|Year : 2016 | Volume
| Issue : 2 | Page : 157-162
|Risk of herpes zoster and family history: A Meta-analysis of case–control studies
Yi Chun Lai1, Yik Weng Yew2
1 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Dermatology, National Skin Centre, Singapore,
|Date of Web Publication||1-Mar-2016|
Yik Weng Yew
National Skin Centre, 1 Mandalay Road, Singapore - 308205
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Herpes zoster (HZ) results from the reactivation of latent varicella zoster virus (VZV) residing in dorsal root and cranial nerve ganglia. Advanced age and dysfunctional cell-mediated immune responses are well-established risk factors for VZV reactivation. There have been recent interests in whether there is an increased risk of the disease associated with a positive family history. Aims and Objectives: We aimed to conduct a meta-analysis to evaluate the association between HZ infection and family history. In addition, we investigated the dose-response relationship between HZ infection and the number of relatives with a history of HZ. Materials and Methods: Observational studies were searched from MEDLINE, EMBASE, and Cochrane Central Register from inception to April 15, 2015. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed in conducting this study. To estimate the pooled odds ratio, random-effects model of DerSimonian and Laird was used. Heterogeneity between studies was assessed using the I2 statistic. A dose-response meta-analysis with studies that reported appropriate data were done using the generalized least squares for trend method. Results: Five studies, yielding a total of 4169 subjects, were identified for meta-analysis. Cases with HZ were 3.03 (95% confidence interval [CI]: 1.86–4.94, P < 0.001) and 3.27 (95% CI: 1.75–6.10, P < 0.001) times more likely to report the first-degree relatives and total relatives with a history of HZ, respectively. A significant positive dose-response relationship between the risk of HZ infection and the number of relatives with a history of HZ was also demonstrated (P < 0.001). Conclusions: This meta-analysis demonstrated that family history is a significant risk factor for HZ infection. This risk has a dose-response relationship with the number of relatives with a history of HZ.
Keywords: Family history, herpes zoster, meta-analysis
|How to cite this article:|
Lai YC, Yew YW. Risk of herpes zoster and family history: A Meta-analysis of case–control studies. Indian J Dermatol 2016;61:157-62
|How to cite this URL:|
Lai YC, Yew YW. Risk of herpes zoster and family history: A Meta-analysis of case–control studies. Indian J Dermatol [serial online] 2016 [cited 2016 Jul 23];61:157-62. Available from: http://www.e-ijd.org/text.asp?2016/61/2/157/177748
What was known?
- Old age and cell-mediated immunosuppression are known risks factors for herpes zoster (HZ)
- HZ results from the reactivation of latent varicella zoster virus.
| Introduction|| |
Herpes zoster (HZ), also known as shingles, is a viral disease characterized by painful vesicular rash confined to a dermatome. HZ results from reactivation of latent varicella zoster virus (VZV) residing in dorsal root and cranial nerve ganglia. Approximately 30% of individuals will develop HZ at some point in their lives  and it is estimated that 1 million adults in the USA are afflicted with HZ every year. The risk of developing HZ increases considerably with age, reaching 50% in those aged 85 or older. Advanced age and dysfunctional cell-mediated immune responses are two well-established risk factors for VZV reactivation. Other risk factors, such as female gender, Caucasian ethnicity, diabetes mellitus, psychological stress, mechanical trauma, heavy metal exposure, as well as family history, have also been postulated.,, Genetic susceptibility to HZ has been demonstrated by several genetic studies., In contrast, the results of epidemiological studies investigating the relationship between the risk of HZ infection and family history were inconsistent. We aimed to conduct a systematic review and meta-analysis of published studies to evaluate the association between HZ infection and family history. In addition, we investigated the dose-response relationship between the risk of HZ and the number of relatives with a history of HZ.
| Materials and Methods|| |
The Meta-analysis of Observational Studies in Epidemiology guidelines were followed in conducting this study. A systematic and quantitative synthesis of all studies that evaluated the relationship between HZ infection and family history of HZ was planned a priori.
A comprehensive database search was performed independently by using MEDLINE, EMBASE, and Cochrane Central Register. The following search criteria were used: “Herpes zoster” [MeSH] and “family history” [MeSH]. The search was limited to English-language studies published from inception to April 15, 2015. All abstracts were evaluated based on the inclusion criteria to determine eligibility for meta-analysis. Additional studies were identified from manual searches of references in retrieved articles.
Selection of articles
The following inclusion criteria were used to select original studies for the analysis: Cohort, case–control, or cross-sectional study design; analysis of the association between HZ infection and family history of HZ (i.e., presence of relatives with a history of HZ); availability of cases and controls, and description of exposure (i.e., presence and numbers of first-degree/total relatives with HZ). Studies needed to report sufficient information, such as odds ratio (OR) and 95% confidence interval (CI), so that the corresponding standard errors could be calculated. Where such information was not readily available, crude data with the number of cases in the exposed and unexposed groups should be reported. Two reviewers independently reviewed the titles and abstracts of these articles. Based on the inclusion criteria and information from abstract, articles were identified for full-text review. Reviewers independently evaluated the full-text articles to determine their eligibility for inclusion in the analysis. Any disagreements were resolved by consensus.
Reviewers independently extracted the data with a standardized data extraction form. Relevant information extracted included the study year, country of study, study design, exposure (i.e., number of relatives with a history of HZ infection) in cases versus control group, OR and their respective 95% CIs when available, and confounding factors adjusted.
All studies reported matched and adjusted measure of association. The adjusted ORs were included for meta-analysis when available; otherwise, ratios were estimated from the crude data. A pooled estimate of ORs was calculated by combining ratios obtained from the included studies. To estimate the pooled OR, random-effects model of DerSimonian and Laird was used. Heterogeneity between studies was assessed using the I2 statistic. To qualitatively evaluate publication bias, a funnel plot was constructed and visually inspected for any asymmetry. Egger's test, which evaluated small study effects, was utilized to quantitatively assess publication bias. To further explore any potential dose-dependent relationship between number of relatives with a history of HZ and the risk of having HZ infection, a dose-response meta-analysis with studies that reported appropriate data were performed. The generalized least squares for trend (GLST) method , was utilized to test for a linear trend of ORs across the numbers of relatives. All analyses were performed using STATA Version 12·0 (StataCorp, College Station, TX, USA).
| Results|| |
A search using MEDLINE and EMBASE yielded a total of 94 articles as shown in [Figure 1]. No study was identified from the Cochrane Central Register. There were 33 duplicates, which were removed from further evaluation. Of the 61 articles (after removing duplicate studies) initially identified, nine studies were selected based on the prescribed inclusion criteria. After assessing full-length articles, four studies were excluded for the following reasons: Review articles (n = 2) and insufficient information (n = 2). After these exclusions, five studies, yielding a total of 4169 subjects, were included in the meta-analysis.
Description of included studies
All five studies utilized case–control study design. The studies were conducted in various geographic regions, including the USA, Europe, and the Middle East. [Table 1] summarizes the study population characteristics.,,,, All five studies ascertained cases of HZ or postherpetic neuralgia through clinical diagnoses and assessed exposure via standardized questionnaires. All five studies had matched controls. The covariates matched variables included age, sex, ethnicity, and immune status. [Table 2] summarizes the association between HZ infection and family history of HZ in each study.,,,,
|Table 1: Study population characteristics: Risk of herpes zoster and family history|
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Meta-analysis and publication bias
There were considerable heterogeneity between studies for meta-analyses involving the first-degree relatives (I2 = 86.1%, P < 0.001) and total relatives (I2 = 93.2%, P < 0.001). To account for study heterogeneity, the random-effects model of meta-analysis was employed. Cases with HZ were 3.03 (95% CI: 1.86–4.94, P < 0.001) and 3.27 (95% CI: 1.75–6.10, P < 0.001) times more likely to report first-degree relatives and total relatives with a history of HZ, respectively, as shown in [Figure 2] and [Figure 3].
|Figure 2: Forrest plot risk of herpes zoster and the first-degree relatives with previous herpes zoster|
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|Figure 3: Forrest plot risk of herpes zoster and all family relatives with previous herpes zoster|
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Publication bias cannot be ruled out by visual inspections of the funnel plots [Figure 4]. Both funnel plots showed a lack of small size studies with negative association. Formal testing with Egger's test, however, failed to provide any evidence for small study effect in meta-analyses of the first-degree relatives (P = 0.557) and total relatives (P = 0.513).
|Figure 4: Funnel plots risk of herpes zoster and first-degree/all family relatives with previous herpes zoster|
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Dose-response analysis using the GLST method showed a significant positive dose-dependent relationship between cases of HZ and the number of first-degree/total relatives with a history of HZ (P < 0.001). The risks of having HZ increase by 2.86 and 2.91 times for every additional first-degree and total relative, respectively, with a history of HZ. In other words, an individual with two relatives with a history of HZ has almost 3 times the risk of having HZ infection, compared to those with only one relative with such history.
| Discussion|| |
To our knowledge, the present study is the first meta-analysis that evaluates the association between HZ infection and family history. By analyzing data from five studies involving 2247 cases of HZ infection and 1922 controls, we found that those who had HZ were 3 times more likely to report a family history of HZ. This relationship was statistically significant and corroborated by sensitivity analysis. The dose-response analysis of three studies with appropriate data demonstrated that an individual's risk of having HZ infection increased as he/she reported a greater numbers of first-degree/total relatives with a history of HZ. This lends further support to the circumstantial evidence that genetic predisposition may play a role in mediating the risk of HZ infection, especially within families with a similar allelic expression of certain components of cellular immunity.
Various studies have explored genetic susceptibility to HZ by evaluating the risk of infection in certain families with no known history of immunosuppression. An allelic expression of ATA haplotype at the promoter region of interleukin 10 (IL-10) genes has been reported in a significant proportion of HZ patients. This genetic polymorphism may affect the immune functions of this cytokine and, therefore, predisposes an individual to HZ infection. Similarly, another genetic study of the Korean population demonstrated that polymorphism in IL-10 promoter region, especially the GCC haplotype, was associated with susceptibility to HZ. Another study reported the relationship of human leukocyte antigen (HLA) Class I alleles with an individual's immune response to the virus and the risk of postherpetic neuralgia. While genetic susceptibility is associated with an increased risk of HZ infection, other risk factors also tend to cluster within the family. Recent studies have reported associations between HZ infection and other chronic medical conditions with strong genetic components, including depression,, systemic lupus erythematosus, inflammatory bowel diseases, and diabetes mellitus , [Table 3].,, A dysfunctional cell-mediated immunity has been postulated as the reason for such association. These chronic illnesses tend to run in the family, and the underlying immunosuppression may partially explain the role of family history in increasing the occurrence of HZ, in addition to genetic susceptibility.
|Table 3: Chronic medical conditions as possible risk factors for herpes zoster infection|
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To examine the effect of an individual study on the pooled estimate, influence analysis was performed by omitting one study at a time. The influence analysis demonstrated that the study by Gatti et al. exerted a strong effect on the overall measure of association. Gatti et al. reported that family history was not a significant risk factor for HZ in patients with postherpetic neuralgia. Unlike other studies included in the analysis, this study only evaluated the risk of HZ in patients who were older than 65 years and affected by postherpetic neuralgia, suggesting that family history may not be an important risk factor in the more severe forms of HZ. Another potential reason for a lack of association may be partly attributed to a low number of case examined, leading to a lower statistical power to detect a modest relationship in this study.
It is interesting to note that there appeared to be a gender predilection in HZ infection, with women more likely to be affected than men. A female predominance was observed in four of the five included studies, with females accounting for 53.5–59.5% of the HZ cases.,,, The study by Gatti et al., on the other hand, demonstrated that men represented 58.4% of the cases with postherpetic neuralgia. This is in contrast with the results of other epidemiological studies, which showed postherpetic neuralgia as being more prevalent in female than male HZ patients., More research is needed to explore the association of gender with the prevalence of HZ infection and its sequelae.
The major strength of this study was the large sample size and dose-response analysis. The conglomeration of multiple studies of varying sizes overcomes the lack of statistical power in individual studies. All included studies were matched case–control studies, adjusting for important confounders such as age, sex, race, and immune status. However, only one study had matched all above-mentioned variables including immune status, which served as a proxy for predisposing diseases for HZ infection. For other studies, it is not known if family history occurs in same frequency in both the predisposing disease group and control group. Most of the included studies failed to take into account predisposing disease factors for HZ, which may be a potential confounder distorting the true relationship. Another important limitation of this study was the substantial heterogeneity between the included studies. Despite the matched case–control study design, there might still be residual or unmeasured confounding. The mean age of HZ cases also varied considerably across studies, ranging from 49.1 to 72.4 years. However, data on age of occurrences of HZ in relatives were not available, limiting our ability to account for any differences in age of HZ onset between the cases and their relatives. In addition, these studies included subjects from diverse ethnic backgrounds. Genetic polymorphisms in IL-10 promoter region or HLA haplotype will likely vary in different populations. Another potential source of heterogeneity stems from the ascertainment of exposure from standardized questionnaire, which can be subjected to recall bias. Patients who had HZ infection might be more likely to remember family members with similar infection in the past, leading to differential misclassification and, thus, a biased estimate of the true association. We have addressed heterogeneity by employing random-effects model. However, as a result of considerable heterogeneity, the results may be difficult to interpret and not generalizable to all patients with HZ.
| Conclusion|| |
This meta-analysis demonstrated that a positive family history significantly increased the risk of occurrence of HZ. Furthermore, a dose-response relationship was observed between the number of relatives with a history of HZ and the risk of infection. While a significant family history may provide an indirect evidence for certain genetic susceptibility, more genome-wide association studies are required to get a better understanding of the mechanism underlying such genetic predisposition for HZ infection. Currently, zoster vaccine (Zostavax ®) is recommended for healthy individuals ≥60 years old to reduce the incidence of HZ. Earlier prophylactic vaccination with Zostavax ® can be considered in selected individuals with a positive family history, before the age of 60, to lower the likelihood of VZV reactivation and prevent the development of postherpetic neuralgia.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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What is new?
- Family history appeared to be a significant risk factor for patients with HZ infection
- This risk has a dose-response relationship with the number of relatives with a history of infection.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]
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