Aging Clinical and Experimental Research

https://doi.org/10.1007/s40520-018-0968-z

ORIGINAL ARTICLE

Cross-sectional study on hospitalizations related to herpes zoster

in an Italian region, 2008–2016
Silvia Cocchio1 · Tatjana Baldovin1 · Patrizia Furlan1 · Chiara Bertoncello1 · Alessandra Buja1 · Mario Saia2 ·
Marco Fonzo1 · Vincenzo Baldo1

Received: 11 January 2018 / Accepted: 4 May 2018

© Springer International Publishing AG, part of Springer Nature 2018

Abstract
Introduction  To assess the burden of herpes zoster (HZ) by analyzing HZ-related hospital admissions.
Methods  We conducted a population-based descriptive cross-sectional study on all hospitalizations for HZ among the
resident population admitted to all public and accredited private hospitals in the Veneto Region (north-east Italy) during the
years 2008–2016. HZ hospitalizations were identified from the International Classification of Diseases codes in the hospital
discharge records.
Results  During the period considered, we identified 3566 HZ-associated admissions, 194 (5.4%) of which were readmis-
sions within 30 days. A complicated HZ diagnosis was mentioned for 44.4% of the patients admitted once and for 65.9%
of those admitted twice. In the sample as a whole, 27.0% of patients had at least one comorbidity. Overall, our analysis
revealed a gradual increase in hospitalizations with age for both genders, reaching a hospitalization rate for the population
over 80 years old of 51.2 × 100,000 for males and 52.8 × 100,000 for females. The average hospitalization rate for HZ-related
conditions during the years 2008–2016 was 7.7 per 100,000 population. Postherpetic neuralgia was diagnosed in 8.2% of
hospitalizations, with no difference between the genders. The estimated overall cost of HZ-related conditions was approxi-
mately €2.7 million a year.
Conclusions  This study suggests that the burden of HZ and its impact on quality of life are of critical relevance to public
health decision-making.

Keywords  Herpes zoster · Postherpetic neuralgia · Hospitalization · Epidemiology · Public health

Abbreviations Background
HZ Herpes zoster
VZV Varicella zoster virus Herpes zoster (HZ) is a painful, debilitating disease. It is
CMI Cell-mediated immunity caused by latent varicella zoster virus (VZV) reactivation in
COPD Chronic obstructive pulmonary disease the dorsal root ganglia. The primary infection usually occurs
PHN Postherpetic neuralgia in childhood, causing varicella. Clinical manifestations typi-
ICD-9-CM International Classification of Diseases, cally show a dermatomal distribution and involve the skin
Ninth Revision, Clinical Modification and nervous system. What causes virus reactivation is yet to
DRG Diagnosis-related groups be fully clarified, but the cell-mediated immune system has
AAPC Average annual percent changes an important role in preventing it [1, 2].
The latent virus is widespread in numerous sensitive gan-
glia in adult individuals. The aging process and an impaired
virus-specific cell-mediated immunity can make way for the
* Chiara Bertoncello
chiara.bertoncello@unipd.it virus reactivation and the onset of clinical manifestations
[3]. More than 90% of individuals living in Europe develop
1
Department of Cardiac, Thoracic and Vascular Sciences, immunity to VZV before they reach adolescence, however,
Hygiene and Public Health Unit, University of Padua, Via and virus-specific immunity may be boosted periodically by
Loredan, 18, 35121 Padua, Italy
exposure to VZV or by asymptomatic reactivations of the
2
EuroHealth Net, Veneto Region Health Directorate, Veneto, latent virus [4].
Italy

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The age-related decline in virus-specific cell-mediated
immunity starts to become relevant by the age of 50 years,
when the risk of developing HZ consequently begins to
increase. Estimates indicate that more than 1.7 million indi-
viduals in the population of Europe carry HZ [5].
The HZ incidence rate thus increases with aging, rang-
ing from 2 to 3 per 1,000 person-years between the ages of
20 and 50 years and reaching 6.3 per 1000 person-years in
the population aged over 50 years [6]. More in detail, the
incidence is around 10 per 1000 person-years between the
ages of 90 and 100 years [5]. The risk of developing HZ is
higher in the case of certain medical conditions, such as dia-
betes, chronic obstructive pulmonary disease (COPD), major
depressive disorder, and all conditions requiring immuno-
suppressive treatments [7–11].
Postherpetic neuralgia (PHN) is conventionally defined as
dermatomal pain persisting at least 90 days after the appear-
ance of the acute herpes zoster rash. The incidence and prev-
alence approximately rose from 8% at 50 years of age to 21%
at 80 years of age. PHN results in suffering and reduced
quality of life as well as individual and societal health-care
costs [12]. More in detail, recent estimates from an Italian
population-based study on individuals aged over 50 years
show that the proportion of HZ cases suffering from PHN at
1 and 3 month is 22.7 and 17.7%, respectively [13].
Aim
The primary aim of the present study was to estimate the
HZ-related hospitalization rate and its temporal trend in a
given area. Secondary objectives were to analyze the associ-
ated comorbidities, assess the burden of postherpetic neu-
ralgia, and obtain a preliminary estimate of the economic
impact of HZ-related conditions.
Methods
This was a population-based descriptive cross-sectional
study conducted on all hospital discharge records relating
to HZ affecting residents of the Veneto Region (north-east
Italy) from 1 January 2008 to 31 December 2016.
During the period considered, Veneto had an average
population of 4.8 million. The hospital beds amounted to
an average 19,804 (3.81 per 1000 population), and the fig-
ure tended to drop continuously over the 9-year period. The
hospitalization rate was 136.4 per 1000 population, with an
average of 0.8 million patients being admitted to hospital
each year, a hospital bed occupancy rate of 75%, and a mean
hospital stay of 7.2 days.
We analyzed the data in the hospital records concern-
ing all discharges from all public and accredited private
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Aging Clinical and Experimental Research
hospitals in the region. Hospitalizations for HZ-related
conditions were identified by selecting records containing
the code 053 according to the International Classification
of Diseases, Ninth Revision, Clinical Modification (ICD-
9-CM) in all diagnosis on discharge (first list and secondary
list). The subcodes for complicated HZ were: 053.0: herpes
zoster with meningitis; 053.1: herpes zoster with other nerv-
ous system complications; 053.2: herpes zoster with oph-
thalmic complications; 053.7 herpes zoster with other speci-
fied complications; 053.8: herpes zoster with unspecified
complications. Cases were classified as “uncomplicated”
when the diagnostic code was 053.9. Hospital admissions for
PHN were identified among all discharge records by seeking
the ICD-9-CM codes 053.12 or 053.13. If the same patient
was readmitted to hospital for the same condition, only the
first admission was considered.
Annual total and age-specific hospitalization rates were
obtained by dividing the annual number of hospitalizations
for HZ by the population in each year according to data pro-
vided by the Veneto Statistics Office. Hospitalization rates
are given per 100,000 individuals. For patients readmitted
within 30 days, only the first hospital stay was considered for
the purpose of calculating the hospitalization rates.
The mean length of hospital stay was calculated. We also
assessed the chronic conditions usually associated with HZ
by checking the ICD-9-CM diagnostic codes for: diabetes
mellitus (code: 250), renal failure (codes: 584–586), malig-
nant neoplasms (codes: 140–209), autoimmune diseases
(systemic lupus erythematosus codes 695.4, 710.0; rheu-
matoid arthritis code 714.0, and Sjogren’s syndrome code
710.2), and COPD (codes: 491–496).
The diagnosis-related groups (DRG) of the hospitalized
patients, including readmissions within 30 days, were used
to estimate the costs to the health-care system. The DRGs
were calculated using the Core Grouping System Software,
considering ICD-9-CM code, age, sex, and resource con-
sumption. The total cost was calculated taking the total num-
ber of hospital discharges into account, and based on the
primary diagnosis. These data may be useful for developing
cost-effectiveness models with a view to establishing priori-
ties and strategies, and for assessing the economic impact of
VZV vaccination.
The data were analyzed using the Chi-square test, Stu-
dent’s t test for unpaired data, and Pearson’s test as appropri-
ate. A p value < 0.05 was considered significant. Analyses
were performed using the Statistical Package for the Social
Sciences (SPSS 25; SPSS Inc., Chicago, IL, USA). Signifi-
cant trends over the years considered were assessed as aver-
age annual percent changes (AAPC), a summary measure
of the trend over a given fixed interval that is computed
as a weighted average of the annual percent change emerg-
ing from the joinpoint model, using weights equating to the
length of the annual percent change interval. If an AAPC lies
Aging Clinical and Experimental Research

entirely within a single joinpoint segment, the AAPC is the Overall, our analysis by age group, gender and type
same as the annual percent change for that segment [13, 14]. of diagnosis (complicated vs uncomplicated) showed a
gradual increase in the number of hospitalizations with
Availability of data and materials aging (p < 0.05) in both genders (p < 0.05), reaching a rate
of 56.9 × 100,000 in males and 56.1 × 100,000 in females
We used only aggregated data from routine administrative among the population over 80 years old. This trend was
sources provided by the Veneto region. confirmed with regard to the diagnosis of complicated HZ
(p < 0.05) (Fig. 1), which accounted for 58.0% of the cases
of HZ indicated in the first-listed diagnosis on discharge,
Results and 31.8% of the cases in a secondary-listed diagnosis on
discharges (p < 0.01).
From 2008 to 2016, we identified 3566 hospitalizations for
diseases associated with HZ, 194 (5.4%) of which were read-
missions within 30 days. A complicated HZ diagnosis was
recorded for 43.1% of the patients admitted once, and for
65.9% of those admitted twice.
The characteristics of the sample by gender are shown in
Table 1: 57.6% of the patients were female, and the mean age
of the female patients was significantly higher than for the
males (74.4 ± 18.1 vs 68.5 ± 19.9; p < 0.001). A diagnosis of
complicated HZ was recorded for 45.4% of the males and
41.5% of the females (p < 0.01). In general, the most com-
mon associated complications were those in the subgroup
of other nervous system complications (19.0%), followed by
ophthalmic complications (11.5%). No significant gender-
related differences emerged vis-à-vis the types of complica-
tion. In the sample as a whole, 26.7% of patients had one or
more comorbidities, which remained stable by age groups.
Cases of malignant neoplasms and renal failure were signifi- Fig. 1  HZ-related hospitalization rate (cases with and without com-
cantly more common in males (Table 1). plications), by age and gender

Table 1  Characteristics of study Characteristics Males 1429 Females 1943 Total 3372

group according to the position
of HZ diagnosis (2008–2016) Age [mean (SD)] 68.5 (19.9) 74.4 (18.1) 71.9 (19.1)
Herpes zoster [n (%)]
 Uncomplicated 780 (54.6) 1136 (58.5) 1916 (56.8)
 Complicated by 649 (45.4) 807 (41.5) 1456 (43.2)
 Meningitis 42 (2.9) 34 (1.7) 76 (2.3)
 Ophthalmic complications 174 (12.2) 213 (11.0) 387 (11.5)
 Other nervous system complications 267 (18.7) 375 (19.3) 642 (19.0)
 Other specified complications 103 (7.2) 118 (6.1) 221 (6.6)
 With unspecified complications 63 (4.4) 67 (3.4) 130 (3.9)
Comorbidity [n (%)] 413 (28.9) 487 (25.1) 900 (26.7)
 Malignant neoplasms 122 (8.5) 134 (6.9) 256 (7.6)
 COPD 83 (5.8) 105 (5.4) 188 (5.6)
 Renal diseases 113 (7.9) 113 (5.8) 226 (6.7)
 Diabetes 151 (10.6) 159 (8.2) 310 (9.2)
 Autoimmune diseases 9 (0.6) 24 (1.2) 33 (1.0)
Length of hospital stay [mean (DS)] 13.0 (11.7) 13.9 (13.2) 13.5 (12.6)
Diagnosis [n (%)]
 First-list 623 (43.6) 829 (42.7) 1452 (43.1)
 Other 806 (56.4) 1114 (57.3) 1920 (56.9)

13

The average annual hospitalization rate for HZ diseases
over the years from 2008 to 2016 was 7.8 per 100,000
population (6.7 per 100,000 males, and 8.8 per 100,000
females). Considering both genders together, the hospitali-
zation rate attributable to HZ dropped from 9.0/100,000 in
2008 to 7.4/100,000 in 2014, with an AAPC of − 1.9 (CI
95% − 3.6; − 0.2). For males, the HZ-related hospitalization
rate went from 7.1/100,000 in 2008 to 7.2/100,000 in 2016
[AAPC − 1.2 (CI 95% − 3.6; 1.3)], and for females from
10.8/100,000 in 2008 to 7.6/100,000 in 2016 [AAPC − 2.6
(CI 95% − 5.1; 0.1)] (Fig. 2).
PHN was recorded in 6.1% of cases and was more com-
mon in female patients (6.7 vs 5.3% in male; p = n.s.) and
rose with age (from 3.5% in < 50  years old to 6.7% in
60 + years old; p < 0.05). Comorbidities were identified in
21.0% of these cases. 8.7% had diabetes, 4.6% had malig-
nant neoplasms, 3.7% had COPD, 5.0% had renal failure and
immunodeficiency disorders was 2.3%.
Overall, the annual estimated costs of hospitalizations due
to HZ (all related diagnoses) was €1.1 million; and the cost
of hospitalizations for which HZ was the primary diagnosis
was approximately €0.37 million. The average cost of each
HZ-related hospital admission was €2692 (€2180 when HZ
was recorded as the primary diagnosis). The average cost
of each PHN-related hospital admission was €2633 (€2303
when PHN was recorded as the primary diagnosis). Peo-
ple over 50 years old accounted for 88.0% of the estimated
overall cost.
Discussion
Our results show that HZ-related hospitalization has a con-
siderable impact. During the period considered, 95.6% of
the patients involved had one hospital stay, while 124 were
Fig. 2  Temporal trends of HZ-related hospitalization rates by gender
(2008–2016)
13
Aging Clinical and Experimental Research
re-admitted to hospital within 30 days of being discharged.
Our findings are consistent with a study conducted in France,
which estimated that 95% of HZ hospitalizations concerned
single admissions [15]. Our investigation also revealed that
60% of patients who were re-admitted for HZ-related condi-
tions were diagnosed as complicated cases.
The hospitalization rate was found significantly higher
for women than for men, as in several other studies, and
female patients were significantly older than male patients
[2, 16]. Our study also identified a linear positive correlation
between HZ hospitalization and age, and this applied to both
genders and to complicated cases too.
In our sample, around one in three inpatients had at least
one comorbidity. The most common comorbidities in both
genders were malignant neoplasms and diabetes, a picture
consistent with a greater risk of HZ in patients with these
underlying diseases [11].
Overall, 44.9% of our cases were classified as compli-
cated. The complications most often involved the nervous
system, and in another study conducted in Tuscany neuro-
logical and ophthalmic complications were reported in 24.2
and 16.5% of cases, respectively [17].
The most frequent complication following an acute epi-
sode of HZ is PHN. The risk factors for the onset of this
complication are: severe acute pain, old age, severe cuta-
neous manifestations and immunodeficiency conditions
unrelated to aging [12, 18–22]. Prodromal pain, female
gender, diabetes and ophthalmic complications have also
been shown to play a part in the onset of PHN [7, 12]. We
found that 6.2% of hospitalizations were associated with a
diagnosis of PHN, and the rate was higher in females than in
males; the most often associated comorbidity was diabetes.
In Italy, between 2001 and 2013, there was a significant
decrease in the rate of hospitalizations for all causes. A simi-
lar decreasing trend has been also described for both HZ and
complicated HZ and confirmed in our study. This decrease,
consistent with the national trend, has been induced by the
reduction of inappropriateness of admissions and by the
change of care settings in place in our country. In particu-
lar, the analysis of the temporal trend showed that in the
three Italian “pilot” regions that first introduced the univer-
sal childhood varicella immunization, a greater significant
decrease of HZ-related hospitalization rates occurred in
comparison to other regions [23].
VZV is the causative agent behind varicella (chickenpox),
and the virus reactivation can cause HZ. Because exposure
to varicella naturally boosts immunity against latent VZV,
some authors believe that the incidence of HZ may increase
as a consequence of a more extensive varicella vaccine cover-
age, which limits the circulation of wild varicella [24]. But an
increase in the incidence of HZ was reported before varicella
vaccination was deployed, and there was evidence of a drop
in the hospitalization rates for both varicella and HZ [25, 26].
Aging Clinical and Experimental Research
This idea can be traced back to Hope-Simpson’s hypothesis,
in which a person’s immune status determines the likelihood
that he/she will develop HZ. Immunity decreases over time
and can be boosted by contact with a person experiencing vari-
cella (exogenous boosting) or by a reactivation attempt of the
virus (endogenous boosting). However, mathematical models
showed that exogenous boosting is stronger than endogenous
immune boosting in children and adults, and that it is conceiv-
able that endogenous boosting exceeds exogenous boosting in
other age strata [27].
Since 2005, the Veneto Region has adopted universal
varicella vaccination program for children, achieving a stable
vaccine coverage rate of about 88% since 2006, and record-
ing a gradual reduction in the number of varicella cases and
related hospitalizations [28–30]. No extensive anti-HZ vaccine
strategy was implemented, but our study revealed a signifi-
cant downward trend in the HZ-related hospitalizations over
the period considered (2008–2016). It is important to bear in
mind, however, that our data refer to clinically severe medical
conditions and may not reflect the overall epidemiological situ-
ation in our region. Continuous monitoring at local level would
be needed to identify any association between the frequency
of HZ and the post-vaccination decrease in the incidence of
varicella.
The estimated hospitalization costs of HZ in our sample
was much the same as the economic burden of HZ elsewhere
in Italy [31]: the average cost of each HZ-related hospital
admission was €2678 and €2633 when PHN was involved.
Overall, the economic burden of disease is increasing over the
years. A population-based cohort study conducted in Canada
reported an increase of 174% between 1997/98 and 2011/2012
in the total costs of treating pain associated with HZ and PHN
[32].
A strength of the present study is that we investigated the
trend of HZ-related hospitalizations, though data were col-
lected from all over the Veneto Region (population 5 mil-
lion). The analysis of routinely available records can prove an
efficient method for monitoring trends in the state of health
of populations. As for the limitations of the study, the first
concerns the fact that it relied on a large administrative data-
base, which may pose concerns relating to miscoding and data
reporting inaccuracies, and it lacks fine clinical details. Finally,
using only discharge diagnosis method for epidemiological
evaluations of infectious diseases can result in an underesti-
mation of sensitivity and timeliness, but hospital discharge
data can prove useful for assessing the cases severe enough to
warrant hospitalization.
Conclusion
In conclusion, the burden of HZ and its impact on qual-
ity of life is a crucial issue to consider in public health
decision-making. Major issues concern the treatment and
management of complicated HZ-related conditions. Since
an extended vaccination strategy is not currently planned, it
seems reasonable to assume that intervention may focus pri-
marily on groups at high risk of HZ. Persons with a reported
history of zoster can be eligible for vaccination. Disease
recurrence is not in any case frequent, as the active replica-
tion of acute VZV boosts VZV-specific immunity reducing
the future risk of a subsequent attack [6]. Despite that the
level of awareness of varicella and HZ in people aged over
50 years is high (98 and 95%), an Italian study reported
than 91% of people were not aware of the existence of the
vaccination against HZ. However, 58% of participants were
in favor of vaccination and around two-thirds of the par-
ticipants who were not initially favorable stated that would
change their decision thanks to their GP’s advice [33].
In conclusion, the use of evidence-based cost-effective
therapies such as vaccination can reduce the incidence of
HZ and manage the economic burden of HZ-PHN treatment
[31].
Funding  The authors did not receive any funding or support for the
manuscript.
Compliance with ethical standards 
Conflict of interest  On behalf of all authors, the corresponding author
states that there is no conflict of interest.
Human and animal rights statement and consent to participate The
study was conducted on data routinely collected by the health services
and linked to anonymized records that make it impossible to iden-
tify the individuals concerned. The data analysis was performed on
anonymized aggregated data in the Local Health Authority registries
that are recorded with the patient’s consent and can be used in aggre-
gate form for scientific studies without further authorization (Gazzetta
Ufficiale della Repubblica Italiana. 2012, 72: 47–52). This study com-
plies with the Declaration of Helsinki and with Italian privacy law
(Decree n. 196/2003 on the protection of personal data).
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