Abstract
The main objective of this systematic review was to evaluate the economic burden of Herpes Zoster (HZ) infection.
The review was conducted in accordance with the standards of the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” guidelines. The following databases were accessed: ISI/Web of Knowledge (WoS), MEDLINE/PubMed, Scopus, ProQuest, the Cochrane Library and EconLit. Specific literature on health economics was also manually inspected. Thirty-three studies were included.
The quality of the studies assessed in accordance with the Consolidated Health Economic Evaluation Reporting Standards checklist was good. All studies evaluated direct costs, apart from one which dealt only with indirect costs. Indirect costs were evaluated by 12 studies.
The economic burden of HZ has increased over time. HZ management and drug prescriptions generate the highest direct costs. While increasing age, co-morbidities and drug treatment were found to predict higher direct costs, being employed was correlated with higher indirect costs, and thus with the onset age of the disease.
Despite some differences among the selected studies, particularly with regard to indirect costs, all concur that HZ is a widespread disease which has a heavy social and economic burden.
Introduction
Herpes zoster (HZ) (also known as shingles or zona) is caused by the Varicella-Zoster Virus (VZV) [also termed Human Herpes Virus type 3 (HHV-3)], an exclusively human neurotropic etiologic agent belonging to the Herpesviridae family.Citation1,Citation2 VZV is a double-stranded DNA virus, whose primary infection results in the disease Varicella (VZ) or chickenpox, which mostly occurs in children and generally confers lifelong immunity to new VZ episodes.Citation3
An important characteristic of the virus is that it is not fully cleared by the host and remains latent in the neurons of dorsal root ganglia, cranial nerve ganglia and autonomic ganglia along the entire neuraxis.Citation4 VZV may be reactivated in approximately 10–30% of persons, causing HZ.Citation5 Upon virus reactivation, new virions are assembled and transported anterogradely to infect dermal cells. HZ is characterized by dermatomal distribution rash and pain.Citation6
Despite advances in research,Citation7 the mechanisms that lead from latency to reactivation are still unknown.Citation8,Citation9 What is known is that cellular-mediated immunity (CMI) contributes to maintaining VZV silent in human organism; a decline in VZV-specific CMI can result in reactivation of the virus.Citation10 In particular, immunosenescence leads to the decline of CMI and explains the increased frequency and severity of HZ with age.Citation11-Citation13 Furthermore, as age increases and CMI declines, the risk of complications increases.Citation4,Citation14 Post-herpetic neuralgia (PHN), a persistent painful condition that can become chronic, is one of the most common complications of HZ, while complications such as vasculopathies, meningoencephalitis, myelopathies and ocular diseases occur less frequently.Citation4 The risk of developing PHN is 5–30%.Citation15 When it becomes a chronic disorder, PHN is characterized by long-lasting pain that severely impairs the social life of patients, reducing their vitality and interfering with their normal activities.Citation16,Citation17
As VZV is a ubiquitous human pathogen with worldwide geographic distribution, HZ is a common disease which imposes a heavy clinical and social burden.Citation18-Citation20 The incidence of HZ ranges from 3.0/1000 to 5.0/1000 person-years worldwide,Citation15 while in Europe it varies from 2.0/1000 to 4.6/1000 person-years.Citation19 In Italy, HZ has a yearly incidence ranging from 1.59 to 4.31 cases/1000 persons.Citation21-Citation27
The main objectives of this study were to carry out a systematic review concerning the economic burden related to HZ infection and to provide researchers with data for use in planning future pharmaco-economic studies aimed at evaluating the benefit of HZ vaccination in the elderly or a combined varicella-HZ vaccination strategy.
Results
The initial search yielded 2,346 results: 380 articles from PubMed/MEDLINE, 592 from ISI/Web of Science (WoS), 838 from Scopus, 352 from ProQuest, 133 from EconLit and 51 from the Cochrane Library. Another two articles were found by manual inspection of the targeted journals and subsequently added to the initial list of manuscripts. After the removal of 462 duplicates, 1,886 articles were screened. We excluded 1,681 manuscripts because they were not of the research article type and/or did not cover the topic of the present review. A total of 205 full-text articles were deemed eligible for evaluation. Subsequently, 172 articles were excluded for the following reasons: 60 reported epidemiological aspects of HZ, 11 focused on clinical aspects of HZ, 14 focused on vaccination, 65 reported cost-effectiveness analyses and not original cost analysis evaluation, 20 concerned the treatment and pharmacological aspects of HZ, and 2 did not contain sufficient quantitative information of costs and relevant outcomes (e.g., details of cost sources, methods used), failing to meet the CHEERS criteria (). The present review therefore examined 33 studies.Citation22,Citation27-Citation58
Figure 1. Flowchart of the studies selected in accordance with the 2009 PRISMA guidelines.Citation67
The overall quality of these studies, as assessed in accordance with the CHEERS checklist, was good. Twelve studies were conducted in Europe, 15 in the USA and Canada, 5 in Asia and 1 in Oceania. Twenty-four were retrospective and 9 were prospective. Selected studies are reported in .
Table 1. Main characteristics of studies included in the current systematic review
All studies assessed direct costs (; A and B), apart from one study, which dealt exclusively with indirect costs. Indirect costs were evaluated by 12 studies (). Global annual costs of the disease were reported in 12 studies (). All the studies used full-rate values (no discount rate applied), apart from one study, which used a 6% discount rate.Citation42
Table 3. Indirect costs for HZ and PHN
Table 4. Global costs for HZ-related infection broken down by country
Direct costs
both A and B sections show the direct costs of HZ and PHN reported in selected studies.
Direct costs were medical costs: the cost of treatment (drugs such as antivirals, analgesics, anti-epileptics, antidepressants, topical agents, antibiotics, ophthalmological products, nerve blocks, laser, surgical therapy and other forms of therapeutic appliance), medical examinations (primary care visits, emergency visits, specialist consultations and other professional visits), hospitalization and hospital emergencies, diagnostic tests and procedures (chest and abdominal X-ray, ultrasound, blood and urine tests, electrocardiograms and molecular tests), and the use of other health-related resources (transcutaneous electrical nerve stimulator, etc).
Hospitalization costs
Over the years, the economic burden of HZ has increased, as has been confirmed by many studies worldwide. In America, for example, Patel et al. reported that the net hospitalization costs for complications of HZ increased from 2004 to 2008 for adults aged 60 y and older.Citation55 Lin et al. reported a 2.2-fold increase in the mean unadjusted costs per HZ hospitalization from 1986 ($7159) to 1995 ($15 583), despite a reduction in the mean length of hospital stay. In Asia, a similar trend was reported by Lin et al.,Citation40 who performed a retrospective, database-based study in Taiwan from 2000 to 2005 and found an increase in HZ hospitalization costs from 250 million New Taiwanese dollars (7.7 million US dollars) in 2000 to 319 million New Taiwanese dollars (9.8 million US dollars) in 2004. After adjusting for inflation, they calculated a 1.22-fold increase, which was particularly marked among the elderly. In Korea, Choi et al. found that HZ-related costs increased each year by 14–20%, with medical costs being the main component (51–54%) of the total costs.Citation34
Particularly high costs are incurred by HZ patients suffering from immuno-deficiencies, severe malignancies and co-morbidities.Citation35,Citation44,Citation47,Citation48,Citation52,Citation54,Citation58 Moreover, costs are correlated with the duration of hospitalization and the severity of the disease.Citation35 A Korean study conducted from 2007 to 2010 found that severely immuno-depressed patient absorbed up to $ 1312.7 (€ 981.38), while mildly immuno-depressed patient absorbed only $ 319.1 (€ 238.56).Citation35 Lin et al. also found that the mean unadjusted costs per HZ hospitalization were higher in co-morbid subjects ($16 587 vs. $11 115).Citation52 Palmer et al. found that HZ in transplant patients contributed to higher healthcare resource utilization.Citation54 Yawn et al. found that the cost for an immuno-competent patient was $1059 ± 67, but increased to $3633 ± 862 in immuno-compromised patients; the difference was more marked in immuno-compromised patients suffering from PHN, who absorbed up to $7569 ± 2103.Citation58
Patients with PHN tend to utilize more health resources than HZ patients without neurological involvement. This leads to higher costs and expenditures,Citation31,Citation47 which generally tend to increase with age, though some scholars have failed to confirm this finding.Citation32,Citation47Yawn et al. estimated that hospital care accounted for 13.5%, 39.4%, and 50.9% of the mean global cost per HZ case, PHN case and complicated non-PHN HZ case, respectively.Citation58
Some studies have found that hospitalized patient treatment, albeit costly, is not the main item of cost for an average HZ case, and that GP management and drug treatment generate higher costs.Citation31,Citation48 Insinga et al. found that hospital care accounted for 18% of total expenditure,Citation48 while Yawn et al. reported a value of 29.3%.Citation58 A similar percentage was found by Mick et al., who estimated that hospital care accounted for 18% of the global cost of shingles and 23% of the global cost of PHN from the third-party payer perspective.Citation31 By contrast, an Australian study found that hospital care absorbed about 60% of the total expenditure.Citation28 Moreover, a similarly high percentage was found in a study performed in Italy, which reported that 50.3% of the total cost was due to hospitalizations.Citation33
Treatment costs
Drug prescriptions account for the highest costs.Citation32 In particular, they are predictors of higher cost for the National Health System (NHS).Citation44 Gauthier et al. found that pharmaceutical costs accounted for 53.6% of total healthcare costs;Citation43 Di Legami et al. reported that drugs constituted 65.4% of the total expenditure,Citation22 and Mick et al. estimated that the cost of drug treatment was 49% of the global cost of shingles and 47% of the expenditure for PHN from the third-party payer perspective.Citation31 Insinga et al. estimated that drug treatment absorbed 32% of expenditure.Citation48 Similar results were obtained by Cebrian-Cuenca et al.,Citation36 who found a value of 33% from the third-party payer perspective and by Sicras-Mainar et al., who reported a percentage of 35.7%.Citation38 By contrast, Arpinelli et al. estimated that drug prescriptions constituted only 15.7% of total healthcare expenditure; however, this finding can be explained by the fact that the hospitalization rate in the sample examined was much higher than the rates usually reported in the literature.Citation33
Outpatient costs
HZ patients have at least one contact with the GP and/or specialists (such as dermatologists and neurologists),Citation22,Citation32 with PHN patients having more referrals and consultations.Citation32 Di Legami et al. reported a mean of 2.1 contacts per case,Citation22 a result similar to that observed by Yawn et al., who found 2.8 consultations per patient.Citation58 Gialloreti et al. obtained a value of 1.9.Citation27
Outpatient treatment is one of the chief costs.Citation48,Citation58 Insinga et al. found that outpatient costs accounted for 40% of total expenditure.Citation48 A similar percentage was found by Cebrian-Cuenca et al., who estimated that visits and consultations accounted for 47% of the total expenditure from the third-party payer perspective.Citation36 Gauthier et al. found that primary care management absorbed 74% and 86% of the entire cost of HZ and PHN cases, respectively, at 3 mo. Primary care and secondary care consultations absorbed 40.9% and 2.9% of HZ costs, respectively, and 63.5% of PHN costs at 1 mo was absorbed by management.Citation43 A similar value (75.2%) was obtained by Gialloreti et al.Citation27 By contrast, in the study performed by Mick et al., GP consultations and referrals were only responsible for 15–18% of expenditure for HZ and 22–23% of expenditure for PHN.Citation31
Indirect costs
shows the indirect costs reported in selected studies.
Indirect costs comprise loss of productivity and absence from work. These costs can be associated directly to the patients or to their careers.
Although the frequency of HZ and PHN cases is lower among young/middle-aged adults (20–50 y) than among individuals aged 50 y and older, societal costs are higher owing to the cost of sick-leave in young/middle-aged subjects.
From a telephone survey performed by Singhal et al, it emerged that each episode of HZ caused the loss of 116 working hours and that absenteeism correlated with age and the severity and duration of the episode.Citation56 In total, 51% of the subjects interviewed reported missing work days as a result of HZ, mainly because of pain and/or discomfort, medical recommendations or appointments, side-effects of HZ medications, fear of spreading HZ, lack of concentration and fatigue. 8.5% of interviewees reported missing full working days for the entire duration of the HZ episode. Among those who continued to work during the episode, productivity was, in any case, affected by the infection: 46% reported difficulties in performing work tasks and 51% reported scant or diminished productivity.Citation56
In Thailand, Aunhachoke et al. investigated a sample of 180 hospitalized subjects. The authors found that 9 of 77 working patients had taken 6.8 ± 6.9 d of sick leave, 9.0 ± 6.9 d of disability leave, and 11.3 ± 5.7 d off work.Citation41 Another 34 patients needed a hospital chaperone or a caregiver. Caregivers were more often needed by patients suffering from cancer. The cost of the caregiver or hospital chaperone ranged from 1500 to 80 520 Thai baht ($43.98–$2361.29).Citation41
Bilcke et al. performed a survey aimed at evaluating the economic burden of HZ in Belgium. They assessed the costs of working days missed by patients treated at a hospital and an outpatient facility. Among outpatients, they found that HZ caused between 1 and 39 missed working days, leading to a mean cost of €234; among hospitalized subjects, 14% of respondents reported missing work for 4–128 d, leading to a mean cost of €600.Citation29
Sicras-Mainar et al. computed a cost of €692.2 per PHN case and € 62.4 per HZ case due to loss of productivity.Citation38
On investigating a sample of 303 HZ patients aged 18–65 y, White et al. found that lost working hours were on average of 26.5 ± 7.2, while days of absence due to short-term disabilities averaged 2.9 ± 0.95 d. The duration of absence correlated with age.Citation57
Arpinelli et al found a mean absence from work of 9 d and an indirect cost of 590 000 lire in 1996/97, absorbing 27.6% of the entire cost.Citation33 Similar results emerged from other studies.Citation27,Citation31,Citation38 Gialloreti et al. computed the indirect costs as a third of the total expenditure.Citation27 Mick et al. found that loss of productivity accounted for 30% of the total cost of shingles and absorbed 10% of the entire expenditure for PHN.Citation31 Sicras-Mainar et al. calculated that indirect costs constituted 24.7% of the total costs.Citation38
Economic burden of HZ and PHN broken down by geographical area
The ranges of costs of HZ and PHN, broken down by geographical area, are reported in . In the computation of the range of costs, incremental costs have been not considered (in case of pre-existing underlying conditions) and all currencies are converted into Euro and adjusted for inflation to 1 January 2013.
Table 5. Range of costs of HZ and PHN broken down by geographical areas
In Europe, a hospitalized HZ case costs from €774.66 to €31 026.22, and in the USA from €9041.36 to €23 219.82. In Asia, costs range from €118.13 to €707.23 in the immunocompetent subjects and from €112.44 to €1945.34 in immunocompromised patients. In Europe, outpatient management costs range from €0 to €6133.48, while in Asia the mean cost per immunocompetent patient is €61.67. Drug costs range from €118.65 to €242.62 in Europe.
Regarding cases with PHN, in Europe a hospitalized case costs an average of €4026.05. In the USA the costs vary from €1538.17 to €3130.88. Outpatient management absorbs from €0.0 to €5,131.91 in Europe and from €2789.84 to €6043.64 in the USA. Drug treatment costs from €278.75 to €614.96 in Europe and from €2946.51 to €6628.79 in the USA.
Discussion
To the best of our knowledge, this is the first systematic review of studies addressing the economic assessment of HZ and its complications. Our review confirmed that HZ imposes a heavy burden worldwide in both social and economic terms.
As HZ and, in particular, its complications mainly affect the elderly, the economic burden is mostly due to high direct costs rather than to indirect costs. On analyzing all the studies included in the current systematic review, it can be seen that predictors of higher direct cost are: older age, co-morbidities and immuno-depression, duration of hospitalization, use of medications (antivirals in particular), and the severity of symptoms. For example, Gauthier et al. reported that symptom severity drives up HZ and PHN costs by more than 3–4 times.Citation43 Despite the fact that HZ and PHN affect more females than males,Citation15 gender does not seem to be a predictor of higher health expenditure.
Regarding indirect costs, being employed predicts higher societal costs.Citation44 The indirect costs of HZ are therefore associated with the onset age of the disease, in that most indirect costs involve cases of HZ in subjects of working age. Thus, given that HZ mostly affects older subjects, who are likely to have retired, indirect costs can be fairly low. Analysis of all the studies dealing with indirect costs reveals some differences in evaluations. Such differences mainly concern the method of assessing and computing costs for sick–leave due to HZ and the different kinds of healthcare and insurance systems involved.Citation32
Generally, there is a dearth of data concerning the costs of complications other than PHN. Indeed, few studies have assessed these, and only Yawn et al. have systematically addressed this issue, and have also economically assessed neurological (such as encephalitis), ocular (such as iritis, uveitis, conjunctivitis, keratitis, or loss of vision), skin and other complications (such as disseminated HZ) and have demonstrated that complicated non-PHN HZ cases can cost more than PHN cases.Citation58 The authors reported mean total health care costs of $2810, $4928, $3850, and $6423 (evaluation 90 d after the initial diagnosis) for a case with ocular complications, a case with neurologic complications, a case with skin complications and other complications, respectively.Citation58
While the epidemiology of HZ does not differ greatly among the various geographical areas of the world, its economic and social impact does, in that this latter aspect is influenced by several factors, such as the level of socioeconomic development of the country or region and the type of healthcare available. Indeed, the mean cost of hospitalization of an HZ patient is higher in the USA (insurance-based health service) than in Europe, and this difference is even more marked if we consider the values reported by the studies conducted in Asia. Moreover, the values reported in reveal that, even within the same geographic area, there are evident differences. For example, in the USA different results are obtained according to whether a Medicare or a Medicaid sample of insured patients is assessed. Asia includes areas with different degrees of development, such as Taiwan or Thailand. Similarly, Europe groups together intrinsically different health-care programs, based on the Beveridge or Bismarck social insurance systems. Our systematic review reveals that, although the disease is present worldwide and imposes a heavy social and healthcare burden, no studies have yet been conducted in some geographic areas. Thus, no data are available for the African continent. Moreover, many PHN-related data are lacking, above all in Asia and Oceania.
Besides socio-economic, geographical and political variables, other aspects of a methodological nature can influence the findings of studies. Indeed, the differences found can be explained by various factors, such as the lack of a universally accepted definition of HZ and PHN (which may be evaluated at 1, 2, 3, or 6 mo). For example, few studies have assessed PHN at different time-points.Citation36,Citation58 Other factors are the study design (prospective vs. retrospective, population- vs. cohort- or database-based), the epidemiological, and the demographic and clinical features of the subjects included.Citation28 Furthermore, the uncertainty in the evaluation of HZ-related mean cost is also due to the fact that HZ is not a notifiable disease by law in many countries, in that only hospitalization costs are known with certainty, while the costs related to ambulatory management and treatment can be approximately estimated by means of surveys conducted in small cohorts, not always necessarily representative and generalizable.Citation22 Then, some inconsistencies may be due to inaccuracies related to data-gathering and database miscoding.Citation28,Citation32,Citation38
In conclusion, we think that the results of our systematic review could be helpful to future pharmaco-economic studies aimed at assessing the benefit of HZ vaccination in the elderly or of a combined varicella-HZ vaccination strategy.
Vaccination is an important means of reducing the epidemiological and economic burden of HZ.Citation31 The currently available vaccine is a live-attenuated vaccine (Zostavax®), which has proved to be safe and effective.Citation59-Citation61 It is highly recommended for the immunization of immuno-competent individuals over age 60 y with no history of recent HZ.Citation62-Citation64
Given the current severity and high costs of HZ disease and the uncertainty of the epidemiological and economic impact of widespread childhood varicella vaccination on the incidence of zoster, it is important to establish surveillance and to monitor the population-based impact of both vaccinations.Citation52 In the USA, Patel et al. have estimated that, while VZ vaccination has contributed to saving up to $100–150 million/year, this potential saving could be outweighed by an increase in HZ-related costs (up to $700 million/year).Citation55 For this reason, many researchers are in favour of combined vaccination strategies (varicella vaccine in childhood and HZ vaccine for the elderly). Pharmaco-economics studies have proved the cost-effectiveness of VZ and HZ vaccines examined separately,Citation65 but there is a lack of studies on the policy of combining both vaccines. Only one study has investigated the cost-effectiveness of a combined VZ and HZ vaccination program,Citation66 and has suggested that this policy can mitigate, in a cost-effective manner, the negative effects of VZ vaccination alone on HZ epidemiology. We therefore think that further pharmaco-economic studies should be conducted in various geographic areas in order to evaluate different strategies and to identify the strategy that can best reduce the number of cases, thereby saving economic resources.
Materials and Methods
Our systematic review was conducted in accordance with the standards of the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines.Citation67 The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 24-item checklist was used in order to assess the quality of the studies reviewed.Citation68
The following databases were accessed: ISI Web of Science (ISI/WoS), MEDLINE/PubMed, Scopus, ProQuest, the Cochrane Library and EconLit. Searches were performed by using complex strings with an appropriate combination of keywords and Boolean operators. Refinement and lemmatization procedures were also applied. The search strategy applied to each database is summarized in . No restrictions were placed on the date or language of publication. All the databases were searched up to 21st June 2014. Targeted journals concerning pharmaco-economics were manually inspected for the further inclusion of potentially eligible studies.
Table 6. Search strategies used in the current systematic review
Inclusion criteria were: all published peer-reviewed articles. Case reports, reviews, editorials, letters to editors and commentaries were excluded. Further, the manuscripts for which the full-text was not available were excluded too. Articles not meeting the quality standards of the CHEERS checklist were excluded.Citation68 For each article included, the list of references was consulted and all the pertinent quoted articles not present in our list were added. This operation was performed in a recursive, iterative manner until no new article was found, in order to obtain an exhaustive list of articles. If any articles contained doubtful, incomplete or discordant data, we contacted the authors in order to obtain further clarification and explanation.
For each study selected, cost-of-illness- (COI) related data were extracted and tabulated. Data extraction, collection and handling were managed by means of ReviewManager software, version 5.3 (RevMan, 2012).Citation69 Alongside the original data provided by the authors, all currencies were converted into Euro and adjusted for inflation to 1 January 2013, in order to compare the values reported in the various studies and to establish a range of the cost of HZ and its complications in each geographic area that could be used by researchers to plan pharmaco-economic studies of prevention strategies.
| Abbreviations: | ||
| AD | = | Administrative Database |
| ADL | = | Activities of Daily Living |
| AR-DRG | = | Australian Refined Diagnosis Related Group |
| CHEERS | = | Consolidated Health Economic Evaluation Reporting Standards |
| CIAP-2 | = | Clasificación Internacional de la Atención Primaria (International classification of primary care) |
| CMI | = | cell-mediated immunity |
| COI | = | Cost-Of-Illness |
| D | = | Direct |
| DRG | = | Diagnosis Related Group |
| ED | = | Emergency Department |
| EQ-5D | = | EuroQol Five-Dimension |
| GP | = | General Practitioner |
| HD | = | Hospital Database |
| HHV-3 | = | Human Herpes Virus type 3 |
| HZ | = | Herpes Zoster |
| I | = | Indirect |
| ICD-9-CM | = | International Classification of Diseases Version 9 Clinical Modification |
| ICD-10 | = | International Classification of Diseases Version 10 |
| ICD-10-AM | = | International Classification of Diseases Version 10 Australian Modification |
| ICPC-2 PLUS | = | International Classification of Primary Care Version 2 |
| ID | = | Insurance Database |
| IZIQ | = | Initial Zoster Impact Questionnaire |
| NHS | = | National Health System |
| P | = | Prospective study |
| PCD | = | Primary Care Database |
| PCR | = | Polymerase Chain Reaction |
| PHN | = | Post-Herpetic Neuralgia |
| PP | = | Pharmaceutical Prescriptions |
| PRISMA | = | Preferred Reporting Items for Systematic Reviews and Meta-Analyses |
| R | = | Retrospective study |
| SDO | = | Schede di Dismissione Ospedaliere (Hospital discharge form) |
| SNF | = | Skilled Nursing Facility |
| SOT | = | Solid Organ Transplant |
| TPP | = | Third-Party Payer |
| VAS | = | Visual Scale |
| VZ | = | Varicella Zoster |
| VZV | = | Varicella Zoster Virus |
| WoS | = | Web of Science |
| ZBPI | = | Zoster Brief Pain Inventory |
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgements
The study was financed by the Italian Ministry of University and Research (MIUR, project PRIN 2009; Grant number: 2009ZPM4X4). The authors thank Dr Bernard Patrick for revising the manuscript.
Related Research Data
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