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At first look, Nakul Shekhawat, MD, MPH, thought the explanation for his research results was obvious. Shekhawat and his colleagues at the University of Michigan found that the incidence of herpes zoster ophthalmicus (HZO)—shingles of the eye—had tripled in the United States from 2004 to 2016. He chalked it up to the aging US population. “That’s what you would think,” he said.
It’s a reasonable assumption. Virtually every US-born adult aged 40 years or older has been infected with varicella zoster virus, which causes chickenpox. Although universal varicella vaccination was introduced in 1995, millions of older adults have waning cell-mediated immunity that leaves them vulnerable to reactivation of varicella virus, which causes shingles. Older age is a prominent risk factor for the condition, which usually causes a painful, itching unilateral rash on the chest and back. Shekhawat’s data showed that older age is a risk factor for HZO, too.
In addition to age as a risk factor, his data also suggested that women were more likely than men to develop HZO as were white adults compared with black, Asian, and Latino adults—the same demographic patterns as with shingles. Among the study population of 21 million adults enrolled in United Healthcare insurance plans, HZO incidence increased from 9.4 cases per 100 000 population in 2004 to 30.1 cases per 100 000 in 2016.
The finding of increased HZO incidence persisted when Shekhawat and his colleagues adjusted their analysis for age, race, and sex, raising some important questions. For example, why is the incidence of HZO and shingles increasing? “Diseases don’t usually double or triple over a 12-year time span,” said Shekhawat, who is now in a cornea fellowship program at the Johns Hopkins Wilmer Eye Institute. Several theories exist, but study results are mixed.
Another central issue is why vaccination against shingles isn’t more widespread. The Centers for Disease Control and Prevention (CDC) reported that in 2016, about 33% of US adults aged 60 years or older had been vaccinated with Zostavax, a live, attenuated virus vaccine that was licensed in 2006 for adults aged 50 years and older.
Shingrix, a more effective recombinant vaccine, was licensed in 2017. The Advisory Committee on Immunization Practices (ACIP), which offers guidance to the CDC, recommends Shingrix for immunocompetent adults aged 50 years or older. For those who aren’t able to receive Shingrix, ACIP recommends Zostavax for immunocompetent adults aged 60 years or older.
“It has been a big problem that primary care doctors haven’t recognized the importance of vaccination against [shingles], and I’m hoping they will do better now that we have a more effective vaccine, said Elisabeth Cohen, MD, a professor of ophthalmology at the New York University (NYU) School of Medicine and NYU Langone Health.
Complications from HZO, in which the varicella virus reactivates in the ophthalmic division of the trigeminal nerve, can be severe. The virus may cause pronounced eyelid edema or skin lesions around the eye. The cornea or other parts of the eye may be affected. Other complications include glaucoma, retinal necrosis, and blindness, as well as an increased risk of stroke. Cohen is well aware of the consequences. Her own vision loss from HZO while still in her 50s caused her to give up a distinguished career as a cornea surgeon.
The CDC estimates that each year, about 1 million people in the United States develop shingles, and the incidence has gradually increased since at least the early 1990s. A cohort study in Minnesota showed that the incidence has increased more than 4-fold over the last 60 years, from 0.76 cases per 1000 person-years from 1945 through 1949 to 3.15 per 1000 person-years from 2000 through 2007. Some 20% of people with shingles will develop HZO, said Shekhawat, who presented his data in May at the Association for Research in Vision and Ophthalmology annual meeting.
The CDC discounts the “boosting” theory that increased shingles cases are related to lower circulating varicella virus following widespread varicella vaccination. But Shekhawat contends that the theory is still in play. “[P]eople are not getting that periodic immune boost against varicella zoster virus that they may have been getting in prior years because they don’t get exposed to their kids getting chickenpox anymore,” he said.
However, Cohen maintained that varicella virus vaccination isn’t a factor. “There’s data to support that that’s not the case,” she said. The Minnesota cohort study came to that conclusion, so did a study of medical records from Group Health Cooperative (now Kaiser Permanente) enrollees in Washington state. The analysis showed that from 1992 through 2002, which covers 3 years before and 7 years after varicella vaccination was introduced, chickenpox incidence steadily declined while the age-adjusted shingles rate remained steady.
A 2013 analysis examined Medicare claims data. The results showed that from 1992 through 2010, the incidence of shingles among adults older than 65 years increased by 39%, from 10 to 13.9 cases per 1000 person-years. But the investigators reported that shingles incidence was increasing before widespread varicella vaccination began and that vaccination did not appear to affect that trend.
Modeling studies that estimated longer-term trends suggest the upticks in incidence eventually give way to decreases. In Germany, a 100-year transmission model predicted that the incidence of shingles would increase by up to 20% for about 50 years because of the lost immune boost but then would decrease by nearly 60% over the longer-term.
In a recent point-counterpoint article, Rafael Harpaz, MD, a CDC shingles expert, cited the Medicare and Group Health studies as well as others to make the case that increases in shingles cases aren’t related to varicella vaccine. But Albert van Hoek, PhD, of the London School of Hygiene and Tropical Medicine in the United Kingdom, suggested that the increases are likely due to several simultaneous phenomena, including reduced immune boosting.
Van Hoek noted that because US fertility and mortality rates were declining long before varicella vaccination began, the proportion of children in the population decreased and fewer adults got an immune boost from exposure to kids with chickenpox. Van Hoek also cited a study showing that the incidence of shingles among adults living with children was lower than in adults without frequent exposure to children.
“The other possibility is that the health status of the overall population has changed,” Shekhawat said. More people may be at greater risk of shingles because they’re immunosuppressed from cancer chemotherapy, HIV/AIDS, treatment for autoimmune diseases, or diabetes, he noted. For now, however, that remains a theory. According to the CDC, the reason for the increases isn’t known.
At NYU Langone Health (NYULH), Cohen has tried to boost awareness about shingles consequences, including HZO, among primary care physicians by using educational efforts, electronic medical record reminders and alerts, and by keeping vaccine in stock. Cohen and her colleagues have surveyed NYULH primary care physicians to get an idea of how effective those efforts have been.
In their most recent survey, of 138 primary care physicians, 76% said shingles vaccination is an important clinical priority. However, 43% of their immunocompetent patients aged 60 years or older and only 11% of patients aged 50 to 59 years had been vaccinated. In contrast, 67% of their patients were vaccinated against influenza and 72% had received pneumococcal vaccine.
“They seem to be somewhat resistant to the educational efforts,” Cohen said. “It kind of surprises me.”
The American College of Physicians recommends that its members follow all ACIP and US Preventive Services Task Force recommendations for adult vaccines, said the group’s president, Robert McLean, MD. However, McLean noted that practicing primary care physicians weigh several factors when they give vaccines, chief among them being risk of serious disease.
By vaccinating against influenza and pneumonia, physicians “are not just decreasing the risk of an illness but they are decreasing the risk of hospitalization and, for people who are older or have underlying conditions, potentially life-threatening illness and complications,” McLean said.
According to the CDC, shingles is the underlying cause of about 96 deaths annually in the United States. In comparison, about 49 000 died of pneumonia and related complications in 2017. During the particularly harsh 2017-2018 flu season, 79 400 deaths were attributed to influenza. “So, the stakes are a bit higher in terms of the severity of illness that one is preventing with both flu [and pneumococcal] vaccine,” McLean added.
But he also acknowledged that shingles “clearly can cause lots of morbidity in terms of chronic pain, especially involving the eye, so I understand where the ophthalmologists are coming from.” Painful postherpetic neuralgia (PHN), which may last for months to years, affects an estimated 10% to 30% of people with HZO compared with about 13% of people with shingles who are aged 60 years or older.
But Cohen said it’s not likely that primary care physicians see many severe shingles cases. “[T]he people who really suffer the complications of the disease are being taken care of by pain management doctors and neurologists and ophthalmologists and [ear, nose, and throat] doctors. They don’t stay in the primary care office,” she noted. “I don’t think primary care doctors understand how bad a disease [shingles] is.”
One example she mentioned is stroke. Research has shown that having shingles is associated with a 30% increase in the relative risk of stroke, but that HZO specifically was associated with a 91% increase in relative risk. A recent review of 15 epidemiological studies and 6 meta-analyses suggested that people with shingles or HZO have up to a 4-fold increased relative risk of cerebrovascular events. In addition, risk of stroke was higher among people younger than 40 years within 1 year after having shingles.
McLean noted barriers associated with shingles vaccination that don’t exist with other adult immunizations. Although Shingrix is more than 90% effective in preventing shingles and PHN among adults aged 50 to 69 years, it requires 2 doses and can cause serious reactions. Some people “actually feel really quite ill for a day or two,” McLean said, adding that some “might be a little gun shy from that,” and forgo the second dose.
Another obstacle is reimbursement. Influenza and pneumococcal vaccinations are “covered, no questions asked, through insurance and Medicare,” McLean said. “With the shingles vaccine, that’s not the case.” Medicare coverage is through the Part D drug plan rather Part B, which covers most other common adult vaccines, or a Medicare Advantage plan with prescription drug coverage. But the cost to patients will vary, depending on the plan’s co-pay or co-insurance and where the vaccine is administered. Patients with only original Medicare pay the retail cost, which can range from $150 to $200 per dose. Most commercial insurance plans do cover the vaccine.
Because of the barriers, shingles vaccine is often given at retail pharmacies. Many physicians’ offices don’t even stock the vaccine, and Cohen said she doesn’t expect them to navigate the reimbursement and cost obstacles. “All we want is to get the doctors to recommend the vaccine,” she explained. “If you really want healthy aging, this is a disease you must prevent.”
Voelker R. Increasing Cases of Shingles in the Eye Raise Key Questions. JAMA. Published online August 07, 2019. doi:10.1001/jama.2019.10743
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