Herpes Zoster Risk Reduction through Exposure to Chickenpox Patients: A Systematic Multidisciplinary Review

Varicella-zoster virus (VZV) causes chickenpox and may subsequently reactivate to cause herpes zoster later in life. The exogenous boosting hypothesis states that re-exposure to circulating VZV can inhibit VZV reactivation and consequently also herpes zoster in VZV-immune individuals. Using this hypothesis, mathematical models predicted widespread chickenpox vaccination to increase herpes zoster incidence over more than 30 years. Some countries have postponed universal chickenpox vaccination, at least partially based on this prediction. After a systematic search and selection procedure, we analyzed different types of exogenous boosting studies. We graded 13 observational studies on herpes zoster incidence after widespread chickenpox vaccination, 4 longitudinal studies on VZV immunity after re-exposure, 9 epidemiological risk factor studies, 7 mathematical modeling studies as well as 7 other studies. We conclude that exogenous boosting exists, although not for all persons, nor in all situations. Its magnitude is yet to be determined adequately in any study field.     

Varicella Vaccination Alters the Chronological Trends of Herpes Zoster and Varicella

Background

Population studies on trends of varicella and herpes zoster (HZ) associated with varicella zoster vaccination and climate is limited.

Methods

This study used insurance claims data to investigate the chronological changes in incident varicella and HZ associated with varicella zoster vaccination. Poisson regression was used to estimate the occurrence of varicella associated with the occurrence of HZ and vice versa by year, season, sex, temperature, and sunny hours.

Results

The varicella incidence declined from 7.14 to 0.76 per 1,000 person-years in 2000–2009, whereas the HZ incidence increased from 4.04 to 6.24 per 1,000 person-years. Females tended to have a higher risk than men for HZ (p<0.0001) but not varicella. The monthly mean varicella incidence was the lowest in September (160 cases) and the highest in January (425 cases), while the mean HZ incidence was lower in February (370 cases) and higher in August (470 cases). HZ was negatively associated with the incidence of varicella before and after the varicella zoster vaccination (p<0.001), increased 1.6% within one week post-vaccination. The effect of temperature on HZ was attenuated by 18.5% (p<0.0001) in association with vaccination. The varicella risk was positively associated with sun exposure hours, but negatively associated with temperature only before vaccination.

Conclusions

The varicella vaccination is effective in varicella prevention, but the incidence of HZ increases after vaccination. HZ has a stronger association with temperature and UV than with seasonality while varicella risk associated with temperature and UV is diminished.     

Evaluation of Chosen Cytokine Levels among Patients with Herpes Zoster as Ability to Provide Immune Response

Aim and Background

Herpes zoster is a viral disease caused by the reactivation of varicella–zoster virus (VZV) which remained latent in the cranial nerve or dorsal root ganglia. Cell-mediated immunity is known to decline with age as part of immunosenescence and can lead to the reactivation of VZV. Whereas herpes zoster is usually mild in healthy young persons, older patients are at increased risk for complications. In the present study we investigated the serum cytokine profile (IL-17, IL-23, IL-21, IL-4, IL-12), representing cellular and humoral immunity and assessed the level of VZV IgG antibodies in patients with herpes zoster.

Methods

We investigated the serum concentrations of IL-17, IL-23, IL-21, IL-4, IL-12 and the level of VZV IgG antibodies in 23 patients with herpes zoster who did not develop superinfection. The control group was represented by 21 individuals in similar age with no inflammatory and infectious diseases. Cytokine and antibodies levels were measured by ELISA method. Statistical analysis was performed using the ROC curve (receiver operating characteristic), t-test, Welch’s t-test, and nonparametric tests with STATISTICA 10 software.

Results

In patients with herpes zoster, the serum level of IL-17, IL-23, IL-21, IL-4 and IL-12 as well as VZV IgG antibodies titer were statistically significantly increased compared to control group.

Conclusion

Our results confirm the broad activation of the immune system involving humoral and cell-mediated immunity.     

Upregulation of CXCL10 in human dorsal root ganglia during experimental and natural varicella-zoster virus infection

Varicella-zoster virus (VZV) reactivation causes herpes zoster, which is accompanied by an influx of lymphocytes into affected ganglia, but the stimulus for this infiltrate is not known. We report that VZV infection of ganglia leads to increased CXCL10 production in vitro, in an explant ganglion model and in naturally infected dorsal root ganglia (DRG) during herpes zoster. Lymphocytes expressing the receptor for CXCL10, CXCR3, were also observed throughout naturally infected ganglia during herpes zoster, including immediately adjacent to neurons. This study identifies VZV-induced CXCL10 as a potential driver of T lymphocyte recruitment into DRG during herpes zoster.     

Several epidemiologic features of the spread of chickenpox and herpes zoster]

Epidemiological and statistical data of herpes zoster and chickenpox by such indices as morbidity level, periodicity and month-by-month changes in the incidence of these diseases were compared. The study included 2345 herpes zoster and 11116 chickenpox cases in the course of 5 years (1972--1976). In comparison with herpes zoster, the intensity of chickenpox spread among the population was on the average 4.7 times greater. Of the total number of chickenpox cases the percentage of herpes zoster contituted 21.0. Chickenpox morbidity had marked seasonal cyclic nature with the amplitude of seasonal variations of about 8; as to herpes zoster--there was no annual or seasonal cyclicity. Thus, in the development of chickenpox and herpes zoster epidemic process there was revealed a peculiar tendency inherent to each of these infections; no common epidemiological and statistical regularities in the spread intensity, annual periodicity and seasonal cyclicity were detected.     

Varicella zoster virus encephalitis during treatment with anti-tumor necrosis factor-alpha agent in a psoriatic arthritis patient

The introduction of targeted immunotherapies has greatly improved the therapeutic options of several inflammatory diseases such as psoriatic arthritis. However treatment-related opportunistic infections and viral reactivations may still occur. We describe a case of varicella zoster virus (VZV) encephalitis due to the reactivation of latent VZV infection during a long therapy with the anti-tumor necrosis factor-alpha (TNF-alpha) drug Adalimumab. The low incidence of VZV encephalitis in patients treated with biological agents does not justify VZV serological screening in these subjects, but careful monitoring of the patients is recommended to recognize early signs and symptoms of herpes zoster to start prompt antiviral therapy to prevent associated complications.     

Predictive Factors of Herpes Zoster HIV-Infected Patients: Another Adverse Effect of Crack Cocaine

A retrospective cohort study was conducted on 1541 HIV-infected patients to determine variables associated with the incidence of herpes zoster. A single failure Cox model showed that herpes zoster incidence increased following the first 6 months of antiretroviral treatment adjusted hazard ratio (AHR)=5 (95%CI=2.6-9.2), P<0.001; in the >60 years age group AHR=2 (95%CI=1-4), P=0.04; in patients in the top CD8 quartile AHR=2.1 (95%CI=1.3-3.6), P<0.001; and in patients previously reported to use crack cocaine AHR=5.9, (95%CI=1.4-25), P=0.02. Herpes zoster incidence increased in patients with CD4 counts<500 per mm³ and gradually declined since 1992-1996, with AHR=0.3 (95%CI=0.2-0.5), P<0.001 for the 1997-2002 period and AHR=0.24 (95%CI=0.14-0.4), P<0.001 for the 2002-2008 period. Contrary to what has been described elsewhere, there was no specific effect of protease inhibitors on herpes zoster incidence. The present study is the first to suggest that crack cocaine is associated with an increased incidence of herpes zoster. The neurological or immunological effects of crack are discussed.     

Diseases of the heart in a working population; a study of morbidity and mortality in relation to cardiac status and nature of job

A sample consisting of 2,252 persons among 20,199 Los Angeles civil service employees was observed for the occurrence of heart disease. The first examination measured the prevalence. Based upon the diagnosis of 165 cases of heart disease, the prevalence was 73 per 1,000 persons examined. Two reexaminations, at intervals of 12 to 18 months, of persons with normal heart on the first examination were carried out and 52 additional cases were diagnosed. There were also 13 deaths of heart disease in persons first diagnosed as having normal heart, making a total of 65 "new" cases (36.6 per 1,000) during the 30-month period of observation. An annual estimated heart disease incidence of 15 per 1,000 appears reasonable. Based on 89 deaths, the cardiovascular disease death rate was 11 per 1,000 among persons entering the study with normal heart, and 133 per 1,000 persons diagnosed as having heart disease at entry. The ratio of newly diagnosed cases to deaths of heart disease was 4 to 1.Among men diagnosed as having normal heart there was little difference in death rates whether their jobs were physically strenuous or sedentary. Among the men with heart disease, however, the highest death rates are observed among those employed at sedentary jobs and at light exertion. This may, of course, be an indication of the employee's selection of the job rather than the effect of inactivity. The relative usefulness of minifilm x-ray, electrocardiograms and questioning as to history were considered.     

Clinically Evident,Non-terminal Infections with Herpesviruses and the Wart Virus in Immunosuppressed Renal Allograft Recipients

The clinical incidence of herpes simplex lesions, herpes zoster, cytomegalovirus infection, and warts has been determined in a group of renal allograft recipients. Herpes simplex lesions appeared to be no more common after transplantation than before in those patients subject to recurrent attacks. Among 74 patients there were seven cases of herpes zoster and seven serologically proved cases of cytomegalovirus infection with clinical manifestations. The incidence of warts increased with length of time after transplantation, 42% of patients being affected more than one year after transplantation. All of the viral infections studied behaved as in healthy adults, and serious illness, dissemination, wide-spread lesions, and complications were not seen. No factors other than immunosuppression and steroid therapy could be identified with certainty as predisposing to these infections.     

DISEASES OF THE HEART IN A WORKING POPULATION—A Study of Morbidity and Mortality in Relation to Cardiac Status and Nature of Job

A sample consisting of 2,252 persons among 20,199 Los Angeles civil service employees was observed for the occurrence of heart disease. The first examination measured the prevalence. Based upon the diagnosis of 165 cases of heart disease, the prevalence was 73 per 1,000 persons examined.Two reexaminations, at intervals of 12 to 18 months, of persons with normal heart on the first examination were carried out and 52 additional cases were diagnosed. There were also 13 deaths of heart disease in persons first diagnosed as having normal heart, making a total of 65 “new” cases (36.6 per 1,000) during the 30-month period of observation. An annual estimated heart disease incidence of 15 per 1,000 appears reasonable.Based on 89 deaths, the cardiovascular disease death rate was 11 per 1,000 among persons entering the study with normal heart, and 133 per 1,000 persons diagnosed as having heart disease at entry. The ratio of newly diagnosed cases to deaths of heart disease was 4 to 1.Among men diagnosed as having normal heart there was little difference in death rates whether their jobs were physically strenuous or sedentary. Among the men with heart disease, however, the highest death rates are observed among those employed at sedentary jobs and at light exertion. This may, of course, be an indication of the employee''s selection of the job rather than the effect of inactivity. The relative usefulness of minifilm x-ray, electrocardiograms and questioning as to history were considered.     

Varicella zoster virus vaccines: potential complications and possible improvements

Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine(v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia(PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.     

Preventing papillomavirus infectious and herpes zoster: new vaccines

Two new vaccines have been recently licensed : a quadrivalent vaccine against Human papillomavirus infections (HPV) 6, 11, 16 and 18, recommended to children from 9 years old and to young adults under the age of 26 years, and a vaccine against herpes zoster for adults from 60 years old onwards. A bivalent vaccine against HPV 16 and 18 will be shortly available. HPV vaccines are composed of the L1 structural proteins of 2 or 4 HPV genotypes, produced by genetic engineering and self-assembled. These inert vaccines are devoid of genetic materials and mimic the viral particle (virus-like particle, VLP). They allow, as suggested by the 4.5 to 5 years follow-up, to prevent HPV infections and the onset of pre-cancerous lesions associated with genotypes contained within the vaccine. They represent a major overhang in the vaccinology field, and, as anti-hepatitis B vaccine, will probably be effective in cancer prevention. Their use must be associated with the continued detection of cervix cancer by smears and also with the prevention of other sexually transmitted diseases. The herpes zoster vaccine is a living attenuated vaccine produced from the OKA/Merck strain already used in the vaccine against varicella. Its safety is good among persons 50 years old and over and its efficiency on lowering herpes zoster incidence, on the burden of illness and on post-herpetic neuralgia has been demonstrated in persons over 60 years old.     

Risk of cancer among patients with herpes zoster infection: a population-based study

Background:

Whether the risk of cancer is increased among patients with herpes zoster is unclear. We investigated the risk of cancer among patients with herpes zoster using a nationwide health registry in Taiwan.

Methods:

We identified 35 871 patients with newly diagnosed herpes zoster during 2000–2008 from the National Health Insurance Research Database in Taiwan. We analyzed the standardized incidence ratios for various types of cancer.

Results:

Among patients with herpes zoster, 895 cases of cancer were reported. Patients with herpes zoster were not at increased risk of cancer (standardized incidence ratio 0.99, 95% confidence interval 0.93–1.06). Among the subgroups stratified by sex, age and years of follow-up, there was also no increased risk of overall cancer.

Interpretation:

Herpes zoster is not associated with increased risk of cancer in the general population. These findings do not support extensive investigations for occult cancer or enhanced surveillance for cancer in patients with herpes zoster.Herpes zoster, or shingles, is caused by reactivation of the varicella–zoster virus, a member of the Herpesviridae family. Established risk factors for herpes zoster include older age, chronic kidney disease, malignant disease and immunocompromised conditions (e.g., those experienced by patients with AIDS, transplant recipients, and those taking immunosuppressive medication because of autoimmune diseases).^1–5 Herpes zoster occurs more frequently among patients with cancer than among those without cancer;^6,7 however the relation between herpes zoster and risk of subsequent cancer is not well established.In 1955, Wyburn-Mason and colleagues reported several cases of skin cancer that arose from the healed lesions of herpes zoster.⁸ In 1972, a retrospective cohort study and a case series reported a higher prevalence of herpes zoster among patients with cancer, especially hematological cancer;^6,7 however, they did not investigate whether herpes zoster was a risk factor for cancer. In 1982, Ragozzino and colleagues found no increased incidence of cancer (including hematologic malignancy) among patients with herpes zoster.⁹ There have been reports of significantly increased risk of some subtypes of cancer among patients aged more than 65 years with herpes zoster¹⁰ and among those admitted to hospital because of herpes zoster.¹¹ Although these studies have suggested an association between herpes zoster and subsequent cancer, their results might not be generalizable because of differences in the severity of herpes zoster in the enrolled patients.Whether the risk of cancer is increased after herpes zoster remains controversial. The published studies^8–11 were nearly all conducted in western countries, and data focusing on Asian populations are lacking.¹² The results from western countries may not be directly generalizable to other ethnic groups because of differences in cancer types and profiles. Recently, a study reported that herpes zoster ophthalmicus may be a marker of increased risk of cancer in the following year.¹³ In the present study, we investigated the incidence rate ratio of cancer, including specific types of cancer, after diagnosis of herpes zoster.     

Varicella morbidity in Czechoslovakia

Data are presented on varicella and herpes zoster morbidity notified in Czechoslovakia in the years 1970 to 1978. The notified varicella incidence is compared with serologically confirmed varicella incidence among the selected groups of children up to the age of 12 from the North-Moravia region. Comparative analysis revealed a considerable difference between the notified and serologically detected cases of varicella. The highest rate of notified varicella was recorded in children of 3 and 4 years of age, while the highest incidence of seropositive cases was detected among the 2-year-old children. The cumulative notified morbidity involved about 35% of 6-year-old and 45% of 12-year-old children, whereas specific antibodies against the varicella-zoster virus were found in about 60% of 6-year-old and 90% of 12-year-old children. The titres of virus-specific antibodies were determined by the method of indirect hemagglutination reaction. No serological methods are applicable for herpes zoster morbidity studies in the population.     

Disease Burden Due to Herpes Zoster among Population Aged ≥50 Years Old in China: A Community Based Retrospective Survey

ObjectiveTo understand the disease burden due to Herpes Zoster (HZ) among people aged ≥50 years old in China and provide baseline data for future similar studies, and provide evidence for development of herpes zoster vaccination strategy.MethodsRetrospective cohort study was conducted in 4 townships and one community. A questionnaire was used to collect information on incidence and cost of HZ among people aged ≥ 50 years old.ResultsThe cumulative incidence rate was 22.6/1,000 among people aged ≥ 50 years old. The average annual incidence rate of HZ was 3.43/1,000 among people aged ≥ 50 years old in 2010–2012. Cumulative incidence and average annual incidence rate increased with age: the cumulative incidence of HZ among people aged ≥ 80 years old was 3.34 times of that among 50- years old (52.3/1000vs15.7/1,000); average annual incidence rate rises from 2.66/1,000 among 50- years old to 8.55/1,000 among 80- year old. Cumulative incidence and average annual incidence rate for females were higher than that for males (cumulative incidence, 26.5/1000vs18.7/1,000; annual incidence rate, 3.95/1000vs2.89/1,000). Cumulative incidence and average annual incidence rate in urban were higher than in rural (cumulative incidence, 39.5/1000vs 17.2/1,000; annual incidence rate, 7.65/1000vs2.06/1,000). The hospitalization rate of HZ was 4.53%. And with the increase of age, the rate has an increasing trend. HZ costs 945,709.5 RMB in total, corresponding to 840.6 RMB per patient with a median cost of 385 RMB (interquartile range 171.7–795.6). Factors associated with cost included the first onset year, area, whether hospitalized and whether sequelae left.ConclusionIncidence rate, complications, hospitalization rate and average cost of HZ increase with age. We recommend that the HZ vaccinations should target people aged ≥50 years old if Zoster vaccine is licensed in China.     

Epidemiology of herpes zoster. The herpes zoster patient as a source of infection with chickenpox

The authors analyse the inpatient findings accumulated from 2,179 observations on herpes zoster cases for 10 years. The clinico-epidemiological characterization of herpes zoster patients as the potential source of chickenpox infection is presented. The clinical data speak for the droplet transfer of the agent (varicella zoster virus) in this infection, which has permitted the formulation of exact practical recommendations of quarantine and isolation measures in the focus of herpes zoster.     

Herpes zoster as a rare complication of liposuction

Liposuction typically has a low incidence of complications and is associated with significant cosmetic benefit. In this case, the patient developed a dermatomal rash with vesicles on an erythematous base consistent with herpes zoster 8 days after liposuction to the back and flanks. To the authors' knowledge, herpes zoster has not been previously reported as a complication of liposuction. Although the precise relationship of herpes zoster infection to the liposuction procedure is difficult to determine, mechanical irritation most likely reactivated the varicella zoster virus in the involved dermatomal distribution. The patient was treated with antiviral and analgesic medications and healed without any further complications.     

Twenty Years of Medically-Attended Pediatric Varicella and Herpes Zoster in Ontario,Canada: A Population-Based Study

ObjectiveTo determine if reductions in medically-attended pediatric varicella and herpes zoster occurred in Ontario, Canada, after publicly-funded varicella immunization was implemented in 2004.MethodsFor fiscal years (FY) 1992-2011, we examined data on varicella and herpes zoster physician office visits, emergency department (ED) visits, hospitalizations (including for varicella-associated skin and soft tissue infections [SSTI]), and intensive care unit (ICU) admissions, among those aged <18 years. The pre-vaccine, privately-available, and vaccine program eras were FY1992-1998, FY1999-2003, and FY2004-2011, respectively. We used Poisson regressionand Kruskal-Wallis tests (all at the p<0.05 level of significance), and compared rates using incidence rate ratios (IRRs) and 95% confidence intervals (CIs).ResultsIncidence of varicella office visits declined over the study period from a high of 25.1/1,000 in FY1994 to a low of 3.2/1,000 in FY2011. ED visits and hospitalizations followed similar patterns of decreasing rates later in the study period. IRRs comparing the vaccine program versus pre-vaccine eras were 0.29 (95%CI: 0.26-0.32) for office visits, 0.29 (95%CI: 0.21-0.40) for ED visits, and 0.41 (95%CI: 0.10-1.69) for hospitalizations. Annual declines in varicella office visits were 7.7%, 9.1%, 8.4%, and 8.4% per year among children aged <1 year, 1-4 years, 5-11 years, and ≥12 years, respectively (all p<0.001). Age-specific rates of varicella-associated SSTI declined significantly among children <12 years (p<0.001) and rates of ICU admissions decreased significantly for children <1 year (p = 0.02). (p<0.001) over the study period. For children aged 5-17 years, herpes zoster office visits decreased whereas ED visits increased (both p<0.001) and there was a small, non-significant (p = 0.07), decrease in hospitalizations.ConclusionMedically-attended varicella decreased during the study period, particularly since varicella vaccine was publicly-funded. Results suggest immunization program-related changes in varicella epidemiology, including herd effects, demonstrated by reductions in varicella in program-ineligible age groups. We did not observe a consistent impact on herpes zoster.