19 February 2015
Study explores risk for shingles in the current era
Infection with VZV (varicella zoster virus), a member of the herpes virus family, is relatively common. In general, in childhood VZV causes chickenpox and in adults it recurs to cause shingles. After the signs and symptoms of chickenpox resolve, VZV goes into a state of latent infection inside nerve cells. It is generally held in check by the immune system. However, as the immune system weakens with age, VZV can become reactivated, resulting in shingles (also called herpes zoster). Shingles is a painful skin condition that is most commonly seen in people over the age of 50. However, there are cases when the immune system becomes weakened, such as stress from another infection, that can allow the reactivation of VZV leading to shingles even in younger people.
People dealing with the following health issues can also, sometimes, develop shingles:
- HIV infection
- type 2 diabetes
- organ transplant
- corticosteroid use
Focus on HIV
In the time before the availability of potent combination anti-HIV therapy (commonly called ART or HAART), rates of shingles were high among HIV-positive people. Fortunately, ART became available in high-income countries in 1996, and since then serious infections arising from weakened immunity are less common among people taking ART.
HIV, ART and shingles
To better understand trends in shingles cases as well as the impact of ART, researchers in Paris, France, analysed health-related information collected from both HIV-positive and HIV-negative people. They found that cases of shingles decreased significantly once ART became available in France in 1996. However, even after 1996, researchers found that HIV-positive people had a generally elevated risk for shingles. Shingles is relatively common in older people but in the French study HIV-positive people aged 15 to 44 years were at greatest risk for this condition.
Researchers reviewed health-related information collected from major clinics across France and centralized in the French Hospital Database (FHDB). The data from HIV-positive people were collected from 1992 to the end of 2011. Health-related information from HIV-negative people was collected between 2005 and 2008. The data for HIV-negative people was provided by a network of general practitioners (family doctors) called Réseau Sentinelles. This network reports any cases of certain diseases and conditions (including shingles) that occur in France. Other research has shown that this network is broadly reflective of the diseases and conditions that family doctors treat across France.
Researchers analysed data from 91,044 HIV-positive people and found that 7,167 had been diagnosed with shingles. Below is a brief average profile of HIV-positive people with shingles:
- 72% men, 28% women
- age – 38 years
- CD4+ count – 304 cells/mm3
- lowest-ever CD4+ count – 176 cells/mm3
- proportion with an HIV viral load less than 500 copies/ml – 29%
Overall, researchers found that cases of shingles among HIV-positive people fell significantly once ART was introduced.
Among HIV-positive people, there were always more cases of shingles in men than women. However, this difference decreased in more recent years.
Rebuilding the immune system
Untreated HIV infection significantly weakens the immune system. As a result, the immune system may not recognize some germs; even in cases when it does, the immune system may sometimes fail to produce an effective immune response against germs. This dysfunction allows germs to accumulate in the body.
Once a person initiates ART their immune system begins to gradually improve its ability to detect germs and rapidly respond to them. Depending on the degree of pre-ART immunological dysfunction and injury, during the first six months after initiating ART, immunological responses toward germs may not be ideal.
People who have accumulated a high degree of immunological injury prior to initiating ART have an increased risk of inflammatory reactions in the first three months after initiating ART. Such reactions are called immune reconstitution inflammatory syndrome (IRIS). This occurs because the recovering immune system is still somewhat dysfunctional but thanks to ART it can now recognize germs and mount a response to attack them. The response is often exaggerated, perhaps partly driven by a high amount of a particular germ, perhaps driven in part by immunological dysfunction. Whatever the underlying reason, IRIS can cause tissue injury.
Symptoms of IRIS can vary depending on the organ system affected and can range from mild fever and lack of energy to more serious symptoms that can resemble an infection. IRIS reactions are more common in people whose lowest pre-ART CD4+ counts were less than 100 cells/mm3. In all cases, IRIS is driven by an exaggerated inflammatory reaction to a germ. Doctors may prescribe anti-inflammatory agents such as the temporary use of corticosteroids to reduce the intensity of IRIS.
Starting ART and shingles
In the FHDB study, researchers noticed that after 1996 (when ART became available in France) cases of shingles would sometimes occur within three months of participants initiating ART. This is likely the result of participants initiating ART when their immune systems were weakened.
Among HIV-negative people in France, researchers found that half of people with shingles were 60 years or older. Also, shingles in this population was more common in women than in men.
The researchers also found that, overall, HIV-positive people, regardless of gender, were generally three-fold more likely to develop shingles than HIV-negative people. The risk for shingles among HIV-positive people was greatest for people aged 15 to 44 years. In this group, the risk for shingles was six-fold greater than among HIV-negative people.
Once HIV-positive people reached the age of 65 years, their risk for shingles was similar to that of HIV-negative people.
Due to the high risk of shingles among relatively young HIV-positive people, the French researchers stated that “the benefits and safety of VZV vaccination should be studied in [this population].”
They concluded their report by stating: “Clinicians and patients should be aware that ART temporarily increases the risk of shingles during the first six months of treatment.”
About chickenpox and shingles
Below is some brief information about these conditions.
VZV, a member of the herpes virus family, causes chickenpox and shingles.
Chickenpox was formerly a common childhood infection, but is now less common due to routine vaccination of all children in Canada and many high-income countries. In most cases, chickenpox results in a skin rash, low-grade fever and lack of energy. Generally, chickenpox itself is not life threatening. However, because the rash results in skin lesions that can be very itchy, affected children are prone to scratching them, which makes the underlying soft tissue susceptible to infection by bacteria that normally live on the skin. Such so-called secondary bacterial infections can be serious, rarely leading to “flesh-eating disease" (necrotizing fasciitis) and/or toxic shock syndrome. Pneumonia and inflammation of the brain (encephalitis) can also be complications of chickenpox.
According to the Public Health Agency of Canada (PHAC), “complications are more common in adolescents, adults and people with conditions that compromise their immune system who have higher rates of pneumonia, encephalitis and death.” It is also dangerous to infants whose mothers develop chickenpox around the time of delivery.
The virus that causes chickenpox is easily spread through the air when people with chickenpox sneeze or cough. It can also be spread by touching the fluid that comes from chickenpox lesions and by kissing. A person with chickenpox is no longer contagious once all the skin lesions have crusted over.
After signs and symptoms of chickenpox clear, the virus that causes it can go into a state of latency.
Shingles occurs when latent VZV infection becomes reactivated. Although shingles can occur at any age, it is generally most common in adults who are 50 years and older.
Shingles in adults initially appears as an intense tingling or burning pain on one side of the body. This pain is followed by the appearance of red patches and the formation of small sores. Blisters form and these eventually become crusted, dry and fall off. The pain and blisters are usually along the parts of the skin supplied by a single nerve that was latently infected with VZV which has reactivated. While scars from shingles are not common, older adults can sometimes develop persistent burning or tingling pain where their shingles appeared; this is called “post-herpetic neuralgia” and may require treatment. During shingles some people develop symptoms similar to a flu. An episode of shingles usually lasts for between one and two weeks.
Shingles is not spread through the air like chickenpox, but can be spread when a person touches the fluid from a blister. Keeping blisters covered greatly helps to reduce the possible spread of shingles. People with shingles are not infectious before the appearance of blisters or after blisters have become crusted.
In cases of weakened immunity
In people with HIV and other immunological disorders, both chickenpox and shingles can take longer to clear, up to four weeks in some cases. What’s more, shingles can recur in such people.
Treatment of shingles can include the antiviral drugs valacyclovir or famciclovir. These drugs can speed the healing of lesions and sometimes cause a reduction in pain and the risk for post-herpetic neuralgia.
Although vaccines are licensed to reduce the risk of developing chickenpox and shingles, they contain weakened but live virus. People with HIV infection (or parents of children with HIV) should consult an infectious disease or HIV specialist about whether it is safe for them (or their children) to receive these vaccines. If someone with a weak immune system is in contact with a person infected with chickenpox, it is important that they contact their health care provider to find out if they need treatment to prevent developing chickenpox themselves.
Two candidate shingles vaccines are being tested for possible use in people with immunological disorders. These vaccines are:
- a heat-treated vaccine – this contains virus that has been treated with heat so that it cannot cause infection. However, it can stimulate immunity to VZV. This vaccine is being developed by Merck.
- a subunit vaccine – this contains a protein from VZV that is coupled with a protein derived from bacteria. The purpose of the bacterial protein is to stimulate the immune system when it is exposed to the protein from VZV, amplifying the immune response to VZV. Neither the protein from VZV nor the protein from bacteria can cause infections. This vaccine is being developed by GlaxoSmithKline.
Preliminary results from clinical trials of both of these vaccines suggest that they are safe and cause immunity to VZV.
We thank infectious disease specialist Jason Brophy, MD, for his helpful comments, expert review and research assistance.
—Sean R. Hosein
- Whitley RJ. Chapter 180. Varicella-Zoster Virus Infections. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
- Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurology. 2007 Nov;6(11):1015-28.
- Grabar S, Tattevin P, Selinger-Leneman H, et al. Incidence of herpes zoster in HIV-infected adults in the combined antiretroviral therapy era: results from the FHDH-ANRS CO4 cohort. Clinical Infectious Diseases. 2015; in press.
- Mary-Krause M, Grabar S, Lièvre L et al. Cohort Profile: French hospital database on HIV (FHDH-ANRS CO4). International Journal of Epidemiology. 2014 Oct;43(5):1425-36.
- Berkowitz EM, Moyle G, Stellbrink HJ, et al. Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: A phase 1/2a randomized, placebo-controlled study. Journal of Infectious Diseases. 2015; in press.
- Mullane KM, Winston DJ, Wertheim MS, et al. Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) in immunocompromised adults. Journal of Infectious Diseases. 2013 Nov 1;208(9):1375-85.
- Meintjes G, Scriven J, Marais S. Management of the immune reconstitution inflammatory syndrome. Current HIV/AIDS Reports. 2012 Sep;9(3):238-50.
- Martin-Blondel G, Mars LT, Liblau RS. Pathogenesis of the immune reconstitution inflammatory syndrome in HIV-infected patients. Current Opinion in Infectious Diseases. 2012 Jun;25(3):312-20.