800

A. Gershon, J. Chen and M. Gershon. Use of saliva to identify varicella zoster virus infection in the gut. Clinical Infectious Diseases. Vol. 61, August 15, 2015, P. 536. doi: 10.1093/cid/civ320

H. Lal et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. New England Journal of Medicine. Vol. 372, May 28, 2015, p. 2087. doi: 10.1056/NEJMoa1501184

D. Gilden et al. Prevalence and distribution of VZV in termporal arteries of patients with giant cell arteritis. Neurology. Vol. 84, May 12, 2015, p. 1948. doi: 10.1212/WNL.0000000000001409

S. M. Langan et al. Risk of stroke following herpes zoster: a self-controlled case-series study. Clinical Infectious Diseases. Vol. 58, June 1, 2014, p. 1497. doi: 10.1093/cid/ciu0898

S. Weinmann et al. Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005-2009. Journal of Infectious Diseases. Vol. 208, December 1, 2013, p. 1859. doi: 10.1093/infdis/jit405

A. Cunningham and M. Levin. Herpes zoster vaccines. The Journal of Infectious Diseases, Vol. 218, September 22, 2018, Pages S127. doi: 10.1093/infdis/jiy382

M. Gershon and A. Gershon. Varicella zoster virus and the enteric nervous system. The Journal of Infectious Diseases, Vol. 218, September 22, 2018, p.S113. doi: 10.1093/infdis/jiy407

M. Nagel and A. Bubak. Varicella zoster virus vasculopathy. The Journal of Infectious Diseases, Vol. 218, September 22, 2018, p. S107. doi: 10.1093/infdis/jiy425

K. Schmader. Herpes zosterAnnals of Internal Medicine. Vol. 169, August 7, 2018. doi: 10.7326/AITC201808070

A. John and D. Canaday. Herpes zoster in the older adult. Infectious Disease Clinics of North America. Vol. 31, December 2017, p. 811.

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Further Reading

N. Seppa. Shingles vaccine linked to lower disease risk. Science News Online, January 11, 2011.

N. Seppa. Itchy and scratchy. Science News Online, May 19, 2008.

G. Morse. Chicken pox vaccine works. Science News. Vol. 125, June 9, 1984, p. 357.

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