Evaluation of the economic burden of Herpes Zoster (HZ) infection.

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Evaluation of the economic burden of Herpes Zoster (HZ) infection a

a

a

b

Donatella Panatto , Nicola Luigi Bragazzi , Emanuela Rizzitelli , Paolo Bonanni , Sara b

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Boccalini , Giancarlo Icardi , Roberto Gasparini & Daniela Amicizia a

Department of Health Sciences; University of Genoa; Genoa, Italy

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Department of Health Sciences; University of Florence; Italy Accepted author version posted online: 01 Nov 2014.Published online: 09 Feb 2015.

Click for updates To cite this article: Donatella Panatto, Nicola Luigi Bragazzi, Emanuela Rizzitelli, Paolo Bonanni, Sara Boccalini, Giancarlo Icardi, Roberto Gasparini & Daniela Amicizia (2015) Evaluation of the economic burden of Herpes Zoster (HZ) infection, Human Vaccines & Immunotherapeutics, 11:1, 245-262, DOI: 10.4161/hv.36160 To link to this article: http://dx.doi.org/10.4161/hv.36160

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Research Paper

Research Paper

Human Vaccines & Immunotherapeutics 11:1, 245–262; January 2015; © 2015 Landes Bioscience

Evaluation of the economic burden of Herpes Zoster (HZ) infection A systematic literature review

Donatella Panatto1,*, Nicola Luigi Bragazzi1, Emanuela Rizzitelli1, Paolo Bonanni2, Sara Boccalini2, Giancarlo Icardi1, Roberto Gasparini1, and Daniela Amicizia1 Department of Health Sciences; University of Genoa; Genoa, Italy; 2Department of Health Sciences; University of Florence; Italy

Downloaded by [UQ Library] at 05:05 12 July 2015

Keywords: Herpes zoster, Post-herpetic neuralgia, systematic review, economic burden, direct and indirect cost 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

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.1,2 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.3 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.4 VZV may be reactivated in approximately 10–30% of persons, causing HZ.5 Upon virus reactivation, new virions are assembled and transported anterogradely to infect

*Correspondence to: Donatella Panatto; Email: [email protected] Submitted: 07/22/2014; Accepted: 07/30/2014; Published Online: 08/27/2014 http://dx.doi.org/10.4161/hv.36160 www.landesbioscience.com Human Vaccines & Immunotherapeutics 245

©2015 Landes Bioscience. Do not distribute.

1

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 fulltext 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 (Fig. 1). The present review therefore examined 33 studies.22,27-58

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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. All studies assessed direct costs (Table 2; A and B), apart from one study, which dealt exclusively with indirect costs. Indirect costs were evaluated by 12 studies (Table 3). Global annual costs of the disease were reported in 12 studies (Table 4). All the studies used full-rate values (no discount rate applied), apart from one study, which used a 6% discount rate.42 Direct costs Table 2 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 healthrelated 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.55 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.,40 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.34 Particularly high costs are incurred by HZ patients suffering from immuno-deficiencies, severe malignancies and comorbidities.35,44,47,48,52,54,58 Moreover, costs are correlated with the duration of hospitalization and the severity of the disease.35 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).35 Lin et al. also found that the mean unadjusted costs per HZ hospitalization were higher in co-morbid subjects ($16 587 vs. $11 115).52 Palmer et al. found that HZ in transplant patients contributed to higher healthcare resource utilization.54 Yawn et al. found that the cost for an immunocompetent patient was $1059 ± 67, but increased to $3633 ± 862 in immuno-compromised patients; the difference was more

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dermal cells. HZ is characterized by dermatomal distribution rash and pain.6 Despite advances in research,7 the mechanisms that lead from latency to reactivation are still unknown.8,9 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.10 In particular, immunosenescence leads to the decline of CMI and explains the increased frequency and severity of HZ with age.1113 Furthermore, as age increases and CMI declines, the risk of complications increases.4,14 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.4 The risk of developing PHN is 5–30%.15 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.16,17 As VZV is a ubiquitous human pathogen with worldwide geographic distribution, HZ is a common disease which imposes a heavy clinical and social burden.18-20 The incidence of HZ ranges from 3.0/1000 to 5.0/1000 person-years worldwide,15 while in Europe it varies from 2.0/1000 to 4.6/1000 person-years.19 In Italy, HZ has a yearly incidence ranging from 1.59 to 4.31 cases/1000 persons.21-27 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.

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marked in immuno-compromised patients suffering from PHN, contrast, Arpinelli et al. estimated that drug prescriptions constituted only 15.7% of total healthcare expenditure; however, this who absorbed up to $7569 ± 2103.58 Patients with PHN tend to utilize more health resources than finding can be explained by the fact that the hospitalization rate HZ patients without neurological involvement. This leads to in the sample examined was much higher than the rates usually higher costs and expenditures,31,47 which generally tend to increase reported in the literature.33 with age, though some scholars have failed to confirm this findOutpatient costs ing.32,47 Yawn et al. estimated that hospital care accounted for HZ patients have at least one contact with the GP and/or spe13.5%, 39.4%, and 50.9% of the mean global cost per HZ case, cialists (such as dermatologists and neurologists),22,32 with PHN PHN case and complicated non-PHN HZ case, respectively.58 patients having more referrals and consultations.32 Di Legami et Some studies have found that hospitalized patient treatment, al. reported a mean of 2.1 contacts per case,22 a result similar to albeit costly, is not the main item of cost for an average HZ case, that observed by Yawn et al., who found 2.8 consultations per and that GP management and drug treatment generate higher patient.58 Gialloreti et al. obtained a value of 1.9.27 costs.31,48 Insinga et al. found that hospital care accounted for Outpatient treatment is one of the chief costs.48,58 Insinga et 48 18% of total expenditure, while Yawn et al. reported a value al. found that outpatient costs accounted for 40% of total expenof 29.3%.58 A similar percentage was found by Mick et al., who diture.48 A similar percentage was found by Cebrian-Cuenca et estimated that hospital care accounted for 18% of the global cost al., who estimated that visits and consultations accounted for of shingles and 23% of the global cost of PHN from the third- 47% of the total expenditure from the third-party payer perparty payer perspective.31 By contrast, an Australian study found spective.36 Gauthier et al. found that primary care management that hospital care absorbed about 60% of the total expenditure.28 absorbed 74% and 86% of the entire cost of HZ and PHN cases, 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.33 Treatment costs Drug prescriptions account for the highest costs.32 In particular, they are predictors of higher cost for the National Health System (NHS).44 Gauthier et al. found that pharmaceutical costs accounted for 53.6% of total healthcare costs; 43 Di Legami et al. reported that drugs constituted 65.4% of the total expenditure,22 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.31 Insinga et al. estimated that drug treatment absorbed 32% of expenditure.48 Similar results were obtained by Cebrian-Cuenca et al.,36 who found a value of 33% from the third-party payer perspective and by SicrasMainar et al., who reported Figure 1. Flowchart of the studies selected in accordance with the 2009 PRISMA guidelines.67 a percentage of 35.7%.38 By

Country


Australia

Ref.

Study years

Year evaluation costs

Study design

Concerned population/ Cohort

Age

Case definition

Type of costs

Cost sources

28

1998–2006 (1998–2005 for hospitalizations and ED admissions; 2000–2006 for medical consultations; 2002–2006 for pharmaceuticals)

2007 for medical consultations and pharmaceuticals; 2004–2005 for hospitalizations

R

Patients of about 1,000 GPs; hospitalized patients

≥ 50 y

GP’s clinical diagnosis, ICD-10-AM/ AR-DRG

D

AD, HD, ID, PCD, PP

Patients of 150 sentinel GPs (about 1.5% of the Belgian population); a sample of 900 hospitalized patients

All ages

GP’s clinical diagnosis and ICD-9-CM

D, I

AD, HD, ID, ad hoc questionnaires

Belgium

29

2000–2009

2010

R

Canada

30

1992–1996

1992–1996

R

British Columbia population

All ages

ICD-9

D

AD, HD

≥ 50 y

GP’s clinical diagnosis

D

HD, PCD, PP

France

31

2005

2006

R

Immunocompetent patients of 231 GPs, 41 dermatologists, 15 neurologists and 5 specialists in pain medicine out of an initial list of attendants of 567 GPs, 75 dermatologists and 30 neurologists

Germany

32

2004–2009

2010

R

A sample of the Hesse insured population (about 240,000 individuals)

All ages

ICD-10

D, I

AD, HD, ID, PCD, PP

1997

1996 for the GP management and specialist referrals and consultations, 1997 for the hospitalizations and the pharmaceutical

P

61 subjects out of an initial cohort of 396 patients

All ages

Specialist’s clinical diagnosis

D, I

AD, PCD

2004

2003 for the consultations, GP management and for the hospitalizations, 2004–2005 for the pharmaceutical

P

26,394 patients of 24 GPs

≥ 14 y

GP’s clinical diagnosis, ICD-9-CM

D

AD, HD, PCD, PP

ICD9-CM

D, I

AD, HD, PP, expert panel and focus group

33

Italy 22

27

2003–2005

2005

R

About 450,000 patients of 342 GPs

≥ 50 y for direct costs, 50–64 y for indirect costs

34

2003–2007

2006–2007 for the direct costs, 2006–2008 for the indirect costs

R

Korean insured population (about 48–49 million individuals)

All ages

ICD-10

D, I

AD, ID

P

582 subjects out of an initial cohort of 12,635 individuals hospitalized in Seoul and in Gyeonggi-do

All ages

Clinical diagnosis

D

HD

Korea 35

2007–2010

2010

Abbreviations: AD: Administrative Database, ADL: Activities of Daily Living, CIAP-2: Clasificación Internacional de la Atención Primaria second revision, D: Direct, ED: Emergency Department, EQ5D: EuroQol five-dimension questionnaire, GP: General Practitioner, HD: Hospital Database, HIV: Human Immunodeficiency Virus, HZ: Herpes Zoster, I: Indirect, ICD-9: International Classification of Diseases Ninth revision, ICD-9-CM: International Classification of Diseases Ninth revision Clinical Modification, ICD-10: International Classification of Diseases Tenth revision, ID: Insurance Database, IZIQ: Initial Zoster Impact Questionnaire, P: Prospective study, PCD: Primary Care Database, PCR: Polymerase Chain Reaction, PP: Pharmaceutical Prescriptions, R: Retrospective study, SNF: Skilled Nursing Facility, SOT: Solid Organ Transplant, VAS: Visual Analogue Scale, ZBPI: Zoster Brief Pain Inventory.

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Table 1. Main characteristics of studies included in the current systematic review (continued)

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.56 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.41 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).41 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 €600.29 Sicras-Mainar et al. computed a cost of €692.2 per PHN case and € 62.4 per HZ case due to loss of productivity.38

Table 1. Main characteristics of studies included in the current systematic review (continued) Country

Spain

Ref.

Study years


Study design


Age

Case definition

Type of costs

Cost sources

36

2006–2007

2007

P

118 subjects out of an initial cohort of 146 individuals attending 25 GPs in Valencia

> 14 y


D, I

AD, PCD, PP

37

1998–2004

2004

R

Hospitalized patients

≥ 30 y

ICD9-CM

D

AD, HD

P

1,506 patients attending 6 primary care centres and resident in Badalona

> 30 y

GP’s clinical diagnosis, CIAP-2

D, I

AD, HD, PCD, PP

All ages

ICD-9-CM

D

AD

38

2007–2010

39

2000–2006

Average exchange rate in the period 2000–2006

R

1,000,000 persons (about 5% of Taiwan’s population), a sample of the National Health Insurance database which comprises more than 21 million and half individuals

40

2000–2005

2000–2005

R

Insured population resident in Taiwan (approximately 22.9 million individuals)

All ages

ICD-9-CM

D

AD, ID

P

180 subjects (138 immunocompetent, 34 HIV positive, 7 suffering from cancer, 1 transplanted)

≥ 50 y and healthy, ≥ 20 y and immunedepressed


D, I

HD, PP, questionnaires (ZBPI, IZIQ, ADL and EQ-5D)

All ages


D, I

AD, HD, PCD, ad hoc questionnaires (such as VAS), literature review

Taiwan

Thailand

UK

2009

41

2007–2008

2008

42

1987–1991

1991–1992

P

168 attendants of a clinic for HZ-pain (Centre for Pain Relief, Walton Hospital, Liverpool)

43

2000–2006

2005–2006

R

Immunocompetent patients of 603 GPs, hospitalized patients

≥ 50 y

ICD-10

D

AD, HD, PCD, PP

44

2003

2003

P

158,716 patients of 18 GPs from an initial list of attendants of 45 GPs in Tower Hamlets and Hackney

All ages

GP’s clinical diagnosis, confirmed when necessary with PCR

D, I

AD, PCD, PP, estimations from EQ-5D and ad hoc surveys

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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.43 A similar value (75.2%) was obtained by Gialloreti et al.27 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.31 Indirect costs Table 4 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.56 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,


Country

Ref.

Study years


Study design


Age

Case definition

Type of costs

Cost sources

45

2001–2003

2004

R

Medicare and Medicaid insured population (approximately 28 million individuals)

All ages

ICD-10

D

ID

46

2001–2003

2004

R


All ages

ICD-10

D

ID

All ages

ICD-9

D

ID

47

2005–2006

2006

R


48

2000–2001

2005

R

American privately insured population (> 4 million individuals)

All ages

ICD-9

D

ID, PP, panel of experts and review of literature

R

A convenience sample of 2.3 million subjects generalizable to approximately 31% of the American insured Medicare population (about 15.3 million retirees)

≥ 65 y

ICD-9-CM

D

AD, HD, ID, PCD, PP

R

Medicaid insured population resident in Florida, Iowa, Missouri and New Jersey (approximately 10 million individuals)

All ages

ICD-9-CM

D

ID, PP

All ages

ICD-9-CM

D

ID, PP

49

50

2008–2009

1997–2007

2010

2007

51

1997–2007

2007

R

Medicaid insured population resident in Florida, Iowa, Missouri and New Jersey (approximately 10 million individuals)

52

1986–1995

1986–1995

R

Connecticut residents hospitalized in Connecticut, New York, Massachusetts and Rhode Island hospitals

All ages

ICD-9-CM

D

HD

53

2002–2007

2007

R

404 SNF residents from an initial list of 426 eligible patients

All ages

ICD-9

D

AD

54

1999–2007 (1999–2006 for Medicaid patients, 1999–2007 for commercially insured and Medicare patients)

2007

R

Commercially insured, Medicare and Medicaid SOT recipients

All ages

ICD-9-CM

D

AD, ID

55

1993–2004

2007

R

American hospitalized patients from 17 states in 1993 and from 37 states in 2004

All ages

ICD-9-CM

D

AD, HD, ID

50–64 y

ICD-9-CM

I

AD, ID, telephone survey (ad hoc ADL and clinical questionnaires)

USA

56

2005

2010

P

A sample target of 150 American insured population from an initial list of 3,859 eligible subjects

57

1998–2003

2008

R

American insured subjects (approximately 14 million individuals)

All ages

ICD-9

D, I

ID

58

1996–2001

2006

R

Olmsted county insured population

≥ 22 y

ICD-9-CM

D

ID


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Table 1. Main characteristics of studies included in the current systematic review (continued)

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.43 Despite the fact that HZ and PHN affect more females than males,15 gender does not seem to be a predictor of higher health expenditure. Regarding indirect costs, being employed predicts higher societal costs.44 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.32 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 nonPHN HZ cases can cost more than PHN cases.58 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.58 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 Table 5 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.36,58 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.28 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




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.57 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.33 Similar results emerged from other studies.27,31,38 Gialloreti et al. computed the indirect costs as a third of the total expenditure.27 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.31 Sicras-Mainar et al. calculated that indirect costs constituted 24.7% of the total costs.38 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 Table 5. 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. 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.

252


Volume 11 Issue 1

No data

No data

22

45

46

No data

€4,725.72a (average hospital admission), €3,550.88a (day-hospital), €5,001.17a (ordinary admission), €3,062.10 with HZ as the principal diagnosis, €2,803.40a without complications, €3,289.06a with complications

€3,857.73a (average hospital admission), €2,898.68a (dayhospital), €4,082.59a (ordinary admission), €2,499.67a with HZ as the principal diagnosis (€2,288.49a without complications, €2,684.95a with complications)

35

47

€981.38a (range €247.39– 1,945.34) ^, €237.28a (range €112.44–871.41) ^, €238.56a (range €118.13– 707.23) *

$1,312.7a (range $330.9– 2,602.1) ^, $317.4a (range $150.4–1,165.6) ^, $319.1a (range $158.0–946.0) *

No data

No data

No data

€136.06 -360.69 a

No data

No data

No data

€136.13 -441.85 a

No data

a

No data

No data

No data

€102.76 -214.39 a

No data

€71.48a ± 56.44c at 1 mo €81.61a ± 59.38c at 3 mo

No data

a

No data

No data

No data

€121.46 -253.41 a

No data

€81.49 a ± 64.34 c at 1 mo €93.04 a ± 67.69 c at 3 mo

No data

No data

€241.97a-242.62a

L. 336,100a-337,000a No data

Values 2013

Values

€6,100.32 a -11,829.90 a §§, €5,982.94 a -11,602.27

$6,220a -12,062a §§, $6,100.32a -11,829.90a §§

a

€4,118.40 a -6,874.13 a

€719.84 a-1,248.55 a (excess cost)

$757a-1,313a (excess cost) $4,331a -7,229a

€4,291.52a as computed from the study sample, €505.16a estimated

No data

€221.66 a ± 102.78 c at 1 mo €265.59 a ± 136.13 c at 3 mo

No data

No data

€1,036.07a

Values 2013

€3,503.28a as computed from the study sample, €412.37a estimated

No data

€194.44a ± 90.16c at 1 mo €232.97a ± 119.41c at 3 mo

No data

No data

L. 1,439,100a

Values

Mean inpatient/outpatient cost


No data

No data

No data

No data

No data

36

No data

a

€122.96a ± 70.31c at 1 mo €151.36a ± 103.60 c at 3 mo

a

€140.17 a ± 80.15 c at mo €172.55 a ± 118.10 c at 3 mo

€247a (range €0–2,148)

€5,856.73a (range €780.83–31,026.22)

€5,438a (range €725–28,808)

29

No data

€266.02a (range €0–2,313.40)

No data

€68.05 a ± 111.40 c

$90.41a ± 148.00c

€19.95a-20.10a

41

L. 27,000a-27,200a

€774.66a

L.1,076,000a

Values 2013

33

Values

Values 2013

Treatment cost and diagnostic procedures

A. Direct costs of a HZ case

Outpatient and consultations cost

Values

Inpatient cost

Ref.

Table 2.


www.landesbioscience.com Human Vaccines & Immunotherapeutics 253 €68.56 a ± 10.67 b (incremental cost)

€3,200a-3,719.53a

$79 a ± 12.3b (incremental cost)

27

37

48

$12,834a (range $7,15915,583), $16,587a in patients with comorbidities, $11,115a in patients without comorbidities

No data

52

40

€1,224.70a

€3,843.20a -4,467.16a

€2,592a ± 1,313c *

43

39

€45.59a (additional cost)

£27a (additional cost)

No data

No data

€53.30a

No data

No data

€61.67a

€147.53 a ± 9.81 b (incremental cost)

$170 ± 8.3 (incremental cost) a

No data

No data

b

€145.01 a ± 115.26 c*

€122.68a ± 97.51c *

Values 2013

€127.69a for the management (range 101.55–210.85 according to pain severity), €59.27 a ± 76.37c for consultations (range €38.85–120.70 according to pain severity)

a

£75.63 for the management (range 60.15–124.89 according to pain severity) £35.11a ± 45.24 c for consultations (range £23.01–71.49 according to pain severity)

Values


No data

No data

No data

$137 a ± 3.3 b (incremental cost)

No data

No data

£40.52 a (range £37.14–53.40 according to pain severity)

Values

No data

No data

No data

€118.89a ± 2.86 b

No data

No data

€68.38a (range €62.71–90.15

Values 2013


Up to $204

No data

Up to €177.03

No data

No data

€374.01 ± 15.27 (incremental cost) €323.68 ± 13.19 (incremental cost *), €584.88 ± 59.96 (incremental cost ^)

$431 ± 17.6 (incremental cost), $373 ± 15.2 (incremental cost *), $674 ± 69.1 (incremental cost ^ No data

No data

€196.21a

€173.90

Values 2013

No data

€166a

£103a

Values



No data

€16,208.52a (range €9,041.36–19,680.32), $20,948.31a in patients with comorbidities, $14,037.52a in patients without comorbidities

€1,416.98a

€3,063.74 a ± 1,551.97 c *

Values 2013

Values

Inpatient cost

Ref.

Table 2.



Volume 11 Issue 1

€16,284.60 for the stay in the SNF, incremental cost of €933.99-€1,448.15 (incremental cost of €403.37a for the stay on the SNF, incremental cost of €530.61–1,044.79 for the hospitalization) No data

€5,647.20a ± 30,109.16c in the commercially insured and Medicare SOT patients, €6,428.84a ± 21,329.34c in the Medicaid patients

€19,727.11a in 1993, €23,219.82a in 2004

$18,813 for the stay in the SNF, incremental cost of $1,079–1,673 (incremental cost of $466a for the stay on the SNF, incremental cost of $613–1,207 for the hospitalization)

No data

$6,524a ± 34,784c in the commercially insured and Medicare SOT patients, $7,427a ± 24,641c in the Medicaid patients

$22,790a in 1993, $26,825a in 2004

No data

No data

$4,527a-4,764a

53

31

54

55

44

38

28

No data

€203.67a for non-ED a dmitted case, €24.68a-31.51a per GP consultation, €51.63a for specialists consultations and referrals

$298.2a for non-ED admitted case, $36.13a-46.14a per GP consultation, $75.60a for specialists consultations and referrals

€373.25a (€37.67–6,133.48)

£198.2a (range £20–3,257)

No data

No data

No data

$175a

No data

£70a

No data

$523a ± 488c in the commercially insured and Medicare SOT patients, $537a ± 810c in the Medicaid patients

€621.51 ± 2,654.81c in the commercially insured and Medicare SOT patients, 899.36a ± 1,566.75c in the Medicaid patients

$957a ± 3,067c in the commercially insured and Medicare SOT patients, $647a ± 1,810c in the Medicaid patients

a

No data

No data

Values

€211.64

No data

Values 2013

€119.53a

No data

€131.82a

No data

€452.71 ± 422.42c in the commercially insured and Medicare SOT patients, €464.82a ± 701.13c in the Medicaid patients a

No data

No data

Values 2013


€182.92a

No data

Values


€366.77a-383.17a

€431.45a (€369.75a for the GP management, €61.70a for the specialist referrals and consultation, including also drug costs)

€395.1a (€338.6a for the GP management, €56.5a for the specialist referrals and consultation, including also drug costs)

$537a-561a

No data

No data

€6,999.27a ± 30,425.97c 150c in the commercially insured and Medicare SOT patients, €7,515.18a ± 18,750.19c 694c in the Medicaid patients

No data

No data

Values 2013

No data

No data

$8,086a ± 35,150c in the commercially insured and Medicare SOT patients, $8,682a ± 24,694c in the Medicaid patients

No data

No data

Values



€3,064.84a-3,225.30a

No data

No data

a

Values 2013

a

Values

Inpatient cost

Ref.

Table 2.


www.landesbioscience.com Human Vaccines & Immunotherapeutics 255

No data

€236.78a-299.5a (incremental cost)

No data

No data

No data

$249a-315a (incremental cost)

36

42

45

46

a

a

1 mo, €151.08a ± 178.68c; 3 mo, €273.82a ± 283.54c

£325

a

€491.11 (range €0–5,131.91) 1 mo, €282.20a ± 198.63c; 3 mo, €412.05a ± 253.75c €516.22a (€185.31 for the GP management, €330.91 for specialist consultations)

€456 (range €0–4,765) 1 mo, €247.54a ± 174.24c; 3 mo, €361.45a ± 222.59c £273a (£98 for the GP management, £175 for specialist consultations)


No data


No data

No data

€41.04a

L. 57,000a


No data

a

No data

Values

a

b

€382.49 ± 11.77 * €395.24a ± 27.46b^ a


No data

€614.96

a

1 mo, €172.23a ± 203.70; 3 mo, €312.15a ± 323.24c

No data

No data

Values 2013


B. direct costs of a PHN case

b

$390 ± 12 *, $403 ± 28b ^ a

No data

€701.25a ± 34.33b §, €706.14a ± 34.33b §§, €1,038.63a ± 65.71b* €1,111.19 ± 174.58b^

€8,544.89a-9,560.45a

€2,053.01a -5122.55a for confirmed PHN; €2,179.49a -5,460.13a for possible PH (excess cost)

$2,159a-5,387a for confirmed PHN;$2,292a5,742a for possible PHN (excess cost) $8,986a-10,054a

€1,456.01a (€56.7222,691.10), adjusted €1,134.55–1,872.02

1 mo, €454.43a ± 284.51c; 3 mo, €724.21a ± 410.95c

No data

No data

Values 2013

£770a (£30–12,000), adjusted £600–990

1 mo, €398.62a ± 249.57c; 3 mo, €635.27a ± 360.48c

No data

No data

Values

Mean inpatient/outpatient Cost

$715a ± 35b §, $720a ± 35b §§, $1,059a ± 67b *, $1,133a ± 178b ^

€438.80a ± 20.32b at 3 mo, €742.13a ± 43.66b at 1 y (€1,313.40a ± 353.75b ^, 739.87a ± 42.90b*) (incremental costs)

$583a ± 27b at 3 mo, $986a ± 58b at 1 y ($1,745a ± 470b ^, $983a ± 57b*) (incremental costs)

No data

€226,17a (range €204.63a-247.71a)

€210a (range €190a-230a)

€118,65a (€55.81a for drug prescription, €62.84a for procedures)

€110.17a (51.82a for drug prescription, 58.35a for procedures)

Values 2013

Values

Values 2013

Mean inpatient/outpatient Cost

Values

Values 2013

Values

b

€318.74 ± 8.83 * €356.02a ± 37.27b^ a

Outpatient and Consultations cost

b

No data

€88.45a

Values 2013



No data

No data

No data

No data

29

No data

Values 2013

No data

Values

Inpatient cost

33

Ref.

a

$325 ± 9 *, $363 ± 38b ^

a

$240 ± 52 *, $253 ± 153b ^

58

b

€230.86a ± 51.00b*,, €248.13a ± 150.05b ^

a

No data

No data

No data

57

€82.13a

€3,214.00a

€2,984.22a §

32

Values

Values 2013

Outpatient and Consultations cost

Values

Inpatient cost

Ref

Table 2.


2 Human Vaccines & Immunotherapeutics

Volume 11 Issue 1

€4,026.05 (annualized)

$2,995a-3,617a

$1,777a-2,076a

No data

No data

€3,738.21 (annualized)

No data

50

51

31

38

32

57

$4,345a ± $1,891b^

a

b

^

€4,261.39 ± €1,854.61

No data

a

No data

€1,538.17a -1,796.99c

€2,592.49a -3,130.88c

€3,504.03a ± 11,173.70c

1 mo: €527.29a ± 523.59c 3 mo: €492.48a ± 618.88c

1 mo: €446.10a ± 442.97c 3 mo: €416.65a ± 406.30c

$910a ± 84b ^

No data

€185.79 a

No data

€339.84a

$3,223a-3,249a

$6,418a-6,982a

892.49a ± 82.38b ^

No data

€200.10 a

No data

€393.19a

€2,789.84a -2,812.35a

€5,555.45a -6,043.64a

€1,048.89a ± 2,037.22c

1 mo: €480.12a (€281.30-€758.24 according to the pain severity) 3 mo: €574.09a (€336.77– 1,039.24 according to the pain severity)

1 mo: £284.38a (range £166.62-£519.62, according to the pain severity) 3 mo: £340.04a (range £199.47–615.55, according to the pain severity)

$1,403a ± 2,725c

No data

Value 2013

No data

Value


No data

1,767.32a ± 177.52b for drug prescriptions, 263.82a ± 30.40b ^

$1,802a ± 181b for drug prescriptions, $269a ± 31b ^

€278.75a (€226.67 for drug prescription, €52.08 for procedures)

€258.82a (€210.46 for drug prescription, €48.36 for procedures)

No data

No data

No data

€2,946.51a -3,255.53a

€5,365.01a -6,628.79a

€593.60a ± 1,178.97c

No data

No data

$3,404a-3,761a

$6,198a-7,658a

$794a ± 1,577c

No data

1 mo: €22.94 (range €16.91–38.93 according to pain severity) (mean additional cost) 3 mo: €24.77 (range €18.52–41.67) (mean additional cost)

1 mo: £13.59 (range £10.02–23.06 according to pain severity) (mean additional cost) 3 mo: £14.67 (range £10.97–24.68) (mean additional cost)

No data

No data

Value2013

No data

Value


3 mo: €2,838.32a ± 310.90b, 1 y: €4,303.57a ± 730.67b, 7,423.35a ± 2,062.53b ^

PHN: 3 mo: €1,083.83a ± 158.06b, 1 y: €2,871.43a ± 349.24b (incremental costs) PHN: 3 mo: $1,440a ± 210b, 1 y: $3,815a ± 464b (incremental costs)

3 mo: $2,894a ± 317b, 1y: $4,388a ± 745b, $7,569a ± 2,103b ^

€1.209.47a (range €894.99–1,642.43)

€1,135a (€884.1a for the GP management, €250.8a for the specialist referrals and consultation, including also drug costs)

€1,123a (range €831–1,525)

No data €1,239.42a (€965.44a for the GP management, €273.87a for the specialist referrals and consultation, including also drug costs)

€8,176.49a -8,178.22a

€16,553.80a -17,463.56a

€12,394.55a ± 18,254.28a

€661.92a

No data

$9,446a-9,448a

$19,124a-20,175a

$16,579a ± $24,417c

€560a

1 mo: £341a 3 mo: £397a

1 mo: €575.7 a 3 mo: €670.26a

€10,009.61a -14,255.32a

$10,206 -14,535 a

Value 2013

a

Value



(A) a = mean cost, b = standard error, c = standard deviation, * = for an immuncompetent subject, ^ = for an immunocompromised subject. § = up to 90 d from the diagnosis, §§ = up to 1 y from the diagnosis, SNF = Skilled Nursing Facility, SOT = solid organ transplant. (B) a = mean cost, b = standard error, c = standard deviation, ^ = for an immunocompromised subject

58

No data

$4,687a ± 14,946c

49

a

€3,316.69 ± 3,121.66 c

€2,806 ± 2,641 a

27

c

€96.24 (mean additional cost)

£57 (mean additional cost)

43

a

No data

No data

47

Value 2013

Value

Inpatient cost

Ref

Table 2.


Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 24-item checklist was used in order to assess the quality of the studies reviewed.68 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 Table 6. 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. 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 fulltext was not available were excluded too. Articles not meeting the quality standards of the CHEERS checklist were excluded.68 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).69 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. Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Materials and Methods

Acknowledgements

Our systematic review was conducted in accordance with the standards of the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines.67 The

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.

References 1. Johnson RW. Herpes zoster and postherpetic neuralgia. Expert Rev Vaccines 2010; 9(Suppl):216; PMID:20192714; http://dx.doi.org/10.1586/ erv.10.30 2. Steiner I. Herpes virus infection of the peripheral nervous system. Handb Clin Neurol 2013; 115:54358; PMID:23931801; http://dx.doi.org/10.1016/ B978-0-444-52902-2.00031-X 3. Weinberg A, Levin MJ. VZV T cell-mediated immunity. Curr Top Microbiol Immunol 2010; 342:341-57; PMID:20473790; http://dx.doi. org/10.1007/82_2010_31

4. Gilden D, Nagel MA, Cohrs RJ, Mahalingam R. The variegate neurological manifestations of varicella zoster virus infection. Curr Neurol Neurosci Rep 2013; 13:374; PMID:23884722; http://dx.doi. org/10.1007/s11910-013-0374-z 5. Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 2004; 4:26-33; PMID:14720565; http://dx.doi. org/10.1016/S1473-3099(03)00857-0 6. Baird NL, Yu X, Cohrs RJ, Gilden D. Varicella zoster virus (VZV)-human neuron interaction. Viruses 2013; 5:2106-15; PMID:24008377; http://dx.doi. org/10.3390/v5092106

7.

Zerboni L, Sen N, Oliver SL, Arvin AM. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol 2014; 12:197-210; PMID:24509782; http://dx.doi.org/10.1038/nrmicro3215 8. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin Microbiol Rev 2013; 26:728-43; PMID:24092852; http://dx.doi.org/10.1128/ CMR.00052-13 9. Grinde B. Herpesviruses: latency and reactivation viral strategies and host response. J Oral Microbiol 2013;5.




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.22 Then, some inconsistencies may be due to inaccuracies related to data-gathering and database miscoding.28,32,38 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.31 The currently available vaccine is a live-attenuated vaccine (Zostavax®), which has proved to be safe and effective.59-61 It is highly recommended for the immunization of immuno-competent individuals over age 60 y with no history of recent HZ.62-64 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.52 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).55 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,65 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,66 and has suggested that this policy can mitigate, in a costeffective manner, the negative effects of VZ vaccination alone on HZ epidemiology. We therefore think that further pharmacoeconomic 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.

a

Ref

Economic values

Economic values (2013)

33

HZ: 590,000 Lire (global indirect cost)

HZ: €424.77 (global indirect cost)

41

$43.98–2,361.29 (use of hospital chaperone or caregiver)

€ 33.11–1,777.27 (use of hospital chaperone or caregiver)

29

Ambulatory-treated HZ: €234a for absence from work) (range €0- 4,452), €81a for hire of caregivers (€14°, maximum €415). Hospitalized HZ: €231° for hire of caregivers (range €1-€2,576); €47a for lost work of caregivers, (maximum €1,781), €600a for lost work of HZ patient (maximum €22,790)

Ambulatory-treated HZ: €252.02 for absence from work (range €0–4,794.80), €87.24a for hire of caregivers (€15.08°, maximum €446.96). Hospitalized HZ: €248.79° for hire of caregivers (range €1.08-€2,774.35); €50.62a for lost work of caregivers (maximum €1,918.14), €646.20a for lost work of HZ patient (maximum €24,544.83)

36

HZ: €2.87 ± 9.94 at 1 mo (for absence from work), 41.25 ± 273.64 at 3 mo (€40.60 ± 273.55 for absence from work, €0.65 ± 6.91 for hire of caregiver) PHN1: €112.66 ± 461.56 (€111.44 ± 461.46 for absence from work, €1.22 ± 9.44 for hire of caregivers) PHN3: 130.03 ± 515.71 (for absence from work) **

HZ: €3.27 ± 11.33 at 1 mo (for absence from work), 47.03 ± 311.95 at 3 mo (€46.28 ± 311.85 for absence from work, €0.74 ± 7.88 for hire of caregiver) PHN1: €128.43 ± 526.18 (€127.04 ± 526.06 for absence from work, €1.39 ± 10.76 for hire of caregivers) PHN3: 148.23 ± 587.91(for absence from work) **

42

PHN: £80a for home help service

PHN: €151.27 a for home help service

27

HZ: €556a (global indirect cost) PHN: €795a (global indirect cost)

HZ: €657.19a (global indirect cost) PHN: €939.69a (global indirect cost)

31

HZ: €163.86a for absence from work PHN: €215.72a for absence from work

HZ: €189.59a for absence from work PHN: €249.59a for absence from work

44

HZ: £325.9a for absence from work

HZ: €613.73a for absence from work

38

HZ: €62.4 for loss of productivity PHN: €692.2a for loss of productivity

HZ: €68.14a for loss of productivity PHN: €755.88a for loss of productivity

56

HZ: $2,350a for work loss (absenteeism, presenteeism)

HZ: €1,756.87a for work loss (absenteeism, presenteeism)

32

HZ: €1,759.71 (€380.48 sick-pay, €1,367.11 sick-leave, €12.12 co-payment) annualized cost PHN: 12,020.08 (€5,453.67 sick-pay, €6,529.99 sick-leave, €36.42 co-payment) annualized cost

HZ: €1,895,21 (€409.78 sick-pay, €1,472.38 sick-leave, €13.05 co-payment) annualized cost PHN: €12,945.63 (€5,873.60 sick-pay, €7,032.80 sick-leave, €39.22 co-payment) annualized cost

57

HZ: $471a for short-term disability, $538a for absence from work

€354.50 for short-term disability, €404.93 for absence from work

a

= mean cost, ° = median cost; **the values are referred to base-case on a convenience sample including working and not working subjects.

10. Johnson RW, Wasner G, Saddier P, Baron R. Herpes zoster and postherpetic neuralgia: optimizing management in the elderly patient. Drugs Aging 2008; 25:991-1006; PMID:19021299; http://dx.doi. org/10.2165/0002512-200825120-00002 11. Guzzetta G, Poletti P, Del Fava E, Ajelli M, Scalia Tomba GP, Merler S, Manfredi P. Hope-Simpson’s progressive immunity hypothesis as a possible explanation for herpes zoster incidence data. Am J Epidemiol 2013; 177:1134-42; PMID:23548754; http://dx.doi.org/10.1093/aje/kws370 12. Hope-Simpson RE. The nature of Herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 1965; 58:9-20; PMID:14267505 13. Hope-Simpson RE. Epidemiology of shingles. J R Soc Med 1991; 84:184; PMID:20894801 14. Oxman MN. Herpes zoster pathogenesis and cellmediated immunity and immunosenescence. J Am Osteopath Assoc 2009; 109(Suppl 2):S13-7; PMID:19553630 15. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open 2014; 4:e004833; PMID:24916088; http://dx.doi. org/10.1136/bmjopen-2014-004833 16. McElhaney JE. Herpes zoster: a common disease that can have a devastating impact on patients’ quality of life. Expert Rev Vaccines 2010; 9(Suppl):2730; PMID:20192715; http://dx.doi.org/10.1586/ erv.10.31

17. Opstelten W, McElhaney J, Weinberger B, Oaklander AL, Johnson RW. The impact of varicella zoster virus: chronic pain. J Clin Virol 2010; 48(Suppl 1):S813; PMID:20510265; http://dx.doi.org/10.1016/ S1386-6532(10)70003-2 18. Bardach A, Cafferata ML, Klein K, Cormick G, Gibbons L, Ruvinsky S. Incidence and use of resources for chickenpox and herpes zoster in Latin America and the Caribbean--a systematic review and meta-analysis. Pediatr Infect Dis J 2012; 31:12638; PMID:23188098; http://dx.doi.org/10.1097/ INF.0b013e31826ff3a5 19. Pinchinat S, Cebrián-Cuenca AM, Bricout H, Johnson RW. Similar herpes zoster incidence across Europe: results from a systematic literature review. BMC Infect Dis 2013; 13:170; PMID:23574765; http://dx.doi.org/10.1186/1471-2334-13-170 20. Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology 2013; 81:928-30; PMID:23999562; http://dx.doi.org/10.1212/ WNL.0b013e3182a3516e 21. Del Zotti F, Guglielmetti L, Conti M, Valentinotti R, Cazzadori A, Concia E. [Herpes zoster in general medicine: experience of the Italian group Netaudit]. Infez Med 2011; 19:106-12; PMID:21753250


22. Di Legami V, Gianino MM, Ciofi degli Atti M, Massari M, Migliardi A, Tomba GS, Zotti C; Zoster Study Group. Epidemiology and costs of herpes zoster: background data to estimate the impact of vaccination. Vaccine 2007; 25:7598-604; PMID:17889410; http://dx.doi.org/10.1016/j.vaccine.2007.07.049 23. di Luzio Paparatti U, Arpinelli F, Visonà G. Herpes zoster and its complications in Italy: an observational survey. J Infect 1999; 38:116-20; PMID:10342652; http://dx.doi.org/10.1016/S0163-4453(99)90079-8 24. Gabutti G, Serenelli C, Cavallaro A, Ragni P. Herpes zoster associated hospital admissions in Italy: review of the hospital discharge forms. Int J Environ Res Public Health 2009; 6:2344-53; PMID:19826547; http://dx.doi.org/10.3390/ijerph6092344 25. Gabutti G, Serenelli C, Sarno O, Marconi S, Corazza M, Virgili A. Epidemiologic features of patients affected by herpes zoster: database analysis of the Ferrara University Dermatology Unit, Italy. Med Mal Infect 2010; 40:268-72; PMID:19836913; http:// dx.doi.org/10.1016/j.medmal.2009.09.005 26. Gialloreti LE, Divizia M, Pica F, Volpi A. Analysis of the cost-effectiveness of varicella vaccine programmes based on an observational survey in the Latium region of Italy. Herpes 2005; 12:33-7; PMID:16209858

Volume 11 Issue 1



Table 3. Indirect costs for HZ and PHN

Ref

Country

Hz incidence

Hospitalization rate

Annual total cost

Adjusted figure in € (1st januari 2013)

36

Spain

4.1/1000 population per year

No data

€59.6 million

€67.94 million €57.13 million in 2003 (€49.3 Million for direct costs, €7.83 Million for indirect costs) – €108.23 million in 2007 (€93.18 Million for direct costs, €50.62 Million for indirect costs)

34

Korea

No data

0.22–0.32/1000 population per year

$75.9 million in 2003 ($65.5 million for direct costs, $10.4 million for indirect costs) $143.8 million in 2007 ($123.8 million for direct costs, $20.0 million for indirect costs)

42

Uk

4.0/1000 Population per year

No data

£4.8–17.9 million (total cost due to phn) £1.5–5.8 million (best scenario) £10–37.6 million (worst scenario)

€9.07–33.85 million (total cost due to phn) €2.8–11.0 million (best scenario) €18.9–71.1 million (worst scenario)

22

Italy

1.59/1,000 population per year


€2,427,209.82 (piedmont region)

€2,868,962.01 (piedmont region)

27

Italy



€41.2 million global cost (€28.2 million direct cost, €13 million indirect cost)

€48.7 million global cost (€33.3 million direct cost, €15.4 Million indirect cost)

37

Spain

No data


€12,731,954

€15.291.076,75

52

Usa

No data


$8,182,235 (connecticut state)

€10,333,634.07 (connecticut state)

40

Taiwan



$7.7 million in 2000 - $9.8 million in 2004

€10.16 million in 2000 – €9.32 Million in 2004

31

France


No data

€170 million (€61 million for the insurance)

€196.69 million (€70.58 million for the insurance) €4.47 million (€0.39 million dollars for medical honoraries, €4.08 million dollars for hospitalized hz cases)

30

Canada

No data

No data

$5.33 million ($0.46 million dollars for medical honoraries, $4.87 million dollars for hospitalized hz cases)

55

Usa

No data

0.25/1,000 population per year

$1.2 billion in 1993 - $1.9 billion in 2004

€1.04 billion in 1993 €1.64 billion in 2004

0.28–0.39/1000 Population per year

$32.8 million ($8.0 million for principal diagnosis hz cases, $10.8 million for non principal diagnosis hz cases, $8.2 million for drug prescriptions, $4.2 for hz management, $181,000 for specialist referrals, $562,000 for non-admitted ed hz cases, $710,000 for other encounters with gps for drug prescriptions)

€22.40 million (€5.5 million for Principal diagnosis hz cases, €7.4 million for non principal diagnosis hz cases, €5.6 million for drug prescriptions, €2.9 for hz management, €123,609.76 for specialist referrals, €383,804.9 for non-admitted ed hz cases, €484,878.1 for other encounters with gps for drug prescriptions)

No data

€105.06 million from the payer perspective (€84.67 million for hz, €20.39 million for phn), €181.74 € million from the societal perspective (€151.87 million for hz, €29.87 million for phn)

€113.09 million from the payer perspective (€91.55 million for Hz, €21.54 million for phn), €196.01 million from the societal perspective (€163.80 millionfor hz, €32.21million for phn)

28

32

Australia

Germany

9.67-10.10/1000 population per year


58

Usa

No data

No data

$1.1 billion

€1.08 billion

57

Usa

No data

No data

$1 billion and more

€0.75 billion and more




Table 4. Global costs for HZ-related infection broken down by country

Table 5. Range of costs of HZ and PHN broken down by geographical areas Geographical area

Inpatient cost



Asia


Europe

Oceania

US

€118.13–707.23 (all ages, *) €112.44– 1,945.34 (all ages, ^)

€61.67a (all ages)

No data (all ages)

€4,725.72 (average hospital admission), €3,550.88 (day-hospital), €5,001.17 (ordinary admission), €3,062.10 with HZ as the principal diagnosis, €2,803.40 without complications, €3,289.06 with complications (> 14 y)

€136.13 a-441.85 a (> 14 y)

€81.49a-253.41a (> 14 y)

€3,843.20a-4,467.16a (> 30 y)

No data (> 30 y)

No data (> 30 y)

€3,063.74a ± 1551.97a (> 50 y)

€145.01a-211.64a (> 50 y)

No data (> 50 y)

€774.66a-31,026.22a (all ages)

€0–6,133.48 (all ages)

€118.65a-242.62a (all ages)

€3064.84 -3225.30 (> 50 y)

€203.67a for non-ED admitted cases, €24.68a-€31.51a per GP consultation, €51.63a for specialists consultations and referrals (> 50 y)

€119.53a (> 50 y)

€230.86a ± 51.00b*, €248.13a ± 150.05b ^ (> 22 y)

€318.74a ± 8.83b* €356.02a ± 37.27b^ (> 22 y)

€382.49a ± 11.77b* €395.24a ± 27.46b^ (> 22 y)

€9,041.36a-23,219.82a; €16,284.60a for the stay in the SNF (all ages)

No data (all ages)

No data (all ages)

€5,647.20a ± 30,109.16c in the commercially insured and Medicare SOT patients, €6,428.84a ± 21,329.34c in the Medicaid patients (all ages)

€621.51a ± 2,654.81c in the commercially insured and Medicare SOT patients, 899.36a ± 1,566.75c in the Medicaid patients (all ages)

€452.71a ± 422.42c in the commercially insured and Medicare SOT patients, €464.82a ± 701.13c in the Medicaid patients (all ages)

$20,948.31a (all ages, in patients with comorbidities)

No data

No data

a

a

Post-herpetic neuralgia Asia

No data

No data

No data (> 14 y)

1 mo, €282.20 ± 198.63 ; 3 mo, €412.05 ± 253.75c(> 14 y)

1 mo:, €172.23a ± 203.70; 3 mo, €312.15a ± 323.24c (> 14 y)

No data (> 30 y)

No data (> 30 y)

No data (> 30 y)

€3,316.69a±3,121.66c (> 50 y)

1 mo, €281.30a-758.24c; 3 mo, €574.09a (€336.77a-1,039.24a) (> 50 y)

No data (> 50 y)

€4,026.05a (all ages)

range €0–5,131.91a (all ages)

€278.75a-614.96a (all ages)

No data

No data

No data

€4261.39 ± 1854.61 ^ (> 22 y)

892.49 ± 82.38 ^ (> 22 y)

1767.32 ± 177.52b for drug prescriptions, 263.82a ± 30.40b for procedures ^ (> 22 y)

€3,504.03a ± 11,173.70c (> 65 y)

€1,048.89a ± 2,037.22c (> 65 y)

€593.60a ± 1,178.97c (> 65 y)

€1,538.17a-3,130.88a (all ages)

€2,789.84a-6,043.64a (all ages)

€2,946.51a-6,628.79a (all ages)

Europe

Oceania

a

c

No data a

a

a

US US

b

a

b

Legend: ^: immunocompromised subjects; *: immunocompetent subjects; ED: Emergency Department; GP: General Practitioner; SNF: Skilled Nursing Facility; SOT: Solid Organ Transplant; amean; bstandard error; cstandard deviation. 26 Human Vaccines & Immunotherapeutics

Volume 11 Issue 1


Herpes Zoster

Group

Search items

1. used keywords

- PubMed/MEDLINE (“herpes zoster”[MeSH] OR “herpes zoster”[title/abstract] OR zona OR shingles[MeSH] OR shingles[title/abstract] OR varicella reactivation [title/abstract]) AND (cost [title/abstract] OR cost of illness [MeSH] OR cost of illness [title/abstract] OR drug cost [MeSH] OR drug cost [title/abstract] OR pharmaceutical fee [MeSH] OR prescription fee [MeSH] OR nursing cost [title/abstract] OR physician cost [title/abstract] OR employer health cost [MeSH] OR healthcare cost [MeSH] OR healthcare cost [title/abstract] OR hospital cost [MeSH] OR hospital cost [title/abstract] OR hospital charge [MeSH] OR cost analysis [title/abstract] OR costs and cost analysis [MeSH] OR economic burden [title/abstract] OR economic impact OR economic model [MeSH] OR economic model [title/abstract] OR econometric model [MeSH] OR econometric model [title/abstract] OR hospital economics [MeSH] OR hospital economics [title/ abstract] OR nursing economics [mesh] OR nursing economics [title/abstract] OR economics [MeSH] OR economics [title/abstract] OR direct service cost [MeSH] OR health expenditure [MeSH] OR societal cost [title/abstract] OR direct cost [title/abstract] OR indirect cost [title/abstract] OR presenteeism [title/abstract] OR absenteeism [title/abstract] OR productivity loss [title/abstract]) - Scopus (“herpes zoster” OR “shingles”) AND (“cost of illness” OR cost OR “economic burden” OR “economic impact” OR “health expenditure” OR “societal cost” OR “direct cost” OR “indirect cost” OR presenteeism OR absenteeism OR “productivity loss”) using the “Article Title, Abstract, Keywords” option - ISI Web of Science (“herpes zoster” OR “shingles”) AND (“cost of illness” OR cost OR “economic burden” OR “economic impact” OR “health expenditure” OR “societal cost” OR “direct cost” OR “indirect cost” OR presenteeism OR absenteeism OR “productivity loss”) using the “Topic” option - ProQuest (“herpes zoster” OR shingles OR “varicella reactivation”) AND (“cost of illness” OR “drug cost” OR “pharmaceutical fee” OR “prescription fee” OR “nursing cost”OR “physician cost” OR “employer health cost” OR “healthcare cost” OR “hospital cost” OR “hospital charge” OR “cost analysis” OR “economic burden” OR “economic model” OR “econometric model” OR “direct service cost” OR “health expenditure” OR “societal cost” OR “direct cost” OR “indirect cost” OR presenteeism OR absenteeism OR “productivity loss”) using the “Peer-reviewed” and “Scholarly Journals” options - The Cochrane Library (“herpes zoster” OR “shingles”) AND (“cost of illness” OR cost OR “economic burden” OR “economic impact” OR “health expenditure” OR “societal cost” OR “direct cost” OR “indirect cost” OR presenteeism OR absenteeism OR “productivity loss”) using the “Title, Abstract, Keywords” option - EconLit (“herpes zoster” OR “shingles”) AND (“cost of illness” OR cost OR “economic burden” OR “economic impact” OR “health expenditure” OR “societal cost” OR “direct cost” OR “indirect cost” OR presenteeism OR absenteeism OR “productivity loss”)

2. targeted journals

Advances in health economics and health services research/Research in Health economics, BMC health services research, European Journal of Health economics, Evidence and policy, Expert review of pharmacoeconomics and outcomes research, Giornale Italiano di Farmacoeconomia e Farmacoutilizzazion, Healthcare management science, Health economics, Health Economics Review, Health policy, Health services and Outcomes research methodology, Journal of clinicoeconomics and outcomes research, Journal of evaluation in clinical practice, Journal of Health Economics, Journal of health organisation and management, Journal of health politics, policy and law, Journal of Health Services Research and Policy, Journal of Medical Economics, Medical decision making, Pharmacoeconomics

27. Gialloreti LE, Merito M, Pezzotti P, Naldi L, Gatti A, Beillat M, Serradell L, di Marzo R, Volpi A. Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: a retrospective, population-based study. BMC Infect Dis 2010; 10:230; PMID:20682044; http://dx.doi. org/10.1186/1471-2334-10-230 28. Stein AN, Britt H, Harrison C, Conway EL, Cunningham A, Macintyre CR. Herpes zoster burden of illness and health care resource utilisation in the Australian population aged 50 years and older. Vaccine 2009; 27:520-9; PMID:19027048; http:// dx.doi.org/10.1016/j.vaccine.2008.11.012 29. Bilcke J, Ogunjimi B, Marais C, de Smet F, Callens M, Callaert K, van Kerschaver E, Ramet J, van Damme P, Beutels P. The health and economic burden of chickenpox and herpes zoster in Belgium. Epidemiol Infect 2012; 140:2096-109; PMID:22230041; http://dx.doi.org/10.1017/S0950268811002640 30. Nowgesic E, Skowronski D, King A, Hockin J. Direct costs attributed to chickenpox and herpes zoster in British Columbia--1992 to 1996. Can Commun Dis Rep 1999; 25:100-4; PMID:10726371 31. Mick G, Gallais JL, Simon F, Pinchinat S, Bloch K, Beillat M, Serradell L, Derrough T. [Burden of herpes zoster and postherpetic neuralgia: Incidence, proportion, and associated costs in the French population aged 50 or over]. Rev Epidemiol Sante Publique 2010; 58:393-401; PMID:21094001; http://dx.doi. org/10.1016/j.respe.2010.06.166

32. Ultsch B, Köster I, Reinhold T, Siedler A, Krause G, Icks A, Schubert I, Wichmann O. Epidemiology and cost of herpes zoster and postherpetic neuralgia in Germany. Eur J Health Econ 2013; 14:101526; PMID:23271349; http://dx.doi.org/10.1007/ s10198-012-0452-1 33. Arpinelli F, Bonzanini AC, Visonà G. La gestione clinica ed i costi dell’Herpes Zoster in Italia. G Farmacoeconomia 2000; 3:98-103 34. Choi WS, Noh JY, Huh JY, Jo YM, Lee J, Song JY, Kim WJ, Cheong HJ. Disease burden of herpes zoster in Korea. J Clin Virol 2010; 47:325-9; PMID:20181512; http://dx.doi.org/10.1016/j. jcv.2010.01.003 35. Choi WS, Kwon SS, Lee J, Choi SM, Lee JS, Eom JS, Sohn JW, Choeng HJ. Immunity and the burden of herpes zoster. J Med Virol 2014; 86:52530; PMID:24166660; http://dx.doi.org/10.1002/ jmv.23830 36. Cebrián-Cuenca AM, Díez-Domingo J, San-MartínRodríguez M, Puig-Barberá J, Navarro-Pérez J; Herpes Zoster Research Group of the Valencian Community. Epidemiology and cost of herpes zoster and postherpetic neuralgia among patients treated in primary care centres in the Valencian community of Spain. BMC Infect Dis 2011; 11:302; PMID:22044665; http://dx.doi.org/10.1186/1471-2334-11-302

37. Gil A, Gil R, Alvaro A, San Martín M, González A. Burden of herpes zoster requiring hospitalization in Spain during a seven-year period (1998-2004). BMC Infect Dis 2009; 9:55; PMID:19422687; http:// dx.doi.org/10.1186/1471-2334-9-55 38. Sicras-Mainar A, Navarro-Artieda R, Ibáñez-Nolla J, Pérez-Ronco J. [Incidence, resource use and costs associated with postherpetic neuralgia: a populationbased retrospective study]. Rev Neurol 2012; 55:44961; PMID:23055426 39. Jih JS, Chen YJ, Lin MW, Chen YC, Chen TJ, Huang YL, Chen CC, Lee DD, Chang YT, Wang WJ, et al. Epidemiological features and costs of herpes zoster in Taiwan: a national study 2000 to 2006. Acta Derm Venereol 2009; 89:612-6; PMID:19997693; http:// dx.doi.org/10.2340/00015555-0729 40. Lin YH, Huang LM, Chang IS, Tsai FY, Lu CY, Shao PL, Chang LY; Varicella-Zoster Working Group; Advisory Committee on Immunization Practices, Taiwan. Disease burden and epidemiology of herpes zoster in pre-vaccine Taiwan. Vaccine 2010; 28:121720; PMID:19944790; http://dx.doi.org/10.1016/j. vaccine.2009.11.029




Table 6. Search strategies used in the current systematic review

51. Kirson NY, Ivanova JI, Birnbaum HG, Wei R, Kantor E, Puenpatom RA, Ben-Joseph RH, Summers KH. Comparing healthcare costs of Medicaid patients with postherpetic neuralgia (PHN) treated with lidocaine patch 5% versus gabapentin or pregabalin. J Med Econ 2010; 13:482-91; PMID:20684669; http://dx.doi.org/10.3111/13696998.2010.506176 52. Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster hospitalizations: the pre-varicella vaccine era. J Infect Dis 2000; 181:1897-905; PMID:10837168; http://dx.doi.org/10.1086/315492 53. Ma L, White RR, Narayanan S, Schmader KE. Economic burden of herpes zoster among skilled nursing facility residents in the United States. J Am Med Dir Assoc 2012; 13:54-9; PMID:21450176; http://dx.doi.org/10.1016/j.jamda.2010.03.015 54. Palmer L, White RR, Johnson BH, Fowler R, Acosta CJ. Herpes zoster-attributable resource utilization and cost burden in patients with solid organ transplant. Transplantation 2014; 97:1178-84; PMID:24892964; http://dx.doi.org/10.1097/01. tp.0000441826.70687.f6 55. Patel MS, Gebremariam A, Davis MM. Herpes zoster-related hospitalizations and expenditures before and after introduction of the varicella vaccine in the United States. Infect Control Hosp Epidemiol 2008; 29:1157-63; PMID:18999945; http://dx.doi. org/10.1086/591975 56. Singhal PK, Makin C, Pellissier J, Sy L, White R, Saddier P. Work and productivity loss related to herpes zoster. J Med Econ 2011; 14:639-45; PMID:21838599; http://dx.doi.org/10.3111/136969 98.2011.607482 57. White RR, Lenhart G, Singhal PK, Insinga RP, Itzler RF, Pellissier JM, Segraves AW. Incremental 1-year medical resource utilization and costs for patients with herpes zoster from a set of US health plans. Pharmacoeconomics 2009; 27:781-92; PMID:19757871; http://dx.doi. org/10.2165/11317560-000000000-00000 58. Yawn BP, Itzler RF, Wollan PC, Pellissier JM, Sy LS, Saddier P. Health care utilization and cost burden of herpes zoster in a community population. Mayo Clin Proc 2009; 84:787-94; PMID:19720776; http:// dx.doi.org/10.4065/84.9.787 59. Gilden D. Efficacy of live zoster vaccine in preventing zoster and postherpetic neuralgia. J Intern Med 2011; 269:496-506; PMID:21294791; http://dx.doi. org/10.1111/j.1365-2796.2011.02359.x 60. Keating GM. Shingles (herpes zoster) vaccine (zostavax(®)): a review of its use in the prevention of herpes zoster and postherpetic neuralgia in adults aged ≥50 years. Drugs 2013; 73:1227-44; PMID:23839657; http://dx.doi.org/10.1007/ s40265-013-0088-1


61. Sanford M, Keating GM. Zoster vaccine (Zostavax): a review of its use in preventing herpes zoster and postherpetic neuralgia in older adults. Drugs Aging 2010; 27:159-76; PMID:20104941; http://dx.doi. org/10.2165/10489140-000000000-00000 62. Centers for Disease Control and Prevention (CDC). Shingles Vaccination: What You Need to Know. Available at: http://www.cdc.gov/vaccines/vpd-vac/ shingles/vacc-need-know.htm Accessed 14, 2014. 63. Morrison VA, Oxman MN, Levin MJ, Schmader KE, Guatelli JC, Betts RF, Gelb LD, Pachucki CT, Keay SK, Menzies B, et al.; Shingles Prevention Study Group. Safety of zoster vaccine in elderly adults following documented herpes zoster. J Infect Dis 2013; 208:559-63; PMID:23633406; http://dx.doi. org/10.1093/infdis/jit182 64. Weaver BA; Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention. Update on the advisory committee on immunization practices’ recommendations for use of herpes zoster vaccine. J Am Osteopath Assoc 2011; 111(Suppl 6):S31-3; PMID:22086893 65. Szucs TD, Pfeil AM. A systematic review of the cost effectiveness of herpes zoster vaccination. Pharmacoeconomics 2013; 31:125-36; PMID:23335045; http://dx.doi.org/10.1007/ s40273-012-0020-7 66. van Hoek AJ, Melegaro A, Gay N, Bilcke J, Edmunds WJ. The cost-effectiveness of varicella and combined varicella and herpes zoster vaccination programmes in the United Kingdom. Vaccine 2012; 30:122534; PMID:22119592; http://dx.doi.org/10.1016/j. vaccine.2011.11.026 67. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6:e1000100; PMID:19621070; http://dx.doi.org/10.1371/journal. pmed.1000100 68. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, Augustovski F, Briggs AH, Mauskopf J, Loder E; CHEERS Task Force. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMJ 2013; 346:f1049; PMID:23529982; http://dx.doi. org/10.1136/bmj.f1049 69. Manager R. (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Volume 11 Issue 1



41. Aunhachoke K, Bussaratid V, Chirachanakul P, ChuaIntra B, Dhitavat J, Jaisathaporn K, Kaewkungwal J, Kampirapap K, Khuhaprema T, Pairayayutakul K, et al.; Thai Herpes Zoster Study Group. Measuring herpes zoster, zoster-associated pain, post-herpetic neuralgia-associated loss of quality of life, and healthcare utilization and costs in Thailand. Int J Dermatol 2011; 50:428-35; PMID:21413953; http://dx.doi. org/10.1111/j.1365-4632.2010.04715.x 42. Davies L, Cossins L, Bowsher D, Drummond M. The cost of treatment for post-herpetic neuralgia in the UK. Pharmacoeconomics 1994; 6:142-8; PMID:10147439; http://dx.doi. org/10.2165/00019053-199406020-00006 43. Gauthier A, Breuer J, Carrington D, Martin M, Rémy V. Epidemiology and cost of herpes zoster and postherpetic neuralgia in the United Kingdom. Epidemiol Infect 2009; 137:38-47; PMID:18466661; http:// dx.doi.org/10.1017/S0950268808000678 44. Scott FT, Johnson RW, Leedham-Green M, Davies E, Edmunds WJ, Breuer J. The burden of Herpes Zoster: a prospective population based study. Vaccine 2006; 24:1308-14; PMID:16352376; http://dx.doi. org/10.1016/j.vaccine.2005.09.026 45. Dworkin RH, White R, O’Connor AB, Baser O, Hawkins K. Healthcare costs of acute and chronic pain associated with a diagnosis of herpes zoster. J Am Geriatr Soc 2007; 55:1168-75; PMID:17661954; http://dx.doi.org/10.1111/j.1532-5415.2007.01231.x 46. Dworkin RH, White R, O’Connor AB, Hawkins K. Health care expenditure burden of persisting herpes zoster pain. Pain Med 2008; 9:348-53; PMID:18366512; http://dx.doi. org/10.1111/j.1526-4637.2006.00196.x 47. Dworkin RH, Malone DC, Panarites CJ, Armstrong EP, Pham SV. Impact of postherpetic neuralgia and painful diabetic peripheral neuropathy on health care costs. J Pain 2010; 11:360-8; PMID:19853529; http://dx.doi.org/10.1016/j.jpain.2009.08.005 48. Insinga RP, Itzler RF, Pellissier JM. Acute/subacute herpes zoster: healthcare resource utilisation and costs in a group of US health plans. Pharmacoeconomics 2007; 25:155-69; PMID:17249857; http://dx.doi. org/10.2165/00019053-200725020-00007 49. Johnston SS, Udall M, Alvir J, McMorrow D, Fowler R, Mullins D. Characteristics, treatment, and health care expenditures of Medicare supplemental-insured patients with painful diabetic peripheral neuropathy, post-herpetic neuralgia, or fibromyalgia. Pain Med 2014; 15:562-76; PMID:24433487; http://dx.doi. org/10.1111/pme.12328 50. Kirson NY, Ivanova JI, Birnbaum HG, Wei R, Kantor E, Amy Puenpatom R, Ben-Joseph RH, Summers KH. Descriptive analysis of Medicaid patients with postherpetic neuralgia treated with lidocaine patch 5%. J Med Econ 2010; 13:472-81; PMID:20684670; http://dx.doi.org/10.3111/13696998.2010.499819

The humanistic, economic and societal burden of herpes zoster in Europe: a critical review.

The burden of disease of Herpes Zoster in Tuscany.

Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective.

Herpes zoster infection and cardiac arrest.

Herpes zoster and human immunodeficiency virus infection.

Herpes Zoster and Recurrent Herpes Zoster.

Herpes zoster: A rash demanding careful evaluation.

Cerebrovascular complications of primary herpes varicella-zoster infection.

MRI evolution of CLIPPERS syndrome following herpes zoster infection.

Herpes zoster of the stomach.

Herpes zoster.

Herpes zoster.

Herpes zoster.

The Global Economic and Health Burden of Human Hookworm Infection.

Burden of herpes zoster: the direct and comorbidity costs of herpes zoster events in hospitalized patients over 50 years in France.

Prolonged herpes-zoster infection associated with immunosuppressive therapy.

Abdominal distention and constipation followed by herpes zoster infection.

Eye and Periocular Skin Involvement in Herpes Zoster Infection.

Orbital apex syndrome secondary to herpes zoster virus infection.

Simultaneous disseminated herpes zoster and bacterial infection in cancer patients.

Colonic changes of herpes zoster.

Treatment of ocular herpes zoster.

Interferon treatment of herpes zoster.

Is Herpes Zoster Contagious?