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Incidence and costs of herpes zoster and postherpetic neuralgia in German adults aged ≥50 years: A prospective study
Accepted Manuscript Title: Incidence and costs of herpes zoster and postherpetic neuralgia in german adults aged ≥50 years: a prospective study Author: Ruprecht Schmidt-Ott, Ulf Schutter, Jörg Simon, Barbara Poulsen Nautrup, Alfred von Krempelhuber, Kusuma Gopala, Anastassia Annastassopoulou, Adrienne Guignard, Desmond Curran, Sean Matthews, Emmanuelle Espié PII: DOI: Reference:
S0163-4453(18)30053-7 https://doi.org/10.1016/j.jinf.2018.02.001 YJINF 4052
To appear in:
Journal of Infection
Accepted date:
3-2-2018
Please cite this article as: Ruprecht Schmidt-Ott, Ulf Schutter, Jörg Simon, Barbara Poulsen Nautrup, Alfred von Krempelhuber, Kusuma Gopala, Anastassia Annastassopoulou, Adrienne Guignard, Desmond Curran, Sean Matthews, Emmanuelle Espié, Incidence and costs of herpes zoster and postherpetic neuralgia in german adults aged ≥50 years: a prospective study, Journal of Infection (2018), https://doi.org/10.1016/j.jinf.2018.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Research article
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Manuscript Title (99/100 characters allowed):
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Incidence and costs of herpes zoster and postherpetic neuralgia in German adults aged ≥50 years:
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a prospective study
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Authors: Ruprecht Schmidt-Otta, Ulf Schutterb, Jörg Simonc, Barbara Poulsen Nautrupd, Alfred
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von Krempelhubere, Kusuma Gopalaf, Anastassia Annastassopouloue, Adrienne Guignarda,
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Desmond Currana, Sean Matthewsg, Emmanuelle Espiéa*
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Affiliations/Institutions:
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a
GSK, Avenue Fleming 20, 1300 Wavre, Belgium
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b
Facharztzentrum am Marienhospital und Marler Arztnetz, Hervester Str. 57, 45768 Marl,
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Germany
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c
Gesundheitsnetz Osthessen, Gerloser Weg 20, 36039 Fulda, Germany
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d
EAH-Consulting, Karlsgraben 12, 52064 Aachen, Germany
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e
GSK Germany, Prinzregentenplatz 9, 81675 München, Germany
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f
GSK Pharmaceuticals, #5, Embassy links, SRT road, Cunningham road, 560052 Bangalore,
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India
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g
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E-mail adresses:
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Ruprecht Schmidt-Ott [email protected]
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Ulf Schutter [email protected]
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Jörg Simon [email protected]
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Barbara Poulsen Nautrup [email protected]
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Alfred von Krempelhuber [email protected]
Freelance c/o GSK, Avenue Fleming 20, 1300 Wavre, Belgium
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Kusuma Gopala [email protected]
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Anastassia Annastassopoulou [email protected]
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Adrienne Guignard [email protected]
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Desmond Curran [email protected]
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Sean Matthews [email protected]
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Emmanuelle Espié [email protected]
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* Corresponding author:
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Name: Emmanuelle Espié R&D Clinical and Epidemiology Department GSK, Avenue Fleming, Wavre, Belgium Email: [email protected] Tel: +32 10 85 58 39
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Running title (17/50 characters allowed): HZ burden in Germany
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Abstract
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Objectives
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Herpes zoster (HZ) mainly affects elderly people and immunocompromised individuals. HZ is
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usually characterized by a unilateral painful skin rash. Its most common complication,
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postherpetic neuralgia (PHN), may cause chronic debilitating pain. This study aimed to estimate
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the HZ incidence in individuals aged ≥50 years in Germany, the proportion of PHN and the
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economic burden.
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Methods
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From 2010 to 2014, HZ-patients were recruited when consulting physicians in physician
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networks covering about 157,000 persons aged ≥50 years. PHN was defined as ‘worst pain’ rated
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≥3 on the zoster brief pain inventory persisting or appearing over 90 days after rash onset. Costs
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were calculated based on medical resource utilization and lost working time.
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Results
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HZ incidence was estimated as 6.7/1,000 person-years, increasing with age to 9.4/1000 in ≥80
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year-olds. Among 513 HZ-patients enrolled, the proportion of PHN was 11.9%, rising with age
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to 14.3% in HZ-patients ≥80 years. Estimated total cost per HZ-patient was €156 from the
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healthcare system perspective and €311 from the societal perspective.
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Conclusions
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The study confirmed previous findings that HZ causes a substantial clinical and economic
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burden in older German adults. It also confirmed the age-related increasing risk of HZ and PHN.
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Trial registration: e-track number (113206)
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Keywords: Varicella zoster virus (VZV); herpes zoster (HZ); postherpetic neuralgia (PHN)
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Word count: No limit indicated in author instructions
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Abstract: 195/200
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Background
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Varicella-zoster virus (VZV) is a DNA virus [1] causing varicella (chickenpox) and herpes
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zoster (HZ, also called shingles), which is typically characterized by a painful, blistering,
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unilateral dermatomal rash [2,3].
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Following the resolution of a primary varicella infection, VZV establishes latency in the neurons
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of sensory ganglia [4] and may later reactivate and cause HZ. Whereas it is not known what
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triggers VZV reactivation and the subsequent development of HZ, it is clear that persons with
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impaired cell-mediated immunity due to advanced age, underlying diseases or medical
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interventions are at increased risk for developing HZ [5-7]. Based on prior published data, the
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lifetime risk of developing HZ is estimated to be between 25 and 30% rising to 50% in people
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aged 80 years or older [8-10]. The overall HZ incidence has been increasing linearly over the
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past decades likely due to the aging of the population, an increasing number of
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immunocompromised people [11], improved diagnostics and other unknown factors [2].
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In most cases, the HZ rash heals and the pain ceases within approximately one month of rash
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onset but in some cases, notably in elderly patients, the pain persists after the rash has healed and
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may develop into postherpetic neuralgia (PHN), which is the most common complication of HZ
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[2,12]. PHN is commonly defined as HZ-related pain persisting or appearing more than three
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months after rash onset but there is no universally accepted definition [2,7,12].
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Pathophysiological observations include damage to the sensory nerves, the sensory dorsal root
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ganglia and the dorsal horn of the spinal cord [12].
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PHN involves chronic pain and is a debilitating syndrome causing physical disability, interfering
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with daily activities and sleep [13]. For most of the PHN patients, the pain ceases within months
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but can last for more than one year after rash onset (reviewed in [2]). Identified risk factors for
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PHN vary somewhat across studies but consistent findings are that older age, greater pain in the
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acute HZ phase and more severe rash are predictors of PHN [11,15].
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A recent worldwide review reported overall incidence rates ranging from 3 to 5 per 1,000
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person-years (PY) [2]. Age-specific incidence shows a steep increase over the age of 50, with
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incidence rates of 5/1,000 PY for those 50-60 years of age (YOA), 6-7/1,000 PY for 70-80 YOA
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and up to 10/1,000 PY for people over 90 YOA with no clearly observed geographical
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differences [2]. The reported proportion of PHN among HZ patients varies widely, from 5% to
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more than 30% [2]. This variation may be explained by differences in study design and settings,
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the use of diverging definitions of PHN and age distributions of the study populations and also a
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lack of objective pain measures [2].
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In Germany, only one prospective study has been performed in 1992-93 in the city of Ansbach to
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assess the incidence of HZ and chickenpox [22]. The most recent burden of disease studies were
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all retrospective database studies using the Association of Statutory Health Insurance Physicians’
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database containing nationwide routine outpatient data [18-21]. With the recent rising HZ
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incidence observed elsewhere, these estimates may not correctly represent the current burden of
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disease in Germany.
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The aim of the present study was to provide an up-to-date estimation of the clinical and
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economic burden of HZ disease in German adults aged 50 years and older as well as its impact
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on patients’ quality of life. In this paper, we describe the age- and gender-specific incidence of
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HZ, the proportion of PHN and other HZ-related complications in a defined population in three
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selected regions of Germany. The estimated direct medical costs and the indirect costs due to
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absence from work of patients and caregivers are also presented.
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Methods
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Study design and study settings
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This was a prospective observational cohort study conducted in general practices and certain
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specialist practices in three different regions of Germany (Fulda, Leverkusen and Marl, see
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Fig.1). The study areas were delimited by a number of postal codes encompassing a well-defined
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geographical area served by a well-established network of primary care physicians including
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some specialists. The catchment areas of the physician networks cover a total of about 157,000
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persons aged 50 years and older. General practitioners (GPs), dermatologists and
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ophthalmologists of the three networks were invited to participate on a voluntary basis.
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Study population and case definition
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Patient recruitment by participating physicians took place between November 2010 and
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December 2014. All patients 50 years and older and diagnosed with a first episode of HZ at the
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initial visit with one of the participating physicians were considered as eligible. Their age, gender
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and residency were recorded to identify the number of eligible patients living inside or outside
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the study areas, by age-group and gender. Participation in the study was proposed to all eligible
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patients who were able to complete the questionnaires and provided a written consent.
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HZ was defined as new unilateral rash accompanied by unilateral pain (including allodynia and
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pruritus) and no alternative diagnosis. The severity of HZ-related pain at the initial visit was
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assessed using the zoster brief pain inventory (ZBPI) questionnaire [23]. The 11-point ZBPI
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scale is divided into four categories of pain: no pain (0); mild (1 - 2); moderate (3 - 6); and
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severe (7 - 10). PHN was defined as the presence of moderate or severe (≥3 on the ZBPI scale)
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‘worst pain’ (i.e., pain at its worst during the last 24 hours) persisting or appearing more than 90
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days after rash onset.
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Data collection
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At the initial visit of each patient enrolled in the study, the physicians recorded the patient’s
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demographic data (age, gender, and residency) and employment status. They further performed a
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medical examination to record the clinical characteristics of HZ, assessed the severity of HZ-
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related pain using the ZBPI scale and enquired about the occurrence of prodromal symptoms.
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Medical history and co-morbidities, including immunosuppressive conditions, were also
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documented as well as previous and current medication, including self-prescribed therapies. HZ-
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related complications (such as HZ ophthalmicus or oticus) were recorded at any physician visit
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during the nine-month follow-up after the initial visit.
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During the follow-up, the patients were asked to complete the ZBPI questionnaire about their
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pain condition 15, 30, 60 and 90 days (+/- 7 days) after the initial visit and return them to the
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physician. At Day 90, patients with ZBPI ‘worst pain’ score < 3 were considered as not having
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developed PHN and were not followed further. Patients with PHN at Day 90 (ZBPI ‘worst pain’
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score ≥3) were followed for another three months and were asked to complete and return the
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questionnaire at Days 120, 150 and 180 after the initial visit.
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At Day 180, only patients with PHN still having a ZBPI ‘worst pain’ score ≥ 3 at that time point
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were required to provide subsequent assessments for three additional months to complete the
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follow-up of nine months after the initial visit (at Days 210, 240 and 270). HZ-related
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complications were recorded during the entire study period (until Day 270).
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To estimate the costs of disease, at the initial visit, the physician recorded any prior use of
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medical resources related to the HZ episode and the visit itself. The patients were then provided
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with a booklet to be completed by any medical care provider encountered in relation to HZ
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during the 90 days (+/- 7) after the initial visit. Patients with PHN at Day 90 and continuing in
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follow-up were asked to have any subsequent HZ-related medical care recorded until the end of
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follow-up. The resources recorded included GP and specialist visits, hospital outpatient visits and
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admissions, procedures and tests performed, and medications taken. Unit costs for GP and
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specialist visits, procedures and medications were taken from official sources (Table SM1). The
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costs of inpatient treatment of HZ patients 50 years and older were taken from a previous
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German study [20] adjusted according to the consumer price index for medical services. As the
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study was carried out in a primary care setting, some hospitalizations and all specialist visits
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were only reported as referrals. Cost calculations were made assuming costs for all referrals.
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Patients in active employment were asked to record the number of days of absence from work
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because of HZ or PHN. Likewise, patients receiving care from personal caregivers who needed
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to be absent from work to be able to care for the patient, were to record the days of absence from
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work of their caregiver. The number of days of absence recorded were multiplied by the national
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average daily earnings (for the patients’ absence from work, stratified for gender and age) to
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estimate the indirect costs due to HZ and PHN (Table SM1).
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Costs were calculated from both the healthcare system (HCS) and the societal perspective. The
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main difference between the two perspectives, apart from patient co-payment for certain types of
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medical care and medications, is that the societal perspective includes the indirect costs caused
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by patients’ and caregivers’ absence from work.
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Statistical analysis
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The HZ incidence was calculated as the number of eligible HZ cases divided by the study
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population living in the study areas defined by the three participating networks of physicians. In
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order to estimate the size of the study population to use as denominator for this calculation, the
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population of people 50 years and older in each study area was extrapolated from 2011 census
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data (Federal Statistical Office and the Statistical Offices of the Länder) and was adjusted to take
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into account that physicians were free to decline participation in the study or to stop participating
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at any time during the study period. The study population was weighted by combining the total
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population with the mean number of eligible HZ cases per physician per specialty and the
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proportion of participating physicians relative to all that could have participated. Separate
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denominators were calculated for each study area, overall and by age group. HZ incidence was
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estimated per 1,000 PY with exact 95% confidence intervals (CI), overall and stratified by
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gender and age groups.
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The proportion of HZ patients developing PHN was calculated with exact 95% CI overall and
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stratified by gender and age groups. The proportion of patients with PHN persisting at six and
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nine months after rash onset was reported in a similar way. Demographic characteristics, medical
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history of HZ and PHN patients and characteristics of HZ and PHN episodes (severity,
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symptoms, presence of complications) were described.
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Exploratory analyses
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To investigate potential risk factors for developing PHN, multivariate logistic regression
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analyses were performed on the patients returning a completed ZBPI questionnaire 90 days after
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the rash onset. Based on risk factors for PHN identified in previous published studies [11], the 10 Page 10 of 31
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following potential risk factors were considered: age, gender, co-morbidities, current
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immunosuppressive therapy and HZ-related pain severity at the initial visit. Using the backward
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elimination strategy (with p-value of 0.05 as the threshold to keep a variable in the model) and
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the method of maximum likelihood, the final model was used to identify any statistically
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significant risk factors.
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All analyses were carried out using SAS software.
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Ethics
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The study was conducted in accordance with ethical principles originating in the Declaration of
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Helsinki, the principles of “good clinical practice” and all applicable regulatory requirements.
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The protocol was reviewed and approved by the ethics committees of the study areas and all
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enrolled participant gave written informed consent.
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Results
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Overall incidence of HZ
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The number of physicians that participated in the study as well as the number collaborating in the
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networks varied over the study period from November 2010 to December 2014. On average,
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about one third of the 403 physicians working in the study areas (125/342 GPs, 6/24
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dermatologists and 6/27 ophthalmologists) participated at least some of the time of the study
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period. A total of 1,551 individuals aged 50 years and older were diagnosed with a first episode
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of HZ during the study period.
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The overall HZ incidence was estimated as 6.7 per 1,000 PY (95% CI: 6.4 - 7.1) (Table 1),
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increasing with age from 4.4 per 1,000 PY for individuals aged 50-59 years to 9.4 per 1,000 PY
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for individuals aged ≥80 years (Table 1). The overall HZ incidence was 7.6 per 1,000 PY (95%
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CI: 7.1 - 8.1) in women and 5.6 (95% CI: 5.2 - 6.1) in men.
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Patient demographics
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Among the 1,551 eligible HZ patients, 513 were enrolled in the study. The majority, 63%, was
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female, 35.5% belonged to the 70-79 years age group and the mean age was 67.8 years (range:
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49-95). Most were retired but 30%, all younger than 65, were still working or seeking work as
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unemployed.
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The gender distribution of the patients enrolled was identical to that of the eligible patients
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whereas the enrolled patients were slightly younger than the eligible, with a higher proportion in
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the group aged 50-59 years (27.7% and 22.4%, respectively).
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Clinical features of the patients with HZ
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The mean delay between rash onset and the initial visit was 3.7 days (range 0-34 days). At the
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initial visit, 36.7% of the patients were deemed to have severe HZ-related pain using the ZBPI
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‘worst pain’ scale, 42.8% moderate and 20.5% mild or no pain. Almost half (49.1%, 252/513)
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the patients reported having experienced one or more symptoms before the onset of rash. Of
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these, 75.8% (191/252) reported prodromal pain and 34.5% (87/252) had experienced malaise
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(Table 2). In total, 419 patients presented a localized rash (restricted to one area of the body),
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including seven with HZ ophthalmicus and two with HZ oticus, whereas 25 patients reported
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widespread skin lesions. One or more pre-existing medical condition(s) were reported by 62.7%
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(315/513) of the patients, the most frequent of which were hypertension (33.3%, 105/315),
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diabetes mellitus (14.6%, 75/513), current emotional problems, stress or depression (9.9%,
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51/513) and cardiovascular diseases (8.4%, 43/513). Thirty-six patients reported being under
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active immunosuppressive treatment, including corticosteroids and chemotherapy.
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Among the patients without PHN, 37 (7.2% of all the enrolled) experienced other HZ-related
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complications such as peripheral nerve palsies, disseminated VZV, bacterial superinfections and
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diverse neurological problems.
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Proportion of HZ patients developing PHN and characteristics of patients with PHN
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The ZBPI questionnaire was completed by 388 of the 513 patients three months after the initial
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visit, by 38 six months after and by 20 nine months after (Figure SM1). The proportion of HZ
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patients with PHN appearing or persisting 90 days after the rash onset was 11.9% (95%CI: 9.2-
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15.0%), higher in women (13.3%; 95%CI: 9.8-17.5%) than in men (9.5%; 95%CI: 5.7-14.6) and
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increasing with age from 10.6% (95%CI: 6.0-16.8%) in those aged 50-59 years to 14.3%
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(95%CI: 6.8-25.4%) in patients aged ≥80 years (Table 3). However, no significant statistical
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difference was observed between age-groups. Six and nine months after the rash onset, the
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respective proportions of patients with persistent PHN were 4.9% (95%CI: 3.2-7.1%) and 2.9%
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(95%CI: 1.7-4.8%). Two patients still reported severe pain (ZBPI ‘worst pain’ score ≥ 7) 270
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days after the rash onset.
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The mean age of the 61 HZ patients with PHN was 68.3 years old (range 50-89 YOA), 70.5%
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were women. More than half the patients with PHN (56.7%) reported experiencing one or more
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symptoms before the rash onset, most frequently (82.4% of these) prodromal pain. Most, 74.6%,
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reported one or more pre-existing medical conditions, most frequently diabetes mellitus. Eleven
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(18.0%) experienced other HZ-related complications in addition to PHN.
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Predictive factors for PHN
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The final logistic regression model showed that the severity of HZ-related pain at the initial visit
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was the only statistically significant predictor for PHN (Table 4). The estimated odds ratio (OR)
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for moderate pain versus no/mild pain was 5.6 (p-value = 0.02) and for severe pain versus
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no/mild pain it was OR = 10.9 (p-value = 0.001).
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Resource utilization and costs
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A total of 641 GP visits were recorded amounting to an average of 1.25 visits per patient.
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However, only 1.04 visits per patient were considered chargeable, as visits occurring during the
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same quarter are only paid for once (as explained in Table SM1). Ninety-four specialist visits
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were reported for 44 patients. Eight hospitalizations were documented for seven patients, four of
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these only as referrals. The procedures most frequently reported were blood collection for
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diverse tests and dressing of the dermatological area with rash, for 2.3% and 1.9% of the
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patients, respectively. The most commonly used prescription medications were antivirals for
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systemic use (51.9% of the patients), analgesics (49.7%), anesthetics (35.7%) and
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ophthalmologicals (29.8%).
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Sixty patients were absent from work due to their HZ, on average for 7.7 working days. Eight
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caregivers (only three of whom were in paid employment) were reported to have been absent
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from their normal work, on average for 8.0 working days, to provide care for the HZ patient.
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The estimated average direct medical cost per HZ patient amounted to €152 when assessed from
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the HCS perspective and to €169 from the societal perspective (Table SM2). These amounts
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were derived by averaging each cost component over all 513 patients and adding them. The main
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cost components per patient from both perspectives were medications (€55 and €69 from the
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HCS and societal perspective, respectively), hospitalizations (€55 and €56) and GP visits (€33
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from both perspectives). The direct medical costs varied across the age groups but not
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monotonically.
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Indirect costs were only incurred for patients under 65 and the patients with caregivers losing
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time from work were also in this younger age group. The estimates of indirect costs are
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presented in Table SM3 with the average societal costs per patient concerned amounting to
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approximately €1,200.
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The estimated average total costs per HZ patient amounted to €156 from the HCS and €311 from
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the societal perspective (Table 5). From the societal perspective, costs for the patients concerned
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were the highest for those younger than 65 because of the high indirect costs for patients still
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working, but to determine the average total societal costs the indirect costs were averaged over
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all 513 patients. Costs were the highest for patients with HZ-related complications other than
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PHN and the lowest for patients with HZ who did not develop PHN and/or other HZ-related
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complications. Focusing only on the patients actually concerned, we estimated the highest costs
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(from either perspective) for the oldest patients with HZ-related complications other than PHN.
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Discussion
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This is the first prospective cohort study conducted in Germany to estimate the HZ incidence
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focusing on people aged 50 years and older, to estimate the proportion of HZ patients who 15 Page 15 of 31
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develop PHN and to assess the economic burden of HZ disease. It was based on data collected
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from patients consulting physicians in the primary healthcare setting for an acute episode of HZ
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whereas other recent studies of the disease burden of HZ and PHN in Germany have been
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performed on claims databases [18-21].
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We found an overall HZ incidence of 6.7/1,000 PY, somewhat higher than the incidences of 2.3-
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6.5 per 1,000 PY (depending on age group) reported in the prospective study conducted in the
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city of Ansbach, Germany [22] but lower than the 9.4-10.5/1,000 PY observed in the German
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claims database analyses [18-21]. The trends observed in our study of HZ incidence increasing
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with age and higher for women than men are similar to those reported in the other German
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studies [18-21]. Our estimated overall HZ incidence is equivalent to the 7-8/1,000 PY reported
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from prospective studies conducted in other European countries [24, 25].
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Our estimate of the proportion of PHN, 11.9%, is within the range of estimates reported in other
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prospective studies using the same definition of PHN as used here, from 7.7 to 22% [2, 11, 24,
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25]. The German claims database studies reported much lower PHN proportions of 6-7% [18-
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21], but identification of PHN cases is notoriously difficult in claims databases and must be
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based on assumptions due to a lack of PHN-specific diagnosis codes in such databases [2].
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Three quarters of the patients returned a completed ZBPI questionnaire 90 days after rash onset.
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Calculating the proportion of PHN including only the patients who returned a completed ZBPI
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questionnaire would thus result in a higher proportion than the 11.9% reported here. Taking the
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conservative approach of assuming that patients who stopped completing the ZBPI questionnaire
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before time were less likely to still have significant pain may, however, have led to a certain
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underestimation of the proportion of PHN, as patients may have dropped out of the study for
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other reasons than resolution of pain. The possible bias due to differential loss to follow-up with
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unknown causes is a problem for prospective observational studies [26].
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We identified only the severity of HZ-related pain at the initial visit as predictor of PHN, which
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is consistent with other studies that have identified the severity of acute pain as a statistically
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significant predictor, alongside the severity of rash and increasing age [11,15,27]. Recent studies
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using the same assessment tools and PHN definition as used in our study, have reported
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conflicting findings with regard to age as a predictor of PHN when controlling for a number of
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other possible predictors in multivariate analyses [11,15,28]. Moreover, the logistic regression
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analysis was performed including only the patients with a completed ZBPI questionnaire 90 days
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after rash onset to ensure the accuracy of the PHN diagnosis. This approach avoided imputing a
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non-PHN status with unknown PHN status, as this could have introduced confounding that could
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not be controlled for by statistical adjustment.
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One of the claims database studies in Germany also estimated the costs of HZ disease from both
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the HCS and societal perspectives. The estimates for patients aged 50 years and older were
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average costs of €222 for an HZ case and €1,039 for a PHN case from the healthcare payer
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perspective and €353 and €1,298, respectively, from the societal perspective [20]. These cost
334
estimates are considerably higher than our estimates. Part of the difference may be explained by
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the proportion of patients hospitalized, which was 3.2% in the study by Ultsch et al. [20] and
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1.4% in our study. With regard to hospitalizations, a retrospective claims database analysis
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would be expected to generate more complete and accurate data than a prospective study
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recruiting patients in the primary setting, which may underestimate the proportion of hospitalized
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HZ patients who might have presented directly at the hospital instead of at an ambulatory
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healthcare setting. Another important difference is the average number of days of sick leave for 17 Page 17 of 31
341
working patients, which were 15.1 days in the study by Ultsch et al. [20] and 7.7 days in our
342
study.
343
Compared to similar studies, the use of medical resources was very limited for the patients in our
344
study, with a mean of one GP consultation per patient, 9% of the patients visiting a specialist (or
345
referred) and 1% being hospitalized. In the UK, 26% of the HZ patients had follow-up GP visits
346
but only 1% was hospitalized [29]. Even for PHN patients in the UK, hospitalization was rare but
347
on average they consulted a healthcare professional 9.5 times in relation to their PHN [29]. In a
348
similar study in South Korea, HZ patients visited their GP on average 7.0 times for their HZ,
349
55% consulted specialists and 33% were hospitalized, on average for 8.9 days [30]. These
350
differences in the use of medical resources may probably be explained by study populations,
351
differences between countries in standards of care, treatment patterns and patient expectations or
352
attitudes.
353
In line with other studies, our study also showed that subjects with PHN had higher costs as
354
compared with subjects who had HZ only [20,31-33]. However, when considering the overall
355
burden of disease, the overall cost of acute HZ is higher than that for PHN [31]. The overall costs
356
of HZ are likely to increase due to aging of the population [33,34].
357
One of the limitations of our study is that it did not include all primary care physicians in the
358
study areas, so that an unknown number of HZ patients may have been missed. The study area
359
populations were adjusted to account for the proportion of physicians declining to participate but
360
it is unknown to what extent this adjustment and the corresponding assumptions succeeded in
361
obtaining more accurate study population sizes. This may have led to an underestimation of the
362
actual HZ incidence. Another limitation is that the participating physicians, who accepted to
363
participate in the study on a voluntary basis, may not be representative for the entire set of 18 Page 18 of 31
364
physicians working in the selected study areas that might be different from the other regions of
365
Germany.
366
Only one third of the eligible patients accepted to participate in the study. This self-selection of
367
patients has had as implication that the characteristics of the enrolled patients differ a little from
368
those of all the eligible patients. The fact that the enrolled patients were a little younger and
369
reported less severe acute HZ pain than the total group of eligible suggest that our study
370
population is healthier than the general older adult German population and therefore may have
371
led to an underestimation of the proportion of HZ patients developing PHN.
372
Strengths of the study are its prospective cohort design allowing simultaneous assessment of
373
several outcomes with direct recording of medical resource utilization, frequent assessments by
374
the patients using the robust and well-validated ZBPI instrument and establishment of the
375
temporal relationship for PHN and HZ-related complications. A further strength is that the
376
relative contribution of different potential risk factors for developing PHN was assessed by
377
multivariate statistical methods and backward selection procedures.
378
Conclusions
379
Our results documented the current clinical and economic burden of HZ and PHN in German
380
adults aged 50 years and older. We confirmed the rise of HZ incidence with increasing age and
381
the higher proportion of PHN in the oldest groups which also had the highest direct medical
382
costs, in particular for patients developing HZ-related complications. The ongoing demographic
383
changes in Germany, as well as throughout the world, with growing numbers of elderly and very
384
old people and of immunocompromised individuals make it likely that the burden of HZ disease
385
will increase considerably in the near future unless appropriate preventive strategies, such as
386
vaccination [35,36], are recommended and implemented in at-risk populations. 19 Page 19 of 31
387
List of Abbreviations:
388
CI: confidence interval; GP: general practitioner; HCS: healthcare system; HZ: Herpes zoster;
389
OR: odds ratio; PHN: Post-herpetic neuralgia; PY: person-years; VZV: varicella zoster virus;
390
YOA: years of age; ZBPI: zoster brief pain inventory
391
Funding Information:
392
GlaxoSmithKline Biologicals SA was the funding source and was involved in all study (e-track
393
number: 113206) activities and overall data management (collection, analysis and interpretation).
394
GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the
395
publishing of the present manuscript. All authors had full access to the data and the
396
corresponding author was responsible for submission of the publication.
397
Conflict of interest:
398
RSO, AG, AvK, EE, DC, AA and KG are employees of the GSK group of companies. DC, EE
399
and AA own stock options as part of their employee remuneration. SM is a freelance consultant
400
working on behalf of GSK (Wavre, Belgium). JS has nothing to disclose. US received a grant
401
from the GSK group of companies (as payment for advisory-board meeting) outside the
402
submitted work. BPN reports personal fees from the GSK group of companies during and
403
outside the conduct of the study.
404
Authors’ contributions:
405
RSO, AG and US participated in the conception and design of the study. US, KG, EE and JS
406
participated in the collection or generation of the study data. DC, RSO, EE, JS and US performed
407
the study. AA, DC, EE and US contributed to the material. AA, DC, RSO, AvK, EE, US, SM,
408
KG, BPN and JS were involved in the analysis or interpretation of the data. All named authors
20 Page 20 of 31
409
provided substantial intellectual and scientific input during the manuscript development,
410
critically reviewing the content, revising the manuscript and giving final approval before
411
submission. The work described was carried out in accordance with the ICMJE
412
recommendations for conducting, reporting, editing and publishing scholarly work in medical
413
journals.
414
21 Page 21 of 31
415
Acknowledgments:
416
The authors would like to thank Christian Neurohr, Franziska Feldl and Karolien Peeters for
417
their contribution to the study. They would also like to thank the Business & Decision Life
418
Sciences platform for editorial assistance and coordination, on behalf of GSK. Niels Neymark
419
provided writing support. Gregory Collet coordinated manuscript development and editorial
420
support.
421
22 Page 22 of 31
422
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2. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open 2014; 4:e004833
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5. Arvin AM, Moffat JF, Redman R. Varicella-zoster virus aspects of pathogenesis and host response to natural infection and varicella vaccine. Adv Virus Res 1996; 46: 263-309.
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8. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007; 82: 1341-9.
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9. Studahl M, Petzold M, Cassel T. Disease burden of herpes zoster in Sweden - predominance in the elderly and in women - a register based study. BMC Infect Dis 2013; 13: 586.
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10. Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology. 2013; 81: 92830.
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11. Drolet M, Brisson M, Schmader K, Levin M, Johnson R, Oxman M et al. Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study. J Pain 2010; 11: 1211-21.
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12. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicellazoster virus infections. Clin Microbiology Rev 2013; 26: 728-43.
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13. Johnson RW, Bouhassira D, Kassianos G, Leplège A, Schmader KE, Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med 2010; 8: 37.
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14. Serpell M, Gater A, Carroll S, Abetz-Webb L, Mannan A, Johnson R. Burden of postherpetic neuralgia in a sample of UK residents aged 50 years or older: findings from the zoster quality of life (ZQOL) study. Health Qual Life Outcomes 2014; 12: 92.
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15. Kawai K, Rampakakis E, Tsai TF, Cheong HJ, Dhitavat J, Covarrubias AO et al. Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia. Int J Infect Dis 2015; 34: 126-31.
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16. Sundström K, Weibull CE, Söderberg-Löfdal K, Bergström T, Sparén P, Arnheim-Dahlström L. Incidents of herpes zoster and associated events including stroke - a population based cohort study. BMC Infect Dis 2015; doi: 10.1186/s12879-015-1170-y
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17. Duracinsky M, Paccalin M, Gavazzi G, El Kebir S, Gaillat J, Strady C et al. ARIZONA study: is the risk of post-herpetic neuralgia and its burden increased in the most elderly patients? BMC Infect Dis 2014; doi: 10.1186/1471-2334-14-529
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18. Schiffner-Rohe J, Jow S, Lilie HM, Köster I, Schubert I. Herpes zoster in Germany. A retrospective analysis of SHL data. (in German). MMW Fortschr Med 2010; 151 (Suppl. 4): 1937.
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19. Ultsch B, Siedler A, Rieck T, Reinhold T, Krause G, Wichmann O. Herpes zoster in Germany: Quantifying the burden of disease. BMC Infect Dis 2011; 11: 173.
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20. Ultsch B, Köster I, Reinhold T, Siedler A, Krause G, Icks A et al. Epidemiology and cost of herpes zoster and postherpetic neuralgia in Germany. Eur J Health Econ 2013; 14: 1015-26.
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21. Hillebrand K, Bricout H, Schulze-Rath R, Schink T, Garbe E. Incidence of herpes zoster and its complications in Germany, 2005 - 2009. J Infect 2014; dx.doi.org/10.1016/j.jinf.2014.08.018.
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22. Paul E, Thiel T. Epidemiology of varicella zoster infection. Results of a prospective study in the Ansbach area. Hautarzt. 1996; 47: 604-9.
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23. Coplan PM, Schmader K, Nikas A, Chan IS, Choo P, Levin M et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 2004; 5: 344-56.
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24. Pinchinat S, Cebrian-Cuenca AM, Bricout H, Johnson RW. Silmilar herpes zoster incidence across Europe: results from a systematic literature review. BMC Infect Dis 2013; 13: 170.
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25. Bricout H, Perinetti E, Marchettini P, Ragni P, Zotti CM, Gabutti G et al. Burden of herpes zoster-associated chronic pain in Italian patients aged 50 years and over (2009-2010): a GPbased prospective cohort study. BMC Infect Dis 2014;14:637.
481 482
26. Grimes DA, Schulz KF. Cohort studies: Marching towards the outcome. Lancet 2002; 359: 341-5.
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27. Torcel-Pagnon L, Bricout H, Bertrand I, Perinetti E, Franco E, Gabutti G et al. Impact of underlying conditions on zoster-related pain and on quality of life following zoster. J Gerontol A Biol Med Sci 2017;72:1091-1097.
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28. Opstelten W, Zuithoff NP, van Essen GA, van Loon AM, van Wijck AJ, Kalkman CJ et al. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: Prospective prognostic study. Pain 2007; 132 (Suppl. 1): 52-9.
489 490 491
29. Gater A, Abetz-Webb L, Carroll S, Mannan A, Serpell M, Johnson R. Burden of herpes zoster in the UK: findings from the zoster quality of life (ZQOL) study. BMC Infect Dis 2014; 14: 402.
492 493 494
30. Song H, Lee J, Lee M, Choi WS, Lee MS, Hashemi M et al. Burden of illness, quality of life, and healthcare utilization among patients with herpes zoster in South Korea: a prospective clinical-epidemiological study. Int J Infect Dis 2014; 20: 23-30.
495 496
31. Gater A, Uhart M, McCool R, Préaud E. The humanistic, economic and societal burden of herpes zoster in Europe: a critical review. BMC Public Health 2015;15:193
497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522
32. Nilsson J, Cassel T, Lindquist L. Burden of herpes zoster and post-herpetic neuralgia in Sweden.BMC Infect Dis 2015; 15:215 33. Friesen KJ, Falk J, Alessi-Severini S, Chateau D, Bugden S. Price of pain: population-based cohort burden of disease analysis of medication cost of herpes zoster and postherpetic neuralgia. J Pain Res 2016;9:543-550. 34. Varghese L, Standaert B, Olivieri A, Curran D. The temporal impact of aging on the burden of herpes zoster. BMC Geriatr 2017;17:30. 35. Maggi S, Gabutti G, Franco E, Bonanni P, Conversano M, Ferro A et al. Preventing and managing herpes zoster: key actions to foster healthy aging. Agin Clin Exp Res 2015;27(1):5-11 36. Gabutti G, Bonanni P, Conversano M, Fanelli G, Franco E, Greco D et al. Prevention of Herpes Zoster and its complications: From clinical evidence to real life experience. Hum Vaccin Immunother 2017; 13 (2):1-8 37. Lauer Taxe: http://www2.lauer-fischer.de/produkte/lauer-taxe/lauer-taxe/
Figure 1. Map of Germany with study areas marked.
25 Page 25 of 31
523
Table 1. Estimated incidence of HZ in Germans ≥ 50 years old by gender and age Age group (years)
524 525 526 527
Women Incidence (per 1,000 PY) 95% CI
Men Incidence (per 1,000 PY)
95% CI
Overall Incidence (per 1,000 PY) 95% CI
50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 ≥80
3.8 6.0 7.8 8.3 8.0 11.2 9.6
3.0 - 4.7 4.9 - 7.2 6.5 - 9.3 6.9 - 9.8 6.8 - 9.4 9.5 - 13.0 8.3 - 11.0
3.3 5.0 4.6 5.9 6.2 7.9 9.2
2.6 - 4.2 4.0 - 6.1 3.6 - 2.9 4.7 - 7.3 5.0 - 7.5 6.3 - 9.7 7.5 - 11.2
3.6 5.5 6.3 7.2 7.2 9.7 9.4
3.0 - 4.2 4.7 - 6.3 5.5 - 7.3 6.2 - 8.2 6.3 - 8.1 8.5 - 11.0 8.4 - 10.6
Overall
7.6
7.1 - 8.1
5.6
5.2 - 6.1
6.7
6.4 - 7.1
HZ = Herpes zoster PY = Person-years CI = Exact Poisson confidence interval
26 Page 26 of 31
528
Table 2. Pain severity and clinical characteristics of the HZ patients at initial visit Characteristics Severity of HZ pain No or mild Moderate Severe Among patients having had symptoms before rash onset Prodromal pain Malaise Fever Other symptoms - non-painful Other symptoms - painful Patients with co-morbidities at initial visit Most frequent pre-existing conditions (> 5% of those with such conditions) Hypertension Diabetes mellitus Current emotional problems, stress or depression Heart disease Thyroid disease Patients under immunological treatment Under active immunosuppressive treatment Oral or parenteral corticosteroids
529 530 531 532 533 534 535 536 537
n
% 1
N = 502 103 215 184
20.5 42.8 36.7
N2 = 252 191 87 5 35 18
75.8 34.5 2.0 13.9 7.1
N3 = 315 105 75 51 43 24
33.3 23.8 16.2 13.7 7.6
N4 = 485 36 17
7.2 3.5
HZ = Herpes zoster n = Number of patients concerned N1 = For 11 patients, the initial pain assessment was missing N2 = The number of patients with symptoms before rash onsets N3 = The number of patients with co-morbidities N4 = Information missing for 28 patients
27 Page 27 of 31
538 539
Table 3. Proportion of PHN 90 days after the rash onset among the enrolled HZ patients by gender and age group Age group (years) 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 ≥80 Overall
540 541 542 543 544 545
N
n
%
95% CI
60 82 59 67 92 90 63 513
8 7 7 10 12 8 9 61
13.3 8.5 11.9 14.9 13.0 8.9 14.3 11.9
5.9-24.6 3.5-16.8 4.9-22.9 7.4-25.7 6.9-21.7 3.9-16.8 6.8-25.4 9.2-15.0
PHN = Postherpetic neuralgia CI = Confidence interval N = Number of patients of this gender in this age group enrolled n= Number of patients of this gender in this age group who had PHN HZ = Herpes zoster
28 Page 28 of 31
546 547
Table 4. Estimated coefficients of the fitted logistic regression model and the final model for potential risk factors for PHN Model
Risk factor
Coefficient
SE
OR*
95% CI for OR
p-value
Age (years): 60-69 vs 50-59** 70-79 vs 50-59** ≥80 vs 50-59** Gender Female vs male** -HZ-related complications Yes vs no** Current immunosuppressive therapy Yes vs no** Pre-existing medical condition Yes vs no** HZ severity at initial visit Moderate vs no/mild pain** Severe vs no/mild pain**
0.197 0.020 0.491
0.412 0.393 0.489
1.22 1.02 1.63
0.54 - 2.73 0.47 - 2.21 0.63 - 4.26
0.63 0.96 0.32
0.280
0.324
1.32
0.70 - 2.50
0.39
0.411
0.458
1.51
0.62 - 3.70
0.37
- 0.351
0.579
0.70
0.23 - 2.19
0.54
0.614
0.342
1.85
0.95 - 3.61
0.07
1.709 2.305
0.754 0.750
5.5 10.02
1.26 - 24.2 2.30 - 45.57
0.02 0.002
1.726 2.387
0.749 0.740
5.62 10.88
1.29 - 24.39 2.55 - 46.40
0.02 0.001
Saturated
Final HZ severity at initial visit Moderate vs no/mild pain** Severe vs no/mild pain**
548 549 550 551 552 553 554 555 556 557
PHN = Postherpetic neuralgia HZ = Herpes zoster SE = Standard error OR* = Adjusted odds ratio ** = Reference category CI = Confidence interval 95% CI for OR, determined as 95% Wald’s CI for OR The saturated model was developed by not following any model building strategy; final model was developed by following a backward model building strategy with p-value ≤ 0.05 as criterion for keeping a variable
29 Page 29 of 31
558
Table 5. Total mean costs by type of complications and age group (€) HZ category
Perspective
≥80 yrs N = 63
50 - 59 yrs N = 142
60 - 64 yrs N = 59
65 - 69 yrs N = 67
70 - 79 yrs N = 182
Overall N = 513
n
Mean (€)
n
Mean (€)
n
Mean (€)
n
Mean (€)
n
Mean (€)
n
Mean (€)
HCS Societal
124 124
115 471
45 45
92 297
49 49
93 109
150 150
94 108
51 51
100 116
419 419
101 237*
HCS Societal
15 15
620 1,456
7 7
134 444
10 10
114 136
20 20
516 552
9 9
103 117
61 61
371 630*
HCS
3
146
7
212
8
129
12
729
3
1279
33
471
Societal
3
167
7
1,003
8
157
12
776
3
1326
33
669*
HCS Societal
142 142
169 569
59 59
111 398
67 67
100 119
182 182
182 200
63 63
157 173
513 513
156 311*
HZ only
PHN
HZ with complication - no PHN All HZ cases
559 560 561 562 563 564 565 566 567 568 569 570 571
N = Number of patients enrolled in this age group yrs = Years HZ = Herpes zoster PHN = Postherpetic neuralgia n = Number of patients concerned * = Indirect costs due to work absence only occurred for patients still working (all of them younger than 65 years) but were averaged over all 513 patients to estimate the average total societal cost per HZ patient (and in each HZcategory) HCS = Healthcare system
30 Page 30 of 31
572 573
Figure 1.tif
31 Page 31 of 31
S0163-4453(18)30053-7 https://doi.org/10.1016/j.jinf.2018.02.001 YJINF 4052
To appear in:
Journal of Infection
Accepted date:
3-2-2018
Please cite this article as: Ruprecht Schmidt-Ott, Ulf Schutter, Jörg Simon, Barbara Poulsen Nautrup, Alfred von Krempelhuber, Kusuma Gopala, Anastassia Annastassopoulou, Adrienne Guignard, Desmond Curran, Sean Matthews, Emmanuelle Espié, Incidence and costs of herpes zoster and postherpetic neuralgia in german adults aged ≥50 years: a prospective study, Journal of Infection (2018), https://doi.org/10.1016/j.jinf.2018.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Research article
2
Manuscript Title (99/100 characters allowed):
3
Incidence and costs of herpes zoster and postherpetic neuralgia in German adults aged ≥50 years:
4
a prospective study
5
Authors: Ruprecht Schmidt-Otta, Ulf Schutterb, Jörg Simonc, Barbara Poulsen Nautrupd, Alfred
6
von Krempelhubere, Kusuma Gopalaf, Anastassia Annastassopouloue, Adrienne Guignarda,
7
Desmond Currana, Sean Matthewsg, Emmanuelle Espiéa*
8
Affiliations/Institutions:
9
a
GSK, Avenue Fleming 20, 1300 Wavre, Belgium
10
b
Facharztzentrum am Marienhospital und Marler Arztnetz, Hervester Str. 57, 45768 Marl,
11
Germany
12
c
Gesundheitsnetz Osthessen, Gerloser Weg 20, 36039 Fulda, Germany
13
d
EAH-Consulting, Karlsgraben 12, 52064 Aachen, Germany
14
e
GSK Germany, Prinzregentenplatz 9, 81675 München, Germany
15
f
GSK Pharmaceuticals, #5, Embassy links, SRT road, Cunningham road, 560052 Bangalore,
16
India
17
g
18
E-mail adresses:
19
Ruprecht Schmidt-Ott [email protected]
20
Ulf Schutter [email protected]
21
Jörg Simon [email protected]
22
Barbara Poulsen Nautrup [email protected]
23
Alfred von Krempelhuber [email protected]
Freelance c/o GSK, Avenue Fleming 20, 1300 Wavre, Belgium
1 Page 1 of 31
24
Kusuma Gopala [email protected]
25
Anastassia Annastassopoulou [email protected]
26
Adrienne Guignard [email protected]
27
Desmond Curran [email protected]
28
Sean Matthews [email protected]
29
Emmanuelle Espié [email protected]
30
* Corresponding author:
31 32 33 34 35
Name: Emmanuelle Espié R&D Clinical and Epidemiology Department GSK, Avenue Fleming, Wavre, Belgium Email: [email protected] Tel: +32 10 85 58 39
36
Running title (17/50 characters allowed): HZ burden in Germany
2 Page 2 of 31
37
Abstract
38
Objectives
39
Herpes zoster (HZ) mainly affects elderly people and immunocompromised individuals. HZ is
40
usually characterized by a unilateral painful skin rash. Its most common complication,
41
postherpetic neuralgia (PHN), may cause chronic debilitating pain. This study aimed to estimate
42
the HZ incidence in individuals aged ≥50 years in Germany, the proportion of PHN and the
43
economic burden.
44
Methods
45
From 2010 to 2014, HZ-patients were recruited when consulting physicians in physician
46
networks covering about 157,000 persons aged ≥50 years. PHN was defined as ‘worst pain’ rated
47
≥3 on the zoster brief pain inventory persisting or appearing over 90 days after rash onset. Costs
48
were calculated based on medical resource utilization and lost working time.
49
Results
50
HZ incidence was estimated as 6.7/1,000 person-years, increasing with age to 9.4/1000 in ≥80
51
year-olds. Among 513 HZ-patients enrolled, the proportion of PHN was 11.9%, rising with age
52
to 14.3% in HZ-patients ≥80 years. Estimated total cost per HZ-patient was €156 from the
53
healthcare system perspective and €311 from the societal perspective.
54
Conclusions
55
The study confirmed previous findings that HZ causes a substantial clinical and economic
56
burden in older German adults. It also confirmed the age-related increasing risk of HZ and PHN.
57
Trial registration: e-track number (113206)
3 Page 3 of 31
58
Keywords: Varicella zoster virus (VZV); herpes zoster (HZ); postherpetic neuralgia (PHN)
59
Word count: No limit indicated in author instructions
60
Abstract: 195/200
4 Page 4 of 31
61
Background
62
Varicella-zoster virus (VZV) is a DNA virus [1] causing varicella (chickenpox) and herpes
63
zoster (HZ, also called shingles), which is typically characterized by a painful, blistering,
64
unilateral dermatomal rash [2,3].
65
Following the resolution of a primary varicella infection, VZV establishes latency in the neurons
66
of sensory ganglia [4] and may later reactivate and cause HZ. Whereas it is not known what
67
triggers VZV reactivation and the subsequent development of HZ, it is clear that persons with
68
impaired cell-mediated immunity due to advanced age, underlying diseases or medical
69
interventions are at increased risk for developing HZ [5-7]. Based on prior published data, the
70
lifetime risk of developing HZ is estimated to be between 25 and 30% rising to 50% in people
71
aged 80 years or older [8-10]. The overall HZ incidence has been increasing linearly over the
72
past decades likely due to the aging of the population, an increasing number of
73
immunocompromised people [11], improved diagnostics and other unknown factors [2].
74
In most cases, the HZ rash heals and the pain ceases within approximately one month of rash
75
onset but in some cases, notably in elderly patients, the pain persists after the rash has healed and
76
may develop into postherpetic neuralgia (PHN), which is the most common complication of HZ
77
[2,12]. PHN is commonly defined as HZ-related pain persisting or appearing more than three
78
months after rash onset but there is no universally accepted definition [2,7,12].
79
Pathophysiological observations include damage to the sensory nerves, the sensory dorsal root
80
ganglia and the dorsal horn of the spinal cord [12].
81
PHN involves chronic pain and is a debilitating syndrome causing physical disability, interfering
82
with daily activities and sleep [13]. For most of the PHN patients, the pain ceases within months
83
but can last for more than one year after rash onset (reviewed in [2]). Identified risk factors for
5 Page 5 of 31
84
PHN vary somewhat across studies but consistent findings are that older age, greater pain in the
85
acute HZ phase and more severe rash are predictors of PHN [11,15].
86
A recent worldwide review reported overall incidence rates ranging from 3 to 5 per 1,000
87
person-years (PY) [2]. Age-specific incidence shows a steep increase over the age of 50, with
88
incidence rates of 5/1,000 PY for those 50-60 years of age (YOA), 6-7/1,000 PY for 70-80 YOA
89
and up to 10/1,000 PY for people over 90 YOA with no clearly observed geographical
90
differences [2]. The reported proportion of PHN among HZ patients varies widely, from 5% to
91
more than 30% [2]. This variation may be explained by differences in study design and settings,
92
the use of diverging definitions of PHN and age distributions of the study populations and also a
93
lack of objective pain measures [2].
94
In Germany, only one prospective study has been performed in 1992-93 in the city of Ansbach to
95
assess the incidence of HZ and chickenpox [22]. The most recent burden of disease studies were
96
all retrospective database studies using the Association of Statutory Health Insurance Physicians’
97
database containing nationwide routine outpatient data [18-21]. With the recent rising HZ
98
incidence observed elsewhere, these estimates may not correctly represent the current burden of
99
disease in Germany.
100
The aim of the present study was to provide an up-to-date estimation of the clinical and
101
economic burden of HZ disease in German adults aged 50 years and older as well as its impact
102
on patients’ quality of life. In this paper, we describe the age- and gender-specific incidence of
103
HZ, the proportion of PHN and other HZ-related complications in a defined population in three
104
selected regions of Germany. The estimated direct medical costs and the indirect costs due to
105
absence from work of patients and caregivers are also presented.
106
6 Page 6 of 31
107
Methods
108
Study design and study settings
109
This was a prospective observational cohort study conducted in general practices and certain
110
specialist practices in three different regions of Germany (Fulda, Leverkusen and Marl, see
111
Fig.1). The study areas were delimited by a number of postal codes encompassing a well-defined
112
geographical area served by a well-established network of primary care physicians including
113
some specialists. The catchment areas of the physician networks cover a total of about 157,000
114
persons aged 50 years and older. General practitioners (GPs), dermatologists and
115
ophthalmologists of the three networks were invited to participate on a voluntary basis.
116
Study population and case definition
117
Patient recruitment by participating physicians took place between November 2010 and
118
December 2014. All patients 50 years and older and diagnosed with a first episode of HZ at the
119
initial visit with one of the participating physicians were considered as eligible. Their age, gender
120
and residency were recorded to identify the number of eligible patients living inside or outside
121
the study areas, by age-group and gender. Participation in the study was proposed to all eligible
122
patients who were able to complete the questionnaires and provided a written consent.
123
HZ was defined as new unilateral rash accompanied by unilateral pain (including allodynia and
124
pruritus) and no alternative diagnosis. The severity of HZ-related pain at the initial visit was
125
assessed using the zoster brief pain inventory (ZBPI) questionnaire [23]. The 11-point ZBPI
126
scale is divided into four categories of pain: no pain (0); mild (1 - 2); moderate (3 - 6); and
127
severe (7 - 10). PHN was defined as the presence of moderate or severe (≥3 on the ZBPI scale)
7 Page 7 of 31
128
‘worst pain’ (i.e., pain at its worst during the last 24 hours) persisting or appearing more than 90
129
days after rash onset.
130
Data collection
131
At the initial visit of each patient enrolled in the study, the physicians recorded the patient’s
132
demographic data (age, gender, and residency) and employment status. They further performed a
133
medical examination to record the clinical characteristics of HZ, assessed the severity of HZ-
134
related pain using the ZBPI scale and enquired about the occurrence of prodromal symptoms.
135
Medical history and co-morbidities, including immunosuppressive conditions, were also
136
documented as well as previous and current medication, including self-prescribed therapies. HZ-
137
related complications (such as HZ ophthalmicus or oticus) were recorded at any physician visit
138
during the nine-month follow-up after the initial visit.
139
During the follow-up, the patients were asked to complete the ZBPI questionnaire about their
140
pain condition 15, 30, 60 and 90 days (+/- 7 days) after the initial visit and return them to the
141
physician. At Day 90, patients with ZBPI ‘worst pain’ score < 3 were considered as not having
142
developed PHN and were not followed further. Patients with PHN at Day 90 (ZBPI ‘worst pain’
143
score ≥3) were followed for another three months and were asked to complete and return the
144
questionnaire at Days 120, 150 and 180 after the initial visit.
145
At Day 180, only patients with PHN still having a ZBPI ‘worst pain’ score ≥ 3 at that time point
146
were required to provide subsequent assessments for three additional months to complete the
147
follow-up of nine months after the initial visit (at Days 210, 240 and 270). HZ-related
148
complications were recorded during the entire study period (until Day 270).
8 Page 8 of 31
149
To estimate the costs of disease, at the initial visit, the physician recorded any prior use of
150
medical resources related to the HZ episode and the visit itself. The patients were then provided
151
with a booklet to be completed by any medical care provider encountered in relation to HZ
152
during the 90 days (+/- 7) after the initial visit. Patients with PHN at Day 90 and continuing in
153
follow-up were asked to have any subsequent HZ-related medical care recorded until the end of
154
follow-up. The resources recorded included GP and specialist visits, hospital outpatient visits and
155
admissions, procedures and tests performed, and medications taken. Unit costs for GP and
156
specialist visits, procedures and medications were taken from official sources (Table SM1). The
157
costs of inpatient treatment of HZ patients 50 years and older were taken from a previous
158
German study [20] adjusted according to the consumer price index for medical services. As the
159
study was carried out in a primary care setting, some hospitalizations and all specialist visits
160
were only reported as referrals. Cost calculations were made assuming costs for all referrals.
161
Patients in active employment were asked to record the number of days of absence from work
162
because of HZ or PHN. Likewise, patients receiving care from personal caregivers who needed
163
to be absent from work to be able to care for the patient, were to record the days of absence from
164
work of their caregiver. The number of days of absence recorded were multiplied by the national
165
average daily earnings (for the patients’ absence from work, stratified for gender and age) to
166
estimate the indirect costs due to HZ and PHN (Table SM1).
167
Costs were calculated from both the healthcare system (HCS) and the societal perspective. The
168
main difference between the two perspectives, apart from patient co-payment for certain types of
169
medical care and medications, is that the societal perspective includes the indirect costs caused
170
by patients’ and caregivers’ absence from work.
9 Page 9 of 31
171
Statistical analysis
172
The HZ incidence was calculated as the number of eligible HZ cases divided by the study
173
population living in the study areas defined by the three participating networks of physicians. In
174
order to estimate the size of the study population to use as denominator for this calculation, the
175
population of people 50 years and older in each study area was extrapolated from 2011 census
176
data (Federal Statistical Office and the Statistical Offices of the Länder) and was adjusted to take
177
into account that physicians were free to decline participation in the study or to stop participating
178
at any time during the study period. The study population was weighted by combining the total
179
population with the mean number of eligible HZ cases per physician per specialty and the
180
proportion of participating physicians relative to all that could have participated. Separate
181
denominators were calculated for each study area, overall and by age group. HZ incidence was
182
estimated per 1,000 PY with exact 95% confidence intervals (CI), overall and stratified by
183
gender and age groups.
184
The proportion of HZ patients developing PHN was calculated with exact 95% CI overall and
185
stratified by gender and age groups. The proportion of patients with PHN persisting at six and
186
nine months after rash onset was reported in a similar way. Demographic characteristics, medical
187
history of HZ and PHN patients and characteristics of HZ and PHN episodes (severity,
188
symptoms, presence of complications) were described.
189
Exploratory analyses
190
To investigate potential risk factors for developing PHN, multivariate logistic regression
191
analyses were performed on the patients returning a completed ZBPI questionnaire 90 days after
192
the rash onset. Based on risk factors for PHN identified in previous published studies [11], the 10 Page 10 of 31
193
following potential risk factors were considered: age, gender, co-morbidities, current
194
immunosuppressive therapy and HZ-related pain severity at the initial visit. Using the backward
195
elimination strategy (with p-value of 0.05 as the threshold to keep a variable in the model) and
196
the method of maximum likelihood, the final model was used to identify any statistically
197
significant risk factors.
198
All analyses were carried out using SAS software.
199
Ethics
200
The study was conducted in accordance with ethical principles originating in the Declaration of
201
Helsinki, the principles of “good clinical practice” and all applicable regulatory requirements.
202
The protocol was reviewed and approved by the ethics committees of the study areas and all
203
enrolled participant gave written informed consent.
204
Results
205
Overall incidence of HZ
206
The number of physicians that participated in the study as well as the number collaborating in the
207
networks varied over the study period from November 2010 to December 2014. On average,
208
about one third of the 403 physicians working in the study areas (125/342 GPs, 6/24
209
dermatologists and 6/27 ophthalmologists) participated at least some of the time of the study
210
period. A total of 1,551 individuals aged 50 years and older were diagnosed with a first episode
211
of HZ during the study period.
11 Page 11 of 31
212
The overall HZ incidence was estimated as 6.7 per 1,000 PY (95% CI: 6.4 - 7.1) (Table 1),
213
increasing with age from 4.4 per 1,000 PY for individuals aged 50-59 years to 9.4 per 1,000 PY
214
for individuals aged ≥80 years (Table 1). The overall HZ incidence was 7.6 per 1,000 PY (95%
215
CI: 7.1 - 8.1) in women and 5.6 (95% CI: 5.2 - 6.1) in men.
216
Patient demographics
217
Among the 1,551 eligible HZ patients, 513 were enrolled in the study. The majority, 63%, was
218
female, 35.5% belonged to the 70-79 years age group and the mean age was 67.8 years (range:
219
49-95). Most were retired but 30%, all younger than 65, were still working or seeking work as
220
unemployed.
221
The gender distribution of the patients enrolled was identical to that of the eligible patients
222
whereas the enrolled patients were slightly younger than the eligible, with a higher proportion in
223
the group aged 50-59 years (27.7% and 22.4%, respectively).
224
Clinical features of the patients with HZ
225
The mean delay between rash onset and the initial visit was 3.7 days (range 0-34 days). At the
226
initial visit, 36.7% of the patients were deemed to have severe HZ-related pain using the ZBPI
227
‘worst pain’ scale, 42.8% moderate and 20.5% mild or no pain. Almost half (49.1%, 252/513)
228
the patients reported having experienced one or more symptoms before the onset of rash. Of
229
these, 75.8% (191/252) reported prodromal pain and 34.5% (87/252) had experienced malaise
230
(Table 2). In total, 419 patients presented a localized rash (restricted to one area of the body),
231
including seven with HZ ophthalmicus and two with HZ oticus, whereas 25 patients reported
232
widespread skin lesions. One or more pre-existing medical condition(s) were reported by 62.7%
12 Page 12 of 31
233
(315/513) of the patients, the most frequent of which were hypertension (33.3%, 105/315),
234
diabetes mellitus (14.6%, 75/513), current emotional problems, stress or depression (9.9%,
235
51/513) and cardiovascular diseases (8.4%, 43/513). Thirty-six patients reported being under
236
active immunosuppressive treatment, including corticosteroids and chemotherapy.
237
Among the patients without PHN, 37 (7.2% of all the enrolled) experienced other HZ-related
238
complications such as peripheral nerve palsies, disseminated VZV, bacterial superinfections and
239
diverse neurological problems.
240
Proportion of HZ patients developing PHN and characteristics of patients with PHN
241
The ZBPI questionnaire was completed by 388 of the 513 patients three months after the initial
242
visit, by 38 six months after and by 20 nine months after (Figure SM1). The proportion of HZ
243
patients with PHN appearing or persisting 90 days after the rash onset was 11.9% (95%CI: 9.2-
244
15.0%), higher in women (13.3%; 95%CI: 9.8-17.5%) than in men (9.5%; 95%CI: 5.7-14.6) and
245
increasing with age from 10.6% (95%CI: 6.0-16.8%) in those aged 50-59 years to 14.3%
246
(95%CI: 6.8-25.4%) in patients aged ≥80 years (Table 3). However, no significant statistical
247
difference was observed between age-groups. Six and nine months after the rash onset, the
248
respective proportions of patients with persistent PHN were 4.9% (95%CI: 3.2-7.1%) and 2.9%
249
(95%CI: 1.7-4.8%). Two patients still reported severe pain (ZBPI ‘worst pain’ score ≥ 7) 270
250
days after the rash onset.
251
The mean age of the 61 HZ patients with PHN was 68.3 years old (range 50-89 YOA), 70.5%
252
were women. More than half the patients with PHN (56.7%) reported experiencing one or more
253
symptoms before the rash onset, most frequently (82.4% of these) prodromal pain. Most, 74.6%,
13 Page 13 of 31
254
reported one or more pre-existing medical conditions, most frequently diabetes mellitus. Eleven
255
(18.0%) experienced other HZ-related complications in addition to PHN.
256
Predictive factors for PHN
257
The final logistic regression model showed that the severity of HZ-related pain at the initial visit
258
was the only statistically significant predictor for PHN (Table 4). The estimated odds ratio (OR)
259
for moderate pain versus no/mild pain was 5.6 (p-value = 0.02) and for severe pain versus
260
no/mild pain it was OR = 10.9 (p-value = 0.001).
261
Resource utilization and costs
262
A total of 641 GP visits were recorded amounting to an average of 1.25 visits per patient.
263
However, only 1.04 visits per patient were considered chargeable, as visits occurring during the
264
same quarter are only paid for once (as explained in Table SM1). Ninety-four specialist visits
265
were reported for 44 patients. Eight hospitalizations were documented for seven patients, four of
266
these only as referrals. The procedures most frequently reported were blood collection for
267
diverse tests and dressing of the dermatological area with rash, for 2.3% and 1.9% of the
268
patients, respectively. The most commonly used prescription medications were antivirals for
269
systemic use (51.9% of the patients), analgesics (49.7%), anesthetics (35.7%) and
270
ophthalmologicals (29.8%).
271
Sixty patients were absent from work due to their HZ, on average for 7.7 working days. Eight
272
caregivers (only three of whom were in paid employment) were reported to have been absent
273
from their normal work, on average for 8.0 working days, to provide care for the HZ patient.
14 Page 14 of 31
274
The estimated average direct medical cost per HZ patient amounted to €152 when assessed from
275
the HCS perspective and to €169 from the societal perspective (Table SM2). These amounts
276
were derived by averaging each cost component over all 513 patients and adding them. The main
277
cost components per patient from both perspectives were medications (€55 and €69 from the
278
HCS and societal perspective, respectively), hospitalizations (€55 and €56) and GP visits (€33
279
from both perspectives). The direct medical costs varied across the age groups but not
280
monotonically.
281
Indirect costs were only incurred for patients under 65 and the patients with caregivers losing
282
time from work were also in this younger age group. The estimates of indirect costs are
283
presented in Table SM3 with the average societal costs per patient concerned amounting to
284
approximately €1,200.
285
The estimated average total costs per HZ patient amounted to €156 from the HCS and €311 from
286
the societal perspective (Table 5). From the societal perspective, costs for the patients concerned
287
were the highest for those younger than 65 because of the high indirect costs for patients still
288
working, but to determine the average total societal costs the indirect costs were averaged over
289
all 513 patients. Costs were the highest for patients with HZ-related complications other than
290
PHN and the lowest for patients with HZ who did not develop PHN and/or other HZ-related
291
complications. Focusing only on the patients actually concerned, we estimated the highest costs
292
(from either perspective) for the oldest patients with HZ-related complications other than PHN.
293
Discussion
294
This is the first prospective cohort study conducted in Germany to estimate the HZ incidence
295
focusing on people aged 50 years and older, to estimate the proportion of HZ patients who 15 Page 15 of 31
296
develop PHN and to assess the economic burden of HZ disease. It was based on data collected
297
from patients consulting physicians in the primary healthcare setting for an acute episode of HZ
298
whereas other recent studies of the disease burden of HZ and PHN in Germany have been
299
performed on claims databases [18-21].
300
We found an overall HZ incidence of 6.7/1,000 PY, somewhat higher than the incidences of 2.3-
301
6.5 per 1,000 PY (depending on age group) reported in the prospective study conducted in the
302
city of Ansbach, Germany [22] but lower than the 9.4-10.5/1,000 PY observed in the German
303
claims database analyses [18-21]. The trends observed in our study of HZ incidence increasing
304
with age and higher for women than men are similar to those reported in the other German
305
studies [18-21]. Our estimated overall HZ incidence is equivalent to the 7-8/1,000 PY reported
306
from prospective studies conducted in other European countries [24, 25].
307
Our estimate of the proportion of PHN, 11.9%, is within the range of estimates reported in other
308
prospective studies using the same definition of PHN as used here, from 7.7 to 22% [2, 11, 24,
309
25]. The German claims database studies reported much lower PHN proportions of 6-7% [18-
310
21], but identification of PHN cases is notoriously difficult in claims databases and must be
311
based on assumptions due to a lack of PHN-specific diagnosis codes in such databases [2].
312
Three quarters of the patients returned a completed ZBPI questionnaire 90 days after rash onset.
313
Calculating the proportion of PHN including only the patients who returned a completed ZBPI
314
questionnaire would thus result in a higher proportion than the 11.9% reported here. Taking the
315
conservative approach of assuming that patients who stopped completing the ZBPI questionnaire
316
before time were less likely to still have significant pain may, however, have led to a certain
317
underestimation of the proportion of PHN, as patients may have dropped out of the study for
16 Page 16 of 31
318
other reasons than resolution of pain. The possible bias due to differential loss to follow-up with
319
unknown causes is a problem for prospective observational studies [26].
320
We identified only the severity of HZ-related pain at the initial visit as predictor of PHN, which
321
is consistent with other studies that have identified the severity of acute pain as a statistically
322
significant predictor, alongside the severity of rash and increasing age [11,15,27]. Recent studies
323
using the same assessment tools and PHN definition as used in our study, have reported
324
conflicting findings with regard to age as a predictor of PHN when controlling for a number of
325
other possible predictors in multivariate analyses [11,15,28]. Moreover, the logistic regression
326
analysis was performed including only the patients with a completed ZBPI questionnaire 90 days
327
after rash onset to ensure the accuracy of the PHN diagnosis. This approach avoided imputing a
328
non-PHN status with unknown PHN status, as this could have introduced confounding that could
329
not be controlled for by statistical adjustment.
330
One of the claims database studies in Germany also estimated the costs of HZ disease from both
331
the HCS and societal perspectives. The estimates for patients aged 50 years and older were
332
average costs of €222 for an HZ case and €1,039 for a PHN case from the healthcare payer
333
perspective and €353 and €1,298, respectively, from the societal perspective [20]. These cost
334
estimates are considerably higher than our estimates. Part of the difference may be explained by
335
the proportion of patients hospitalized, which was 3.2% in the study by Ultsch et al. [20] and
336
1.4% in our study. With regard to hospitalizations, a retrospective claims database analysis
337
would be expected to generate more complete and accurate data than a prospective study
338
recruiting patients in the primary setting, which may underestimate the proportion of hospitalized
339
HZ patients who might have presented directly at the hospital instead of at an ambulatory
340
healthcare setting. Another important difference is the average number of days of sick leave for 17 Page 17 of 31
341
working patients, which were 15.1 days in the study by Ultsch et al. [20] and 7.7 days in our
342
study.
343
Compared to similar studies, the use of medical resources was very limited for the patients in our
344
study, with a mean of one GP consultation per patient, 9% of the patients visiting a specialist (or
345
referred) and 1% being hospitalized. In the UK, 26% of the HZ patients had follow-up GP visits
346
but only 1% was hospitalized [29]. Even for PHN patients in the UK, hospitalization was rare but
347
on average they consulted a healthcare professional 9.5 times in relation to their PHN [29]. In a
348
similar study in South Korea, HZ patients visited their GP on average 7.0 times for their HZ,
349
55% consulted specialists and 33% were hospitalized, on average for 8.9 days [30]. These
350
differences in the use of medical resources may probably be explained by study populations,
351
differences between countries in standards of care, treatment patterns and patient expectations or
352
attitudes.
353
In line with other studies, our study also showed that subjects with PHN had higher costs as
354
compared with subjects who had HZ only [20,31-33]. However, when considering the overall
355
burden of disease, the overall cost of acute HZ is higher than that for PHN [31]. The overall costs
356
of HZ are likely to increase due to aging of the population [33,34].
357
One of the limitations of our study is that it did not include all primary care physicians in the
358
study areas, so that an unknown number of HZ patients may have been missed. The study area
359
populations were adjusted to account for the proportion of physicians declining to participate but
360
it is unknown to what extent this adjustment and the corresponding assumptions succeeded in
361
obtaining more accurate study population sizes. This may have led to an underestimation of the
362
actual HZ incidence. Another limitation is that the participating physicians, who accepted to
363
participate in the study on a voluntary basis, may not be representative for the entire set of 18 Page 18 of 31
364
physicians working in the selected study areas that might be different from the other regions of
365
Germany.
366
Only one third of the eligible patients accepted to participate in the study. This self-selection of
367
patients has had as implication that the characteristics of the enrolled patients differ a little from
368
those of all the eligible patients. The fact that the enrolled patients were a little younger and
369
reported less severe acute HZ pain than the total group of eligible suggest that our study
370
population is healthier than the general older adult German population and therefore may have
371
led to an underestimation of the proportion of HZ patients developing PHN.
372
Strengths of the study are its prospective cohort design allowing simultaneous assessment of
373
several outcomes with direct recording of medical resource utilization, frequent assessments by
374
the patients using the robust and well-validated ZBPI instrument and establishment of the
375
temporal relationship for PHN and HZ-related complications. A further strength is that the
376
relative contribution of different potential risk factors for developing PHN was assessed by
377
multivariate statistical methods and backward selection procedures.
378
Conclusions
379
Our results documented the current clinical and economic burden of HZ and PHN in German
380
adults aged 50 years and older. We confirmed the rise of HZ incidence with increasing age and
381
the higher proportion of PHN in the oldest groups which also had the highest direct medical
382
costs, in particular for patients developing HZ-related complications. The ongoing demographic
383
changes in Germany, as well as throughout the world, with growing numbers of elderly and very
384
old people and of immunocompromised individuals make it likely that the burden of HZ disease
385
will increase considerably in the near future unless appropriate preventive strategies, such as
386
vaccination [35,36], are recommended and implemented in at-risk populations. 19 Page 19 of 31
387
List of Abbreviations:
388
CI: confidence interval; GP: general practitioner; HCS: healthcare system; HZ: Herpes zoster;
389
OR: odds ratio; PHN: Post-herpetic neuralgia; PY: person-years; VZV: varicella zoster virus;
390
YOA: years of age; ZBPI: zoster brief pain inventory
391
Funding Information:
392
GlaxoSmithKline Biologicals SA was the funding source and was involved in all study (e-track
393
number: 113206) activities and overall data management (collection, analysis and interpretation).
394
GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the
395
publishing of the present manuscript. All authors had full access to the data and the
396
corresponding author was responsible for submission of the publication.
397
Conflict of interest:
398
RSO, AG, AvK, EE, DC, AA and KG are employees of the GSK group of companies. DC, EE
399
and AA own stock options as part of their employee remuneration. SM is a freelance consultant
400
working on behalf of GSK (Wavre, Belgium). JS has nothing to disclose. US received a grant
401
from the GSK group of companies (as payment for advisory-board meeting) outside the
402
submitted work. BPN reports personal fees from the GSK group of companies during and
403
outside the conduct of the study.
404
Authors’ contributions:
405
RSO, AG and US participated in the conception and design of the study. US, KG, EE and JS
406
participated in the collection or generation of the study data. DC, RSO, EE, JS and US performed
407
the study. AA, DC, EE and US contributed to the material. AA, DC, RSO, AvK, EE, US, SM,
408
KG, BPN and JS were involved in the analysis or interpretation of the data. All named authors
20 Page 20 of 31
409
provided substantial intellectual and scientific input during the manuscript development,
410
critically reviewing the content, revising the manuscript and giving final approval before
411
submission. The work described was carried out in accordance with the ICMJE
412
recommendations for conducting, reporting, editing and publishing scholarly work in medical
413
journals.
414
21 Page 21 of 31
415
Acknowledgments:
416
The authors would like to thank Christian Neurohr, Franziska Feldl and Karolien Peeters for
417
their contribution to the study. They would also like to thank the Business & Decision Life
418
Sciences platform for editorial assistance and coordination, on behalf of GSK. Niels Neymark
419
provided writing support. Gregory Collet coordinated manuscript development and editorial
420
support.
421
22 Page 22 of 31
422
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11. Drolet M, Brisson M, Schmader K, Levin M, Johnson R, Oxman M et al. Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study. J Pain 2010; 11: 1211-21.
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12. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicellazoster virus infections. Clin Microbiology Rev 2013; 26: 728-43.
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13. Johnson RW, Bouhassira D, Kassianos G, Leplège A, Schmader KE, Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med 2010; 8: 37.
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14. Serpell M, Gater A, Carroll S, Abetz-Webb L, Mannan A, Johnson R. Burden of postherpetic neuralgia in a sample of UK residents aged 50 years or older: findings from the zoster quality of life (ZQOL) study. Health Qual Life Outcomes 2014; 12: 92.
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16. Sundström K, Weibull CE, Söderberg-Löfdal K, Bergström T, Sparén P, Arnheim-Dahlström L. Incidents of herpes zoster and associated events including stroke - a population based cohort study. BMC Infect Dis 2015; doi: 10.1186/s12879-015-1170-y
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17. Duracinsky M, Paccalin M, Gavazzi G, El Kebir S, Gaillat J, Strady C et al. ARIZONA study: is the risk of post-herpetic neuralgia and its burden increased in the most elderly patients? BMC Infect Dis 2014; doi: 10.1186/1471-2334-14-529
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18. Schiffner-Rohe J, Jow S, Lilie HM, Köster I, Schubert I. Herpes zoster in Germany. A retrospective analysis of SHL data. (in German). MMW Fortschr Med 2010; 151 (Suppl. 4): 1937.
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21. Hillebrand K, Bricout H, Schulze-Rath R, Schink T, Garbe E. Incidence of herpes zoster and its complications in Germany, 2005 - 2009. J Infect 2014; dx.doi.org/10.1016/j.jinf.2014.08.018.
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32. Nilsson J, Cassel T, Lindquist L. Burden of herpes zoster and post-herpetic neuralgia in Sweden.BMC Infect Dis 2015; 15:215 33. Friesen KJ, Falk J, Alessi-Severini S, Chateau D, Bugden S. Price of pain: population-based cohort burden of disease analysis of medication cost of herpes zoster and postherpetic neuralgia. J Pain Res 2016;9:543-550. 34. Varghese L, Standaert B, Olivieri A, Curran D. The temporal impact of aging on the burden of herpes zoster. BMC Geriatr 2017;17:30. 35. Maggi S, Gabutti G, Franco E, Bonanni P, Conversano M, Ferro A et al. Preventing and managing herpes zoster: key actions to foster healthy aging. Agin Clin Exp Res 2015;27(1):5-11 36. Gabutti G, Bonanni P, Conversano M, Fanelli G, Franco E, Greco D et al. Prevention of Herpes Zoster and its complications: From clinical evidence to real life experience. Hum Vaccin Immunother 2017; 13 (2):1-8 37. Lauer Taxe: http://www2.lauer-fischer.de/produkte/lauer-taxe/lauer-taxe/
Figure 1. Map of Germany with study areas marked.
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523
Table 1. Estimated incidence of HZ in Germans ≥ 50 years old by gender and age Age group (years)
524 525 526 527
Women Incidence (per 1,000 PY) 95% CI
Men Incidence (per 1,000 PY)
95% CI
Overall Incidence (per 1,000 PY) 95% CI
50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 ≥80
3.8 6.0 7.8 8.3 8.0 11.2 9.6
3.0 - 4.7 4.9 - 7.2 6.5 - 9.3 6.9 - 9.8 6.8 - 9.4 9.5 - 13.0 8.3 - 11.0
3.3 5.0 4.6 5.9 6.2 7.9 9.2
2.6 - 4.2 4.0 - 6.1 3.6 - 2.9 4.7 - 7.3 5.0 - 7.5 6.3 - 9.7 7.5 - 11.2
3.6 5.5 6.3 7.2 7.2 9.7 9.4
3.0 - 4.2 4.7 - 6.3 5.5 - 7.3 6.2 - 8.2 6.3 - 8.1 8.5 - 11.0 8.4 - 10.6
Overall
7.6
7.1 - 8.1
5.6
5.2 - 6.1
6.7
6.4 - 7.1
HZ = Herpes zoster PY = Person-years CI = Exact Poisson confidence interval
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528
Table 2. Pain severity and clinical characteristics of the HZ patients at initial visit Characteristics Severity of HZ pain No or mild Moderate Severe Among patients having had symptoms before rash onset Prodromal pain Malaise Fever Other symptoms - non-painful Other symptoms - painful Patients with co-morbidities at initial visit Most frequent pre-existing conditions (> 5% of those with such conditions) Hypertension Diabetes mellitus Current emotional problems, stress or depression Heart disease Thyroid disease Patients under immunological treatment Under active immunosuppressive treatment Oral or parenteral corticosteroids
529 530 531 532 533 534 535 536 537
n
% 1
N = 502 103 215 184
20.5 42.8 36.7
N2 = 252 191 87 5 35 18
75.8 34.5 2.0 13.9 7.1
N3 = 315 105 75 51 43 24
33.3 23.8 16.2 13.7 7.6
N4 = 485 36 17
7.2 3.5
HZ = Herpes zoster n = Number of patients concerned N1 = For 11 patients, the initial pain assessment was missing N2 = The number of patients with symptoms before rash onsets N3 = The number of patients with co-morbidities N4 = Information missing for 28 patients
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538 539
Table 3. Proportion of PHN 90 days after the rash onset among the enrolled HZ patients by gender and age group Age group (years) 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 79 ≥80 Overall
540 541 542 543 544 545
N
n
%
95% CI
60 82 59 67 92 90 63 513
8 7 7 10 12 8 9 61
13.3 8.5 11.9 14.9 13.0 8.9 14.3 11.9
5.9-24.6 3.5-16.8 4.9-22.9 7.4-25.7 6.9-21.7 3.9-16.8 6.8-25.4 9.2-15.0
PHN = Postherpetic neuralgia CI = Confidence interval N = Number of patients of this gender in this age group enrolled n= Number of patients of this gender in this age group who had PHN HZ = Herpes zoster
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546 547
Table 4. Estimated coefficients of the fitted logistic regression model and the final model for potential risk factors for PHN Model
Risk factor
Coefficient
SE
OR*
95% CI for OR
p-value
Age (years): 60-69 vs 50-59** 70-79 vs 50-59** ≥80 vs 50-59** Gender Female vs male** -HZ-related complications Yes vs no** Current immunosuppressive therapy Yes vs no** Pre-existing medical condition Yes vs no** HZ severity at initial visit Moderate vs no/mild pain** Severe vs no/mild pain**
0.197 0.020 0.491
0.412 0.393 0.489
1.22 1.02 1.63
0.54 - 2.73 0.47 - 2.21 0.63 - 4.26
0.63 0.96 0.32
0.280
0.324
1.32
0.70 - 2.50
0.39
0.411
0.458
1.51
0.62 - 3.70
0.37
- 0.351
0.579
0.70
0.23 - 2.19
0.54
0.614
0.342
1.85
0.95 - 3.61
0.07
1.709 2.305
0.754 0.750
5.5 10.02
1.26 - 24.2 2.30 - 45.57
0.02 0.002
1.726 2.387
0.749 0.740
5.62 10.88
1.29 - 24.39 2.55 - 46.40
0.02 0.001
Saturated
Final HZ severity at initial visit Moderate vs no/mild pain** Severe vs no/mild pain**
548 549 550 551 552 553 554 555 556 557
PHN = Postherpetic neuralgia HZ = Herpes zoster SE = Standard error OR* = Adjusted odds ratio ** = Reference category CI = Confidence interval 95% CI for OR, determined as 95% Wald’s CI for OR The saturated model was developed by not following any model building strategy; final model was developed by following a backward model building strategy with p-value ≤ 0.05 as criterion for keeping a variable
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558
Table 5. Total mean costs by type of complications and age group (€) HZ category
Perspective
≥80 yrs N = 63
50 - 59 yrs N = 142
60 - 64 yrs N = 59
65 - 69 yrs N = 67
70 - 79 yrs N = 182
Overall N = 513
n
Mean (€)
n
Mean (€)
n
Mean (€)
n
Mean (€)
n
Mean (€)
n
Mean (€)
HCS Societal
124 124
115 471
45 45
92 297
49 49
93 109
150 150
94 108
51 51
100 116
419 419
101 237*
HCS Societal
15 15
620 1,456
7 7
134 444
10 10
114 136
20 20
516 552
9 9
103 117
61 61
371 630*
HCS
3
146
7
212
8
129
12
729
3
1279
33
471
Societal
3
167
7
1,003
8
157
12
776
3
1326
33
669*
HCS Societal
142 142
169 569
59 59
111 398
67 67
100 119
182 182
182 200
63 63
157 173
513 513
156 311*
HZ only
PHN
HZ with complication - no PHN All HZ cases
559 560 561 562 563 564 565 566 567 568 569 570 571
N = Number of patients enrolled in this age group yrs = Years HZ = Herpes zoster PHN = Postherpetic neuralgia n = Number of patients concerned * = Indirect costs due to work absence only occurred for patients still working (all of them younger than 65 years) but were averaged over all 513 patients to estimate the average total societal cost per HZ patient (and in each HZcategory) HCS = Healthcare system
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572 573
Figure 1.tif
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