Herpes viruses associated with cognitive impairment

The herpes virus that produces cold sores during times of stress now has been linked to cognitive impairment throughout life, according to a new University of Michigan study that for the first time shows an impact on children ages 12-16.

Researchers at the U-M School of Public Health study examined the association between two latent herpes viruses—Herpes Simplex Virus Type 1 and cytomegalovirus (CMV)—and cognitive impairment among individuals across three age groups: 6-16, 20-59, and 60 and older. The researchers used data from the National Health and Nutrition Examination Survey.

HSV-1 is the oral herpes virus. Previous research has linked it with neurological disorders associated with aging, including Alzheimer’s disease and dementia, but few studies have examined whether these pathogens may influence cognition beginning early in life.

“This study is a first step in establishing an association between these viruses and cognition across a range of ages in the U.S. population,” said Allison Aiello, associate professor of epidemiology at the U-M School of Public Health.

The research, published in the Journal of Infectious Diseases, demonstrates that HSV-1 is associated with lower reading and spatial reasoning test scores among children ages 12-16; impaired coding speed, which is a measure of visual motor speed and attention, among middle-aged adults; and immediate memory impairment in older adults. CMV also was associated with impairment in coding speed, learning and recall in middle-aged adults.

More than one third of the U.S. population is positive for these viruses by early childhood. Some individuals may not be symptomatic.

“If HSV-1 begins to have impact on cognitive function early in life, HSV-1 infection in childhood may have important consequences for educational attainment and social mobility across the lifespan,” said Amanda Simanek, formerly an assistant research scientist in the U-M Department of Epidemiology and now an assistant professor of epidemiology at the University of Wisconsin-Milwaukee.

“Once acquired, herpes viruses are never cleared from the body and instead persist in a latent state. Such pathogens are, however, subject to reactivation and capable of invading the central nervous system, where they may exert direct damage to brain.”

Simanek said reactivation of herpes viruses triggers the release of pro-inflammatory cytokines, which have been linked to cognitive impairment. Cytokines are hormones involved in cell signaling and regulation; pro-inflammatory cytokines play an important role in the immunological response to infection and tissue injury. Excessive inflammation, however, has been linked to various chronic disease outcomes.

To date, much of the public health focus surrounding herpes viruses has been on treating symptoms and some on prevention.

“If future research continues to support this work and identifies a definitive mechanistic pathway, there are several implications for public health preventive measures,” Aiello said. “For example, antivirals targeted against these infections may be recommended as well as continued efforts in developing vaccines to target HSV-1 and CMV.

“These viruses are very ubiquitous and reactivate in response to exposure to stressors. If they are truly detrimental to cognitive function, individuals may want to consider reducing stress to avoid reactivation and possible damage associated with these infections, especially if they are known to be positive for HSV-1 as indicated by the presence of cold sores during times of stress.”

The researchers say further studies are warranted to examine the biological pathways by which these herpes viruses may affect cognitive impairment over time.

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Antiviral therapy associated with fewer recurring eye problems from herpes simplex virus

ScienceDaily (Sep. 14, 2010) — Taking oral antiviral medications following infection with the herpes simplex virus may be associated with a reduced risk of recurring eye-related manifestations of the disease, according to a report in the September issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

"Herpes simplex virus (HSV) is a common cause of corneal disease and is the leading infectious cause of corneal blindness among developed nations," the authors write as background information in the article. After the initial exposure to the virus and the resulting systemic infection, herpes simplex establishes a latent infection in sensory nerve structures. Reactivation of this latent infection could lead to initial or recurrent disease in one or both eyes, including inflammation or infection of the cornea, eyelid, membrane inside the eye (conjunctivitis, or pink eye) or middle layer of the eye (uveitis).

Ryan C. Young, B.A., of Mayo Clinic, Rochester, Minn., and colleagues estimated the incidence of HSV eye disease in a community-based cohort, in Olmstead County, Minnesota, from 1976 through 2007. During this time period, 394 patients with ocular HSV were identified, for an annual incidence of 11.8 per 100,000 individuals.

Oral antiviral therapy was prescribed in 175 (44 percent) of these patients, who underwent therapy for an average of 2.8 years (36 percent of the average 7.7 years of follow-up). Patients not taking this prophylactic therapy were 9.4 times more likely to have a recurrence of epithelial keratitis (infection of the top layer of the cornea), 8.4 times more likely to have a recurrence of stromal keratitis (infection of deeper layers of the cornea) and 34.5 times more likely to have a recurrence of blepharitis (eyelid infection) or conjunctivitis than those taking antiviral medications.

A total of 20 patients experienced adverse outcomes, including visual loss and perforation of the cornea; of these, 17 (85 percent) were not taking oral antiviral prophylaxis.

"Overall, this community-based retrospective study demonstrated a stable incidence of HSV eye disease during a recent 32-year period," the authors write. "We found a more dramatic protective effect of oral antiviral prophylaxis on recurrences of ocular HSV than had been described previously."

"The results of this study suggest that oral antiviral prophylaxis should be considered for patients with frequent recurrences of corneal disease," they conclude. "Additionally, we recommend an evaluation of the possible barriers preventing compliance with antiviral prophylaxis and a reassessment of the cost-effectiveness of long-term oral antiviral therapy."

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Journal Reference:

Ryan C. Young; David O. Hodge; Thomas J. Liesegang; Keith H. Baratz. Incidence, Recurrence, and Outcomes of Herpes Simplex Virus Eye Disease in Olmsted County, Minnesota, 1976-2007: The Effect of Oral Antiviral Prophylaxis. Arch Ophthalmol, 2010; 128 (9): 1178-1183 [link]

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Zoster vaccine associated with lower risk of shingles in older adults

ScienceDaily (Jan. 12, 2011) — Vaccination for herpes zoster, a painful rash commonly known as shingles, among a large group of older adults was associated with a reduced risk of this condition, regardless of age, race or the presence of chronic diseases, according to a study in the January 12 issue of JAMA.

"The pain of herpes zoster is often disabling and can last for months or even years, a complication termed postherpetic neuralgia. Approximately 1 million episodes of herpes zoster occur in the United States annually, but aside from age and immunosuppression, risk factors for this condition are not known," the authors write. Although prelicensure data provided evidence that herpes zoster vaccine works in a select study population under idealized circumstances, the vaccine needs to be evaluated in field conditions to show whether benefits of the vaccine can be generalized to conditions of clinical practice, according to background information in the article. The researchers note that this is particularly important for the herpes zoster vaccine, given the medical and physiological diversity in the elderly population for whom the vaccine is indicated.

Hung Fu Tseng, Ph.D., M.P.H., of Southern California Kaiser Permanente, Pasadena, Calif., and colleagues evaluated the risk of herpes zoster after receipt of herpes zoster vaccine among individuals in general practice settings. The study included community-dwelling adults, age 60 years or older, who were members of a managed care organization. There were 75,761 members in the vaccinated cohort, who were age matched (1:3) to 227,283 unvaccinated members.

Compared with the unvaccinated cohort, individuals in the vaccinated cohort were more likely to be white, women, and to have had more outpatient visits, and a lower prevalence of chronic diseases. There were 5,434 herpes zoster cases identified in the study (6.4 cases per 1,000 persons per year among vaccinated individuals and 13.0 cases per 1,000 persons per year among unvaccinated individuals). In the fully adjusted analysis, vaccination was associated with reduced risk of herpes zoster. The reduction in risk did not vary by age at vaccination, sex, race, or with presence of chronic diseases. Herpes zoster vaccine recipients had reduced risks of ophthalmic herpes zoster and hospitalizations coded as herpes zoster. Overall, the vaccine was associated with a 55 percent reduction in incidence of herpes zoster.

"Herpes zoster vaccine was licensed recently, which means the durability of its protection needs to be assessed in future studies. Meanwhile, however, this vaccine has the potential to annually prevent tens of thousands of cases of herpes zoster and postherpetic neuralgia nationally. To date, herpes zoster vaccine uptake has been poor due to weaknesses in the adult vaccine infrastructure and also due to serious barriers to the vaccine among clinicians and patients. Solutions to these challenges need to be found so that individuals seeking to receive herpes zoster vaccine will be able to reduce their risk of experiencing this serious condition," the authors conclude.

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H. F. Tseng, N. Smith, R. Harpaz, S. R. Bialek, L. S. Sy, S. J. Jacobsen. Herpes Zoster Vaccine in Older Adults and the Risk of Subsequent Herpes Zoster Disease. JAMA: The Journal of the American Medical Association, 2011; 305 (2): 160 DOI: 10.1001/jama.2010.1983

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Type Of Rheumatoid Arthritis Medication May Be Associated With Increased Risk For Shingles

ScienceDaily (Feb. 17, 2009) — Use of certain medications known as monoclonal anti– tumor necrosis factor a (TNF-a) antibodies for the treatment of rheumatoid arthritis appears to be associated with an increased risk for herpes zoster (shingles), the painful infection characterized by blisters, according to a new study.

There has been evidence from some studies that patients treated with anti–TNF-a agents are at an increased risk of bacterial infections, but little is known about the risk of viral infections, such as herpes zoster, in patients with rheumatoid arthritis receiving these types of medications. Herpes zoster is one of the most common adverse events reported in clinical trials of anti–TNF-a agents, according to background information in the article. Patients with rheumatoid arthritis are at increased risk of herpes zoster compared with the general population.

Anja Strangfeld, M.D., of the German Rheumatism Research Center, Berlin, and colleagues investigated the association of various rheumatoid arthritis treatments, including anti–TNF-a therapy, with the risk of herpes zoster. The researchers analyzed data from patients who began treatment with adalimumab or infliximab (monoclonal anti–TNF-a antibodies), etanercept (a fusion protein), the monotherapeutic agent anakinra, or when patients changed conventional disease-modifying anti-rheumatic drug (DMARD). Treatment, clinical status and adverse events were assessed by rheumatologists at fixed points during follow-up (of up to three years). A total of 5,040 patients were included in the analysis.

There were 86 cases of herpes zoster among 82 patients. Thirty-nine occurrences could be attributed to treatment with anti–TNF-a antibodies (23 to etanercept, 24 to conventional DMARDs). The researchers found a significant association between herpes zoster and treatment with the monoclonal anti–TNF-a antibodies infliximab and adalimumab, although this risk was lower than the threshold for clinical significance. There was no significant association between herpes zoster and treatment with etanercept, or anti–TNF-a treatment as a class.

A significantly higher risk of developing herpes zoster was found for patients of older age and for treatment with glucocorticoids (steroid hormones that are widely used as anti-inflammatory medications).

"Based on our data, we recommend careful monitoring of patients treated with monoclonal anti–TNF-a antibodies for early signs and symptoms of herpes zoster," the authors conclude.

Editorial: Herpes Zoster in the Age of Focused Immunosuppressive Therapy

In an accompanying editorial, Richard J. Whitley, M.D., and John W. Gnann Jr., M.D., of the University of Alabama at Birmingham, comment on the findings of this study.

"The TNF-a inhibitors provide tremendous benefit to a broad spectrum of patients with systemic inflammatory diseases. As with any therapy, time is required for all of the safety concerns related to these potent medications to become apparent. TNF-a inhibitors have revolutionized the management of a number of difficult diseases, especially inflammatory arthritis, but clinicians must continue to remain aware of the potential for serious infectious complications, which now include herpes zoster."

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Journal Reference:

Anja Strangfeld; Joachim Listing; Peter Herzer; Anke Liebhaber; Karin Rockwitz; Constanze Richter; Angela Zink. Risk of Herpes Zoster in Patients With Rheumatoid Arthritis Treated With Anti%u2013TNF-{alpha} Agents. JAMA, 2009;301(7):737-744 [link]

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Condoms Associated With Moderate Protection Against Herpes Simplex Virus 2

ScienceDaily (July 13, 2009) — Condom use is associated with a reduced risk of contracting herpes simplex virus 2, according to a report based on pooled analysis of data from previous studies.

Herpes simplex virus 2 (HSV-2) typically causes genital herpes, a chronic, life-long, viral infection. Although studies indicate that consistent condom use reduces the spread of HIV and other sexually transmitted diseases such as chlamydia and gonorrhea, the effectiveness of preventing the transmission of HSV-2 through condom use is less certain, according to background information in the article.

Emily T. Martin, M.P.H., Ph.D., of Children's Hospital Research Institute and the University of Washington, Seattle, and colleagues analyzed data from six HSV-2 studies to assess the effectiveness of condom use in preventing the virus. The studies included three candidate HSV-2 vaccine studies, an HSV-2 drug study, an observational sexually transmitted infection (STI) incidence study and a behavioral STI intervention study. These yielded results from 5,384 HSV-2-negative individuals (average age 29) at baseline for a combined total of 2,040,894 follow-up days.

More than 66 percent of those who took part in the six studies were male, 60.4 percent were white, 94.1 percent were heterosexual and most reported no prior STIs.

A total of 415 of the individuals acquired HSV-2 during follow-up. "Consistent condom users [used 100 percent of the time] had a 30 percent lower risk of HSV-2 acquisition compared with those who never used condoms," the authors write. "Risk of HSV-2 acquisition decreased by 7 percent for every additional 25 percent of the time that condoms were used during anal or vaginal sex." The risk of acquiring the virus increased significantly with increasing frequency of unprotected sex acts. There were no significant differences found in condom effectiveness between men and women.

"Based on findings of this large analysis using all available prospective data, condom use should continue to be recommended to both men and women for reducing the risk of HSV-2 acquisition," the authors conclude. "Although the magnitude of the protective effect was not as large as has been observed with other STIs, a 30 percent reduction in HSV-2 incidence can have a substantial benefit for individuals as well as a public health impact at the population level."

Funding for this project was provided by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases. 

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Emily T. Martin, MPH; Elizabeth Krantz, MS; Sami L. Gottlieb, MD, MSPH; Amalia S. Magaret, PhD; Andria Langenberg, MD; Lawrence Stanberry, MD, PhD; Mary Kamb, MD, MPH; Anna Wald, MD, MPH. A Pooled Analysis of the Effect of Condoms in Preventing HSV-2 Acquisition. Arch Intern Med, 2009;169(13):1233-1240 [link]

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