Ant

ORIGINALES
Hospitalizaciones por varicela

en el Hospital Infantil La Fe
(Valencia 2001-2004)
A.I. Piqueras Arenasa, M.C. Otero Reigadaa, D. Prez-Tamarita, F. Asensi Boteta,
N. Diosdado Ortnb y M. Santos Durantezb
aSeccin de Enfermedades Infecciosas Peditricas. bServicio de Microbiologa. Hospital Infantil Universitario La Fe.
Valencia. Espaa.
Introduccin
Conclusiones
La varicela es una enfermedad frecuente, muy contagiosa y por lo general benigna, pero con complicaciones potencialmente graves.
La elevada morbilidad de la varicela y sus complicaciones y el elevado coste social apoyan la instauracin universal de la vacuna, la cual reducira el nmero total de
casos, su gravedad, los gastos directos, generados por el
cuidado mdico y los gastos indirectos, relacionados con
la enfermedad y hospitalizacin.
Pacientes y mtodos
Se revisan las historias clnicas de los nios hospitalizados
por esta enfermedad entre 2001 y 2004 para evaluar las caractersticas clnicas y el coste que lleva consigo la hospitalizacin. Se excluyen los casos que presentaron varicela durante la hospitalizacin y que ingresaron por otros motivos.
Palabras clave:
Varicela. Complicaciones. S. pyogenes. Vacuna antivaricela.
Resultados
De los 1.177 nios que fueron atendidos por varicela en
urgencias, 101 fueron hospitalizados (8,6 %). La edad mediana fue de 3,2 aos (21 das a 18,9 aos). Veintiocho nios tenan enfermedad subyacente. Treinta y siete casos no
presentaron complicaciones y el motivo de ingreso fue:
a) riesgo de desarrollar varicela grave (21 nios con enfermedad de base y 3 neonatos), o b) tenan fiebre alta o
afectacin del estado general (13 nios). Los 64 nios restantes ingresaron por 66 complicaciones. La complicacin
ms frecuente fue la infeccin de piel y tejidos blandos
(33 casos) y su causa ms habitual Streptococcus pyogenes
(n 13) y Streptococcus aureus (n 10) que se aislaron
en sangre o en el lugar de la infeccin. Otras fueron neumona (13 nios), complicaciones neurolgicas (9 nios
con convulsiones febriles, dos meningoencefalitis, una
encefalomielitis diseminada aguda, una cerebelitis), hematolgicas (una neutropenia, una prpura de Schnlein-Henoch y tres prpuras trombocitopnicas) y osteoarticulares (una sinovitis, una artritis sptica). Una paciente
falleci por insuficiencia multiorgnica. Durante el perodo de estudio el nmero de nios atendidos en urgencias
por varicela se duplic y el de ingresos por complicaciones
se triplic. La duracin media de la hospitalizacin fue de
6,8 das (1-28 das) y el coste total asociado fue de
397.314,14 1, excluyendo el tratamiento sintomtico.
HOSPITALIZATIONS FOR VARICELLA

IN THE HOSPITAL INFANTIL LA FE, VALENCIA,
SPAIN, 2001-2004
Introduction
Varicella is a common, highly contagious disease. It is
usually benign but has potentially serious complications.
Patients and methods

To assess the clinical characteristics and the associated
cost of varicella hospitalization, we reviewed the medical
records of children hospitalized for varicella between
2001 and 2004. Children with coincidental varicella hospitalized for a different reason were excluded.
Results
Of 1177 children with varicella attended at the emergency room, 101 (8.6 %) were hospitalized. The median
age was 3.2 years (21 days to 18.9 years). Twenty-eight children had underlying disease. Thirty-seven children had
no complications and the reason for admission was:
a) risk of severe varicella (21 immunocompromised children, three neonates), and b) high fever or observation
(13 cases). The 64 remaining children were admitted for
66 complications of varicella. The most common complications were skin/soft tissue infections (33 patients) and
Correspondencia: Dra. M.C. Otero Reigada.

Seccin de Enfermedades Infecciosas Peditricas.
Hospital Infantil Universitario La Fe.
Avda. Campanar, 21. 46009 Valencia. Espaa.
Correo electrnico: otero_car@gva.es
Recibido en febrero de 2005.
Aceptado para su publicacin en mayo de 2005.
120
An Pediatr (Barc) 2005;63(2):120-4
32
Piqueras AI, et al. Hospitalizaciones por varicela
the leading cause was Streptococcus pyogenes (n 13)

and Staphylococcus aureus (n 10) isolated in blood or
the site of infection. Other complications were pneumonia
(13 children), neurological (febrile seizures in nine,
meningoencephalitis in two, acute disseminated encephalomyelitis in one, cerebellitis in one), hematological (neutropenia in one, Henoch-Schnlein purpura in
one and thrombopenic purpura in three) and osteoarticular (synovitis in one and septic arthritis in one). One patient died of multiorgan failure. During the study period,
the rate of emergency room visits due to varicella doubled
and the number of admissions for complications tripled.
The mean length of hospital stay was 6.8 days (range:
1-28 days) and the total associated cost was 397,314.14 3,
excluding symptomatic treatment.
MATERIAL Y MTODOS
Conclusions
RESULTADOS
The high morbidity associated with varicella and its

complications, as well as the high social costs of this disease, support the implementation of routine varicella vaccination. This could reduce the total number of cases, their
severity, direct costs, generated by medical care, and indirect costs, generated by the disease and hospitalization.
De enero de 2001 a junio de 2004, 101 nios (43 nias y

58 nios) ingresaron en el Hospital Infantil la Fe por varicela o sus complicaciones. La edad mediana de los nios
fue de 3,2 aos (entre 21 das y 18 aos) con predominio
del ingreso por complicaciones entre 1 y 3 aos (fig. 1).
No presentaron complicaciones 37 nios y su ingreso se
debi a que: a) tenan enfermedad subyacente y riesgo de
desarrollar varicela grave (21 de los 28 casos de la tabla 1);
b) eran neonatos (3 casos), o c) presentaban fiebre alta o
afectacin del estado general (13 casos). Cuatro de los nios con enfermedad subyacente (2 casos de leucemia linfoblstica aguda, uno con trasplante renal y otro con sndrome nefrtico) haban recibido la vacuna antivaricela
entre los 2 meses y 2 aos previos al ingreso.
El nmero y tipo de complicaciones que fueron motivo
de ingreso en los restantes 64 nios se expone en la
tabla 2. En 57 casos (89,1 %) se trataba de nios previamente sanos y 7 (10,9 %) tenan enfermedad subyacente:
dermatitis atpica (3 casos), asma (un caso), sida (un
caso), sndrome nefrtico (un caso) e insuficiencia pancretica (un caso). Las complicaciones que presentaron
los 7 nios con enfermedad subyacente fueron: infeccin
de piel y tejidos blandos (IPTB) (4 casos), prpura trombocitopnica (2 casos) y sinovitis de codo (un caso). El
resto de complicaciones se produjeron en nios sanos.
Entre 2001 y 2004 (30 de junio) el nmero de visitas a
urgencias por varicela casi se duplic (288 casos, 251 casos, 419 casos y 219 casos, respectivamente) mientras que
el de ingresos por complicaciones se triplic (fig. 2). En
cambio, en este perodo no se alter el nmero de ingresos por varicela sin complicaciones ni el de nios con
varicela y enfermedad subyacente.
El microorganismo aislado ms frecuentemente en las
complicaciones bacterianas secundarias fue Streptococcus
del grupo A (SGA). Se encontr en 12 enfermos en la lesin de piel y en cuatro en hemocultivo (en 2 casos en
ambos). Staphylococcus aureus se aisl en 9 nios en la
lesin (en dos de ellos tambin en el hemocultivo) y en
un caso el cultivo perifrico fue mixto, con SGA y S. aureus. Se aisl Moraxella catarrhalis en 2 nios (uno en
Key words:
Varicella. Complications. S. pyogenes. Varicella vaccination.
INTRODUCCIN
La varicela en nios es por lo general autolimitada, con
una duracin de 4-7 das, si bien presenta complicaciones al menos el 1 % de los nios menores de 15 aos previamente sanos1. Las complicaciones son ms frecuentes
en algunas poblaciones de riesgo, como los pacientes
inmunodeprimidos o con enfermedades cutneas crnicas, durante el primer ao de vida (sobre todo en perodo neonatal), el adolescente y el adulto. Sin embargo, el
nmero absoluto de hospitalizaciones y de fallecimientos
es mayor en nios menores de 10 aos inmunocompetentes 2,3, ya que en este grupo de edad la enfermedad
es ms frecuente.
La importancia y repercusin de la enfermedad y sus
complicaciones en el mbito de la atencin primaria 4 y
hospitalario 5-9 han sido argumentos a favor de la implantacin de la vacuna de la varicela en el calendario de inmunizaciones sistemticas.
En este trabajo se presentan los nios ingresados por
varicela en nuestro hospital desde 2001 hasta el 30 de junio de 2004 y se analiza la evolucin clnica y el coste
que supuso la hospitalizacin. El Hospital Infantil la Fe
es el principal centro terciario de la Comunidad de Valencia y a su vez es el hospital de zona de dos distritos
de salud, por lo que el estudio refleja los diferentes grados de intensidad, con mayor incidencia en nios con
enfermedad subyacente, y sobre todo sus complicaciones ms graves. Esta informacin es importante a la hora
de evaluar el impacto de la vacuna respecto al perodo
inmediato prevacunal.
33
Se revisaron las historias clnicas de los nios ingresados por varicela desde enero de 2001 a junio de 2004. Los
casos se identificaron por el diagnstico al alta. Se excluyeron los casos en los que la enfermedad se diagnostic
en el transcurso de la hospitalizacin y que, por lo tanto,
fueron ingresados por otro motivo.
Se calcul el coste de la varicela en los nios hospitalizados evaluando en cada uno el coste de su estancia hospitalaria, de las exploraciones complementarias y del tratamiento antimicrobiano segn las tarifas que se especifican en ley
de tasas de la Generalitat Valenciana (ejercicio 2003) y las
que proporcion el Servicio de Microbiologa para este ao.
An Pediatr (Barc) 2005;63(2):120-4
121
25
20
Casos
15
10
6-12
1-5
meses meses
10
> 10
Edad (aos)
Sin complicaciones
Complicaciones
Figura 1. Distribucin por

edad y complicaciones.
TABLA 1. Tipo de enfermedad subyacente

en 28 nios ingresados
por varicela
Enfermedad subyacente
Nmero de casos
Proceso linfoproliferativo
Trasplante*
Sndrome nefrtico
Dermatitis atpica
Sida
Vasculitis
Asma
Insuficiencia pancretica**
9
4
4
3
3
2
2
1
*3 casos con trasplante renal y 1 caso trasplante heptico.

**Insuficiencia pancretica e hipertransaminemia no clasificada.
TABLA 2. Nmero y tipo de complicaciones

de la varicela segn lugar de infeccin
(66 complicaciones en 64 nios)
Complicaciones
Infeccin de piel y tejidos blandos
33
Pulmonares (neumona)
13
Neurolgicas
Convulsiones
Meningoencefalitis
Encefalomielitis
Encefalomielitis diseminada aguda
13
9
2
1
1
Hematolgicas
Prpura trombocitopnica*
Prpura de Schnlein-Henoch
Neutropenia
5
3
1
1
Osteoarticulares
Artritis sptica de rodilla
Sinovitis del codo
2
1
1
*Un caso fulminante, que falleci por fallo multiorgnico.
122
Nmero
An Pediatr (Barc) 2005;63(2):120-4
hemocultivo y otro en lesin de piel y frotis nasal), Pseudomonas en hemocultivo en otro nio y Streptococcus viridans en la lesin de piel en otro.
Se document la etiologa de la neumona en 5 de los
13 casos, tres de ellos en hemocultivo (2 SGA, 2 M. catarrhalis). En un enfermo remitido de otro hospital por
neumona cavitada con derrame purulento que requiri
drenaje, los cultivos fueron negativos pero presentaba un
ASLO (antiestreptolisina O) de 4.239 U/ml y en otro nio
con neumona basal el antgeno del neumococo en orina
fue positivo.
En la nia que falleci con prpura fulminante, se aisl Pseudomonas aeruginosa en el hemocultivo.
Se administraron antimicrobianos a 81 nios, 60 de ellos
recibieron antibiticos y 38 aciclovir (24 con enfermedad
subyacente). La gammaglobulina antivaricela-zster se administr en 15 casos (12 con enfermedad subyacente).
La duracin media de la hospitalizacin fue de
6,8 5,2 das (entre 1 y 28 das). Precisaron ingreso en la
unidad de cuidados intensivos 8 nios entre 1 y 25 das.
El motivo fue un nio con absceso periamigdalino; otro
con encefalomielitis diseminada aguda; dos con prpura
trombocitopnica y cuatro con neumona (dos por SGA,
uno de ellos con sepsis y otro con importante derrame
pleural; uno con neumona cavitada y otro con afectacin
difusa bilateral).
La evolucin fue favorable en 99 enfermos. Un nio
con dermatitis atpica y varicela hemorrgica con trombocitopenia present como secuela cicatrices hipertrficas. Una nia con hipertransaminemia e insuficiencia
pancretica pendiente de clasificacin present prpura
fulminante y falleci (1 %) a causa de un fallo multiorgnico y sepsis por Pseudomonas.
34
El coste total del tratamiento fue de 22.336,24 1 y el de

la hospitalizacin, 397.314,14 1 (tabla 3).
30
DISCUSIN
35
Nmero de casos
En Espaa las publicaciones recientes sobre hospitalizaciones peditricas por varicela son escasas10-12 y los resultados variables, ya que la metodologa, perodo estudiado y grado de cobertura del hospital son diferentes.
Prez-Yarza et al 5 en un estudio retrospectivo multicntrico en Guipzcoa, refieren 71 nios con complicaciones
de la varicela en un perodo de 10 aos (1993-2002). Riaza et al 6, en otro estudio en el Hospital Nio Jess de
Madrid, presentan 84 casos en un perodo de 5 aos
(1993-1999). Moraga et al13 muestran en un estudio prospectivo realizado en Catalua en 1999 una serie de
107 ingresos por complicaciones.
En el presente estudio, en los 3 aos y medio que abarca, la mayor parte de las complicaciones se produjo en
nios sanos y las presentaron 7 de los 28 nios con enfermedad subyacente (25 %). Las caractersticas del Hospital Infantil La Fe pueden explicar el mayor nmero de
complicaciones y pacientes de riesgo.
Como en otros estudios, los nios menores de 5 aos
fueron el principal grupo de riesgo de complicaciones que
requirieron hospitalizacin, sobre todo entre 1 y 3 aos5-8.
De acuerdo con estudios previos 3, la complicacin ms
frecuente fue la IPTB con un aumento de casos a lo largo
del perodo de estudio (4 casos en 2001; 7 casos en 2002;
16 en 2003 y seis hasta junio de 2004). Diversos autores han
constatado un aumento de infecciones por cepas invasoras
de SGA en los ltimos aos14-16. Estas infecciones son ms
frecuentes y mucho ms graves en el curso de una varicela
por lo que la persistencia de fiebre alta ms all del tercer
da o dolor localizado con signos de enrojecimiento e inflamacin local deben hacer sospechar esta complicacin.
En el presente trabajo se confirm la etiologa de infeccin por SGA en 15 nios: 12 en la lesin de piel, dos de
ellos con bacteriemia y uno con cultivo mixto; dos por hemocultivo en nios con neumona y uno de forma indirecta
mediante ASLO. En 2 casos de celulitis facial se aisl SGA en
el frotis farngeo. Por lo tanto, la puerta de entrada de la infeccin por SGA pudo ser la nasofaringe o la lesin de la
piel por la varicela. As pues, a los nios que ingresan con
complicaciones de la varicela se les debe realizar adems
del frotis de la lesin un frotis farngeo, nasal en lactantes,
para investigar el foco de la infeccin. La infeccin por SGA
fue la causa confirmada del 23,4 % de las complicaciones
por varicela. Slo un caso de IPTB por SGA tena enfermedad subyacente (sndrome nefrtico dependiente de corticoides) y el resto eran nios sin enfermedad de base.
Las complicaciones hematolgicas fueron poco frecuentes (4 casos) pero uno de ellos falleci por fallo multiorgnico y sepsis por Pseudomonas. Esta paciente tena una
enfermedad de base no clasificada, hipertransaminemia e
insuficiencia pancretica en estudio en otro hospital.
25
20
15
10
5
0
2001
2002
2003
2004
(hasta 30-36)
Ao
Sin complicaciones
Complicaciones
Figura 2. Distribucin de los nios segn el ao de ingreso y la causa de hospitalizacin.
TABLA 3. Coste de la hospitalizacin

Coste
Euros
Medicacin/paciente
Pruebas complementarias/paciente
Hospitalizacin/paciente
Medicacin
Pruebas complementarias
Total de la hospitalizacin
221,15
589,23
3.933,80
22.336,24
59.512,47
397.314,14
En Estados Unidos, tras la introduccin de la vacuna de

la varicela, se ha constatado una disminucin de las hospitalizaciones, en particular de infecciones por SGA 17,18.
Tambin se ha demostrado que la incidencia de zster
es menor tras la vacunacin que tras la infeccin natural1,19. En los prximos aos, los estudios en poblaciones
vacunadas ayudarn a determinar la duracin de la inmunidad de la vacuna y de replantear la posologa.
En conclusin, la varicela se asocia a complicaciones graves que comportan un gran coste teraputico y de hospitalizacin en la mayora de casos. La infeccin por SGA fue la
complicacin ms frecuente. Existe una vacuna eficaz para
prevenir la enfermedad y la vacunacin universal reducira
el nmero de casos, su gravedad, los gastos directos generados por el cuidado mdico y los gastos indirectos sociales, relacionados con la enfermedad y la hospitalizacin.
La vacuna antivaricela es segura, eficaz e inductora de
inmunidad duradera20,21. Hasta que se generalice su uso y
se demuestre una disminucin global de la morbimortalidad por varicela ser necesario vigilar los casos para prevenir las complicaciones. El estudio que presentamos
creemos que puede ser til como referencia de base con
la que comparar estudios futuros, en los que ya se contemple el uso de la vacuna antivaricela.
An Pediatr (Barc) 2005;63(2):120-4
123
BIBLIOGRAFA
1. Skull SA, Wang EEL. Varicella vaccination-a critical review of
the evidence. Arch Dis Child. 2001;85:83-90.
2. Galil K, Brown C, Lin F, Seward J. Hospitalizations for varicella
in the United States, 1988 to 1999. Pediatr Infect Dis J. 2002;
21:931-4.
13. Moraga-Llop FA, Domnguez A, Roca J, Jan M, Torner N, Alleras L, et al. Paediatric complications of varicella requiring hospitalization. Vacunas Invest Pract. 2000;1:106-11.
3. Peterson CL, Mascola L, Chao SM, Lieberman JM, Arcinue EL,

Blumberg DA, et al. Children hospitalized for varicella: A prevaccine review. J Pediatr. 1996;129:529-36.
14. Vugia DJ, Peterson CL, Meyers HB, Kim KS, Arrieta A, Schlievert PM, et al. Invasive group A streptococcal infections in
children with varicella in Southern California. Pediatr Infect
Dis J. 1996;15:146-50.
4. Dez-Domingo J, Arstegui J, Calbo F, Moraga F, Gonzlez-Hachero J, Pena Guitin J, et al. Epidemiology and economic impact of varicella in immunocompetent children in Spain. A nation-wide study. Vaccine. 2003;21:3236-9.
15. Centres for Disease Control and Prevention. Outbreak of invasive group A streptococcus associated with varicella ina
child care center-Boston, Massachusetts, 1997. MMWR Morb
Mortal Wkly Rep. 1997;46:944-8.
5. Prez-Yarza EG, Arranz L, Alustiza J, Azkunaga B, Uriz J, Sarasua A, et al. Hospitalizaciones por complicaciones de la varicela en nios menores de 15 aos. An Pediatr (Barc). 2003;59:
229-33.
16. Doctor A, Harper MB, Fleisher GR. Group A -hemolytic

streptococcal bacteremia: Historical overview, changing incidence, and recent association with varicella. Pediatrics. 1995;
96:428-33.
6. Riaza Gmez M, De la Torre Esp M, Menca Bartolom S, Molina Cabaero JC, Tamariz-Martel Moreno A. Complicaciones
de la varicela en nios. An Esp Pediatr. 1999;50:259-62.
17. Patel RA, Binns HJ, Shulman ST. Reduction in pediatric hospitalizations for varicella-related invasive group A streptococcal
infections in the varicella vaccine era. J Pediatr. 2004;144:68-74.
7. Ziebold C, Von Kries R, Lang R, Weigl J, Schmitt HJ. Severe

complications of varicella in previously healthy children in
Germany: A 1-year survey. Pediatrics. 2001;108:e79.
18. Davis MM, Patel MS, Gebremariam A. Decline in varicela-related hospitalizations and expeditures for children and adults after introduction of varicella vaccine in the United States. Pediatrics. 2004;114:786-92.
8. Aebi C, Ahmed A, Ramilo O. Bacterial complications of primary varicella in children. Clin Infect Dis. 1996;23:698-705.
124
12. Gil A, Gonzlez A, Oyaguez I, Martn MS, Carrasco P. The burden of severe varicella in Spain, 1995-2000 period. Eur J Epidemiol. 2004;19:699-702.
9. Choo PW, Donahue JG, Manson JE, Platt R. The epidemiology

of varicella and its complications. J Infect Dis. 1995;172:706-12.
19. Hardy I, Gershon A, Steinberg S, LaRussa P. The incidence of

zoster after immunization with live attenuated varicella vaccine: A study in children with leukemia. N Engl J Med. 1991;325:
1545-50.
10. Moraga FA. Complicaciones de la varicela en el nio inmunocompetente. An Pediatr. 2003;59 Supl 1:18-26.
20. Moraga F, Campins M. Vacuna de la varicela. An Pediatr Contin. 2003;1:101-4.
11. Gil A, San-Martn M, Carrasco P, Gonzlez A. Epidemiology of

severe varicella-zoster virus infection in Spain. Vaccine. 2004;
22:3947-51.
21. Vzquez M, LaRussa PS, Gershon AA, Steinberg SP, Freudigman K, Shapiro ED. The effectiveness of the varicella vaccine
in clinical practice. N Engl J Med. 2001;344:955-60.
An Pediatr (Barc) 2005;63(2):120-4
36
Epidemiol. Infect. (2002), 129, 599606. f 2002 Cambridge University Press

DOI : 10.1017/S0950268802007720 Printed in the United Kingdom
Varicella in non-immune persons: incidence, hospitalization

and mortality rates
P. Y. B O E L L E 1
AND
T. HA N S L IK 2*
Department of Public Health, Hopital Saint Antoine, Universite Pierre et Marie Curie, Assistance PubliqueHopitaux de Paris, INSERM U444
2
Department of Internal Medicine, Hopital Ambroise Pare, Universite Paris 5, Assistance Publique-Hopitaux de
Paris, INSERM U444
(Accepted 8 August 2002)

SUMMARY
This study was conducted to estimate the varicella morbidity and mortality rates per age group
among the non-immune population in France. Morbidity and mortality data for the years 19909
were derived from nationwide databases and surveillance systems. An incidence/prevalence model
was designed to quantify the non-immune population per age group. The incidence of varicella
in the non-immune population peaks during childhood and again in the 2535 years age group.
For children aged 1 4 years, adults aged 2534 years and those older than 65 years, the
hospitalization rates are respectively 235, 1438 and 8154 per 100 000 cases, and the death rates
are respectively 7, 104 and 5345 per million cases. Case fatality or case hospitalization rates were
not evenly distributed among adults and increased dramatically with age.
INTRODUCTION
Varicella is usually a mild disease. Nevertheless, it
may cause death, although rarely in adults, pregnant
women and immunosuppressed patients [13]. An
ecient live attenuated vaccine has been licensed in
many countries, but few have adopted routine childhood immunization. Today, it is only practised in the
United States (since 1995), and in Japan and Korea
[1]. Widespread childhood immunization should
greatly reduce the number of primary cases. However,
it may also favour an increase in complications, as
a result of the shift in the age distribution of the remaining cases towards older persons, because of the
waning of vaccine-induced immunity or the reduction of exposure to infection [4]. This is all the more
concerning since during the pre-vaccine period in the
* Author for correspondence : Federation de Medecine Interne,

CHU Ambroise Pare, 9 Avenue Charles de Gaulle, 92104 Boulogne
Billancourt cedex, France.
United States and United Kingdom, the average age

of cases has already risen [57]. Targeting vaccination to non-immune adults or adolescents therefore has a strong appeal in countries where routine
childhood immunization has not yet been considered. Such targeting may be expected to prevent
a signicant portion of complicated or lethal cases of
varicella, while at the same time avoiding an increase
in its incidence among adolescents and adults.
To assess the benet of this strategy, it is necessary
to determine the epidemiology of complications from
primary varicella in the pre-vaccine era, and the frequency of severe and costly complications. Providing
health professionals and the lay public with estimates
of these factors before any vaccination programme is
implemented may help to gain condence and support
for the programme. Estimates of the incidence of
varicella and of its hospitalization and mortality
rates in the general population have been reported in
countries where the vaccine is not currently in use,
and in the United States for the pre-vaccine era [2, 3,
600
P. Y. Boelle and T. Hanslik
Table 1. Average annual number of varicella-related deaths in France (19907 ) and hospitalizations (19979),
by age group
Age group (years)
Varicella related deaths
Varicella related hospitalization
Varicella meningitis
or encephalitis
Varicella pneumonia
Total number of
hospitalization
<1
2.0
1 4
2.4
12.3
35
17.9
10.3
1240
819
514
1524
2534
1.8
1.3
2.5
30.7
6.7
3.7
13
51
172
348
401
5, 717]. However, none of these reports dealt directly

with the risks for non-immune persons, which are
crucial in deciding for or against the immunization
of an adolescent or adult.
In France, the epidemiology of varicella has not
been changed by the vaccine, as the latter is only licensed for children with leukaemia or cancer, for persons in household contact with immunocompromised
persons and for their care-givers. Using a substantial
database of varicella cases collected by a French
national system of surveillance for communicable
diseases over the last 10 years, and an age-specic
incidence/prevalence model for varicella, we estimated
its age-specic incidence rates in non-immune persons, and computed their varicella-related age-specic
hospitalization and mortality rates.
METHODS
Available surveillance data for varicella consist of
case descriptions that do not allow direct calculation
of its incidence in non-immune individuals. To make
this calculation possible, we constructed an incidence/
prevalence mathematical model for the epidemiology
of varicella, and applied it to a population similar to
that of France. We rst modelled the history of infection in a birth cohort in relation to ageing, and included 100 lagged birth cohorts, in order to re-create
the age structure of the general French population.
The age-specic risks were then obtained by dividing
the numbers of incident cases, hospitalizations and
deaths by the number of living non-immune individuals.
The overall incidence of varicella was obtained
from the French general practitioners Sentinelles surveillance network [18]. The members of this network,
4564
o65
o15
( % all ages)
1.5
2.0
5.8
13.1 (69)
19.1
8.3
7.7
36.7 (32)
114.7
9.7
108.4 (78)
139.7
35 44
20.7
124
14
111
90
845 (26)
All
ages
3306
about 500 voluntary unpaid Sentinel General Practitioners (1 % of all GPs), report cases of communicable diseases every week. Incidence estimates for
the whole country are produced by extrapolation of
the cases reported. It was previously shown that the
characteristics of the GPs in the Sentinel network are
comparable to those of all French GPs as regards
regional distribution, the proportion in rural practice, the type of practice and the distribution of the
main clinical skills [19]. The age distribution of incident varicella cases in general practice was estimated
on the basis of all the varicella cases reported and
described between 1 January 1991 and 31 December
1998 (n=28 453).
All-causes age-specic mortality rates were obtained from the French National Mortality Database
(INSERM SC8). Data concerning mortality for varicella were obtained from the French National Mortality Database, for deaths between 1 January 1990,
and 31 December 1997, as were all deaths coded
varicella (International Classication of Disease, 9th
revision, code 052), and information on underlying
medical conditions (Tables 1, 2).
Hospitalization data were obtained by reviewing
all hospital discharge reports from 1 January 1997 to
31 December 1999 (PMSI Data Processing Centre).
These reports constitute a national collection of all
discharges from all short-stay/acute-care hospitals
since 1997. The national hospital discharge register
of information is abstracted by physicians from information found in the patients medical record, using
the International Classication of Diseases, 10th Revision. Varicella hospitalization was dened as hospital discharges with code B01.0-9 for varicella and its
complications, and code P35.8 for congenital varicella. Information on underlying medical conditions
known to increase the severity or risk of occurrence of
Varicella in non-immune persons
601
Table 2. Percentage of deaths and cases hospitalized in France with underlying conditions known to
increase the severity or risk of occurrence of varicella
Underlying condition
International classication of diseases,

9th revision, codes used to
determine underlying conditions
Percentage of
hospitalizations for
varicella
Percentage of
deaths from
varicella
Human immunodeciency virus/AIDS

Leukaemia and other malignancies
Other forms of blood dyscrasia
Immune deciencies
Pregnancy
042.0044.9, 795.8
140.0208.9
284.0284.9
279.0279.9, 288.0288.2
634.0634.9, 647.6, 647.9, 650.0656.9
1.5
3.3
0.5
0.9
1.2
7.5
9.8
17.6
0.7
2
0
Total
varicella was also obtained (Tables 1, 2). The gures

in the Results section include all hospitalizations and
deaths of subjects with varicella-related diagnoses,
either principal or associated.
Data gathered through the Sentinelles network
makes possible the estimation of the number of new
varicella cases per age group per year (denoted Vi,
where i is the age class) ; it is the extrapolated total
number of cases of varicella (V ) in France, over 1 year,
as derived from the Sentinelles data, apportioned
to the observed age-distribution ( fi) of the varicella
cases compiled through the Sentinelles network
(Vi=V * fi ). Assuming the epidemiology of varicella
has been stationary over time, the counts Vi are the
age-specic incidence experienced by a birth cohort
throughout life. The history of varicella in a birth
cohort was therefore simulated as follows : starting
from a totally susceptible birth cohort of size
L0=720 000, counts of living individuals were calculated in relation to age by progressively discounting
deaths (Li=Lix1 * (1xdix1), where Li is the number
of living individuals in age class i and di the all causes
death rate in this age class). The age-specic number
of living non-immune (denoted Ni) was calculated
accordingly, by applying the age-specic incidence of
varicella Vi to the counts of non-immune, starting
from the rst age class (Ni=(Nix1xVix1) * (1xdix1);
N0=L 0=size of the birth cohort). We used 1-year
age classes up to age 20 and 5 years age classes
afterwards.
Using the model, we calculated age-specic incidence rates per population, per living non-immune
(or force of infection ) and determined the lifetime
risk of varicella from the predicted percentage of
immune in the uppermost age class. To assess the
variability of the results due to random uctuations, we replicated all calculations with source data
30
(number of incident cases, hospitalization and deaths,

and age distribution of cases) systematically varied
over a range reecting the degree of uncertainty of
the original data. We performed 1000 independent
simulations, each time using a dierent combination
of resampled source data. We report the results as the
mean and range obtained from the simulations, and
also exhibit the special case where the lifetime risk
of varicella is 100%. Source data were resampled as
follows :
Using data from the Sentinelles network, the extrapolated annual incidence of varicella (V ) diagnosed by GPs in France between 1991 and 1998
was estimated at 680 400 cases (http ://www.u444.
jussieu.fr/sentiweb). It led to a lifetime risk of 96 %
(we restate that the lifetime risk calculation is based
on the percentage of immune individuals in the
uppermost age class predicted by the model). To
account for underestimation, this gure was considered the lower limit of the incidence. To explore
the range of lifetime risk from 96 to 100 % in the
sensitivity analysis, we chose, in each simulation, the
value of V at random between 680 400 and the
annual incidence leading to a lifetime risk of 100 %.
This last gure was determined for each simulation
because it was dependent on the resampled age
distribution of cases ; to study the special case of a
100 % lifetime risk, the above-determined value was
used for V.
The age distribution of cases ( fi) was resampled
by creating, each time, a surrogate series of cases
by resampling with replacement the original series of
cases described to the Sentinelles network (n=28 453
over the period 19918), over which the age distribution was then calculated.
For varicella-related hospital and mortality counts,
the original data were resampled, assuming that these
602
Table 3. Average age-specic incidence rates of varicella per year in the general population and in non-immune
persons, France, 1991 8. For the incidence in non-immune persons, the lifetime risk ranged from 96 to 100 %, with
a mean case corresponding to 98 %. The special case of a 100 % lifetime risk is reported in a separate column
Incidence
per 100 000 general population
Incidence per 100 000 non-immune population
Age group
(years)
Mean (range)
Lifetime risk 96 %x100 %

Mean (range)
Lifetime risk 100 %

Mean (range)
<1
14
514
1524
2534
3544
4564
o65
<15
o15
4 973
12 124
3 600
342
344
92
12
10
5 974
128
4 973
15 015
17 329
3 620
5 751
3 324
691
769
14 168
3 229
5 093
15 439
19 351
4 632
8 557
8 135
2 747
4 829
14 953
5 943
(44875521)
(14 38315 676)
(15 31119 991)
(27104936)
(39048860)
(15099121)
(1853378)
(1617567)
(13 33415 128)
(19016185)
10 866 (896513 497)
Incidence
(per 100 000 non immune)
1 255 (12281285)
Incidence
(per 100 000 population)
Total
(44875521)
(11 70212 534)
(34413764)
(305377)
(309386)
(72110)
(819)
(515)
(58266143)
(119138)
25 000
10 000
0
0
20
40
Age
60
80
(46005552)
(15 09215 802)
(18 62120 058)
(41815087)
(77019330)
(692210 186)
(16824768)
(25538936)
(14 68915 214)
(55146836)
13 287 (12 98213 643)
25 000
10 000
0
0
20
40
Age
60
80
Fig. 1. Incidence in the general French population (left) and the non-immune population (right). Solid line corresponds
to the mean case (lifetime risk of 98 %), dotted lines to the minimum (lifetime risk 96 %) and maximum (lifetime risk 100 %)
from the sensitivity analysis.
counts conformed to the Poisson distribution. For

each age group, the original count was used as an
estimate of the mean number of cases.
R ES U L T S
The incidence of varicella diagnosed by GPs for 1991
4, was not dierent from the incidence for 19958.
There was no sex-related dierence in this incidence.
In the general population, the incidence of varicella
cases seen by GPs peaked among children aged 4
years, and then decreased regularly (Table 3, Fig. 1).
Among individuals aged more than 15 years, the overall incidence was 47 times lower than in children, and
in addition, decreased markedly with age. An annual
estimated average of 57 881 cases were diagnosed by
French GPs in subjects aged 15 years and more

(range : 53 98762 221), i.e. 8.3% of the total annual
number of cases of varicella (range : 7.78.9 %). In a
birth cohort, 10.8 % of subjects remained susceptible
at age 15 (range : 6.414.9%).
The force of infection of varicella, i.e. its incidence
among non-immune persons, peaked during childhood, at age 5, and also displayed a second peak
among subjects 30 years old. Thus, the incidence for
the 2529 years age group was 42 % higher than for
the 2024 years age group, and the incidence in those
aged 3539 years was 36% less than in those aged
3034 years. This feature was found regardless of the
assumed lifetime risk of varicella. However, the risk
starts increasing again in the old when 100 % lifetime
risk is assumed.
603
Table 4. Average hospitalization and mortality rates for varicella per year, in the general French population
and in non-immune persons by age group, France
Hospitalization (19979)
Mortality (19907)
Age group
(years)
per 100 000

population
per 100 000

non-immune
per 100 000

cases
per 1 000 000

population
per 1 000 000

non-immune
per 1 000 000

cases
<1 year
14 years
514 years
1524 years
2534 years
3544 years
4564 years
o65 years
<15 years
o15 years
172
28
5.6
2.4
4.9
1.8
0.8
0.8
23.0
1.9
5.9
172
35
27
25
82
64
46
60
54
47
3467
235
156
707
1438
1945
6902
8154
383
1464
2.86
0.83
0.24
0.18
0.36
0.22
0.15
0.54
0.58
0.29
0.35
2.86
1.03
1.17
1.92
5.98
7.81
8.13
40.2
1.37
7.32
3.00
57
7
7
53
104
235
1219
5345
10
228
Total
(156189)
(2533)
(4.86.6)
(1.93.1)
(4.35.7)
(1.32.2)
(0.61.2)
(0.61.2)
(21.524.4)
(1.72.1)
(5.66.3)
(156189)
(3140)
(2233)
(1737)
(53138)
(26184)
(14194)
(14536)
(4958)
(1792)
51 (3363)
(30754032)
(209269)
(134186)
(528962)
(12001751)
(12252602)
(380412 233)
(468715 183)
(357416)
(12641670)
473 (441504)
Each year, varicella and its complications were

responsible for an average of 3306 hospitalizations, and
19 deaths (Table 1). About 78% of the varicella patients
hospitalized for pneumonia and 70% of the deaths
attributed to varicella concerned persons of 15 years or
more (Table 1). Congenital varicella accounted for an
average of 29 hospitalizations each year. Among nonimmune persons, the risk of varicella-related hospitalization was highest among infants. It was lower
and approximately constant in other age-groups, and
exhibited a marked increase at 30 years (Table 4). The
death rate was U-shaped, decreasing in childhood and
increasing with age thereafter.
The hospitalization and case fatality rates for varicella were highest among adults, and then infants, and
the lowest rates were for children. The risk of hospitalization was 4 50 times higher in adults than in children 514 years old. The case fatality rate showed a
risk of death 7.5 times higher in subjects aged from 15
to 24 years than in children of 514 years, and was
more than 174 times higher in adults aged 45 years or
more. There was a higher risk of death and hospitalization in infants than in children aged 1 4 years.
Underlying conditions known to increase the severity
or risk of occurrence of varicella accounted for 30 %
of varicella-related deaths and for 7.5 % of varicellarelated hospitalizations (Table 2).
Ranges for incidence rates among the general population were narrow. On the contrary, estimates of the
force of infection spanned a wide range around the
mean value for those over 15. For younger individuals however, a 10% range around the mean value
(011.1)
(02.78)
(00.98)
(01.12)
(01.14)
(01.01)
(00.61)
(01.38)
(01.30)
(0.070.62)
(0.200.66)
(011.1)
(03.4)
(04.6)
(010.1)
(024.2)
(053.1)
(093.9)
(2.43501)
(0.03.18)
(1.3721.4)
(1.225.54)
(0221)
(024)
(027)
(0357)
(0338)
(01072)
(04971)
(015 395)
(022)
(53484)
28 (1154)
was observed (Table 3). These variations were mainly

a consequence of the assumed lifetime risk, and indeed
the force of infection increased with the lifetime risk.
Nevertheless, even with a lifetime risk of 100 %,
there were substantial variations resulting from the
age distribution of cases. These increases accounted
in turn for much of the variability in the hospitalization and mortality rates for non-immune persons.
The hospitalization and mortality rates in the general
population and among varicella cases were not
sensitive to the overall incidence of varicella. For
these rates, the main source of variability was in the
counts of hospitalizations or deaths by age group,
which were modelled on the basis of the Poisson
distribution. The lowest bound estimates for mortality were indeed 0, because with this distribution, a
0 death count in an age group was common in the
replicated samples.
DISCUSSION
This work provided estimates of the force of infection
of varicella, and of varicella-related hospitalization
and death rates according to age in France, a country
where no mass immunization has been implemented.
It showed that the force of infection increased in
30-year-old adults, and that although the incidence of
varicella among non-immune individuals decreased
with age, the hospitalization and fatality rates increased exponentially with age.
Estimates of the age-related force of varicella infection, hospitalization and death rate in non-immune
604
persons were obtained on a nationwide level. Certain

previously published estimates of the force of infection were obtained by dividing the yearly incidence of
varicella by the percentage of susceptible adults [20],
with results similar to those reported here. However,
their estimates were limited to young adults. The prevaccination force of varicella infection estimated in
Canada [21] was based on mathematical modelling,
data for antibody prevalence, and billings. This procedure yielded higher rates than those we obtained,
except when the lifetime risk was set to 100 %. For
example, the force of infection in subjects 25 44 years
old ranged from 2 to 8 % in this work for a lifetime
risk increasing from 96 to 100 % ; the upper limit compared to the 8% of the Canadian study. Likewise,
the force of infection ranged from 0.1 to 7 % in individuals older than 65, and the special case of 100 %
lifetime risk yielded an average value of 4%, in
accordance with the Canadian study.
One surprising feature of the force of infection
reported here is that besides the expected peak during
childhood, a second peak appeared in the 2535 years
age group. The occurrence of this peak had previously
been postulated [22], but never actually observed.
Presumably, individuals in this age group are naturally in contact with young children through parenthood, and are therefore likely to be infected if they
are not already immune. This implies that the risk
of varicella may be very heterogeneous among adults,
and that familial or occupational exposure must
be taken into account in the individual risk/benet
analysis of vaccination. On the whole, the 30-year
incidence peak provides a strong justication for
screening young adults before they have their rst
child.
The age-specic yearly incidence rates of varicella
observed in France in the general population and
reported here correspond to those previously published for the United States [1, 3, 20, 23, 24], and
so do the French mortality and hospitalization rates,
per population and per number of cases [1, 3, 10,
11, 23].
It is well known that the complications of varicella
tend to be more severe in adults than in children.
Thus, in previous studies conducted in the United
States, the risks of hospitalization and death were
highest among those aged 20 years or more [1, 3, 8, 10,
23]. For instance, the risk of dying of varicella was 25
times greater in adults than in children aged 1 4 years
[1, 10], and the risk of hospitalization 14 times greater
[3, 23]. Our estimates show a similar trend, as the risk
of death was 30 times greater in subjects over 15 years

than in children aged 1 4 years, but the risk of hospitalization was only 7 times greater. Note that in
previous studies all subjects aged 20 years or more
were considered as adults for the calculation of
varicella-related risks of death and hospitalization
[3, 10, 23]. However, our results show that case fatality or case hospitalization rates, far from being
uniformly distributed in adults, are greatly dependent
on age.
Adults o25 years old accounted for 62 % of all
varicella deaths in France, a higher proportion than
in the United States, where this gure was estimated
at about 54 % [1, 10]. Most of those who died of, or
were hospitalized for, varicella were previously healthy
individuals. We found that an underlying condition,
often immunosuppression, was a factor contributing
to death in 30% of our adult cases, as reported in
other countries [9, 10, 25]. In two studies, 15% of the
persons hospitalized for varicella were reported to
have had an underlying condition known to increase
the severity or risk of occurrence of varicella [2, 11].
The rate we calculated was lower, despite a comparable case hospitalization rate.
In temperate countries, it is often admitted that the
annual incidence of varicella almost equals the size of
the birth cohort. Seroprevalence studies, which are the
gold standard for establishing previous infection by
varicella, showed that the lifetime risk of varicella was
indeed close to 100 %, but published estimates have
generally yielded smaller values : for example, the lifetime risk was estimated at 97.8 % in a recent study
from Spain [26]. The Sentinelles network estimates
that there are approximately 680 400 cases of varicella per year, which leads to a lifetime risk of 96%.
This is likely underestimated, because data is reported by GPs only, hence patients who consulted a
paediatrician, or dermatologist, or went to a hospital
emergency unit were not accounted for. Furthermore, parents may seek medical advice for the index
case in the family but less frequently for subsequent
cases. Nevertheless, the estimated lifetime risk of acquiring varicella was over 95 %, indicating that only
a small percentage of patients are likely to be missed
by the Sentinelles network. We investigated this underestimation in two ways : rst, the sensitivity analysis
took into account the fact that the lifetime risk could
be between 96 and 100%, and we also investigated
the special case of a 100 % lifetime risk. This analysis
showed that there was strong uncertainty regarding
the actual level of the force of infection after age 50,

due to the small percentage of the population still
vulnerable beyond that age.
Our hospitalization and mortality data were certainly closer to reality than those in certain other
reports, because they were obtained from the full set
of hospital discharge reports and death certicates.
Although hospitalization data, unlike those concerning mortality, describe episodes of care and thus are
not person-based, varicella is not a recurrent disease,
and repeated hospitalization seems improbable [27].
The retrospective nature of the present study might
raise the question of the accuracy of the mortality and
hospital discharge data, and of the actual nature of
the cases diagnosed as varicella during a visit with a
physician. Nevertheless, the clinical denition of varicella is simple enough for it to be diagnosed with
precision in clinical practice, and it is unlikely to be
confused with other conditions causing vesicles. At
the same time, we cannot completely rule out the possibility that certain cases of disseminated herpes zoster
in elderly adults might have been misclassied as primary varicella. We also admit that adult cases may
have been more likely to have received medical attention than milder cases in children.
In conclusion, the estimates provided by our study
show that the force of infection of varicella increases
in 30-year-old adults, and conrm the strong dependence of varicella-related mortality and hospitalization rates on age. In countries where no routine
childhood immunization is implemented, targeted
vaccination of non-immune adolescents and adults
could still reduce the current medical and nancial
burden constituted by varicella. Medicoeconomic
evaluation of the benet of such vaccination is therefore needed for decision making.
REFERENCES
1. CDCs. Prevention of varicella. Recommendations of
the Advisory Committee on Immunization Practices.
MMWR 1996 ; 45 : RR-11.
2. Preblud SR. Age-specic risks of varicella complications. Pediatrics 1981 ; 68 : 147.
3. Guess HA, Broughton DD, Melton LJ, Kurland LT.
Population based studies of varicella complications.
Pediatrics 1986 ; 78 (Suppl) : 7237.
4. Halloran ME. Epidemiologic eects of varicella
vaccination. Infect Dis Clin North Am 1996 ; 10 :
63155.
5. Bovill B, Bannister B. Review of 26 years hospital
admissions for chickenpox in North London. J Infect
1998 ; 36 (Suppl 1) : 1723.
605
6. Gray GC, Palinkas LA, Kelley PW. Increasing

incidence of varicella hospitalization in United States
army and Navy personnel : are todays teenagers more
susceptible ? Should recruits be vaccinated ? Pediatrics
1990 ; 86 : 86773.
7. Fairley CK, Miller E. Varicella-zoster virus epidemiology a changing scene ? J Infect Dis 1996 ; 174
(Suppl 3) : S3149.
8. Wharton M. The epidemiology of varicella-zoster
virus infections. Infect Dis Clin North Am 1996 ; 10 :
57181.
9. Joseph CA, Noah ND. Epidemiology of chickenpox in England and Wales, 196785. BMJ 1988 ; 296 :
6736.
10. Meyer PA, Seward JF, Jumman AO, Wharton M.
Varicella mortality : trends before vaccine licensure in
the United States, 19701994. J Infect Dis 2000 ; 182 :
38390.
11. Lin F, Hadler JL. E. Epidemiology of primary varicella
and herpes zoster hospitalizations : the pre-varicella
vaccine era. J Infect Dis 2000 ; 181 : 1897905.
12. Paul E, Thiel T. Epidemiology of varicella zoster infection. Results of a prospective study in the Ansbach area.
Hautarzt 1996 ; 8 : 6049.
13. Salleras L, Dominguez A, Vidal J, Plans P, Salleras M,
Taberner JL. Seroepidemiology of varicella-zoster
virus infection in Catalonia (Spain). Rationale for
universal vaccination programmes. Vaccine 2001 ; 19 :
1838.
14. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in Canada
and the United Kingdom. Epidemiol Infect 2001 ;
127 : 30514.
15. Bramley JC, Jones IG. Epidemiology of chickenpox in
Scotland : 1981 to 1998. Commun Dis Public Health
2000 ; 3 : 2827.
16. Coplan P, Black S, Rojas C, et al. Incidence and hospitalization rates of varicella and herpes zoster before
varicella vaccine introduction : a baseline assessment
of the shifting epidemiology of varicella disease. Pediatr
Infect Dis J 2001 ; 20 : 6415.
17. Gil A, Oyaguez I, Carrasco P, Gonzalez A. Epidemiology of primary varicella hospitalizations in Spain.
Vaccine 2002 ; 20 : 2958.
18. Deguen S, Chau NP, Flahault A. Epidemiology of
chickenpox in France (19911995). J Epidemiol
Commun Health 1998 ; 52 (Suppl 1) : 46S 49S.
19. Chauvin P, Valleron AJ. Attitude of French general
practitioners to the public health surveillance of
communicable diseases. Int J Epidemiol 1995 ; 24 :
435 40.
20. Smith KJ, Roberts MS. Cost eectiveness of vaccination strategies in adults without a history of
chickenpox. Am J Med 2000 ; 108 : 7239.
21. Brisson M, Edmunds WJ, Gay NJ, Law B, De Serres G.
Modelling the impact of immunization on the epidemiology of varicella zoster virus. Epidemiol Infect
2000 ; 125 : 65169.
22. Garnett GP, Grenfell BT. The epidemiology of
varicella-zoster virus infections : the inuence of
606
varicella on the prevalence of herpes zoster. Epidemiol

Infect 1992 ; 108 : 51328.
23. Choo PW, Donahue JG, Manson JAE, Platt R. The
epidemiology of varicella and its complications. J Infect
Dis 1995 ; 172 : 70612.
24. Lieu TA, Cochi SL, Black SB, et al. Cost-eectiveness
of a routine varicella vaccination program for US
children. JAMA 1994 ; 271 : 37581.
25. Miller E, Vurdien J, Farington P. Shift in age in

chickenpox. Lancet 1993 ; 341 : 3089.
26. Munoz MP, Dominguez A, Salleras L. Estimated varicella incidence on the basis of a seroprevalence survey.
Epidemiol Infect 2001 ; 127 : 5017.
27. Wallace MR, Chamberlin CJ, Zerboni L, et al. Reliability of a history of previous varicella infection in
adults. JAMA 1997 ; 278 : 15202.
Vaccine 20 (2002) 295298
Short communication
Epidemiology of primary varicella hospitalizations in Spain

Angel Gil a, , Itziar Oyagez a , Pilar Carrasco a , Antonio Gonzlez b
a
Department of Health Sciences, Rey Juan Carlos University, Avda de Atenas s/n, 28922 Alcorcn, Madrid, Spain
b Medical Department, Aventis Pasteur MSD, P de la Castellana 141, 28046 Madrid, Spain
Received 13 March 2001; received in revised form 3 August 2001; accepted 13 August 2001
Abstract
An approach to the burden of varicella can be obtained from information on the hospitalizations. Data were obtained from the national
surveillance system for hospital data. All hospital discharges for varicella were analyzed for the 19951998 period. A total of 3632 primary
varicella-related discharges were identified, representing an annual incidence of 2.8 per 100,000 population. A total of 58% of cases
were <10 years of age and 33% were 2150 years old. Each year primary varicella will be responsible for 6174 days of hospitalization,
representing an annual cost of 1.6 million euros. There is substantial severe morbidity each year from varicella that, to reduce, would
require vaccination of infants and susceptible adults. 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Varicella; Hospitalization; Spain
1. Introduction
Varicella is a highly infectious disease that is preventable
by vaccination. The attenuated live varicella vaccine prevents most of the morbidity caused by primary varicella in
children [1]. In the United States, population-based surveys
that demonstrated the extent of varicella morbidity and its
complications and costs provided the rationale for adopting
a policy for universal vaccination at the age of 1218 months
[26]. However, data on the health and economic burdens
of varicella in Europe are limited and varicella vaccination
has not become standard practice. In Spain, as in Europe,
varicella vaccination is only limited to high-risk groups and
their contacts.
Hospital discharge databases provide a complete record
of all hospitalizations and are not subject to under diagnosis
and deficiencies in reporting that limit surveillance systems
of outpatient diseases. A recent study of varicella-related
hospital discharges carried out in the USA found that the
positive predictive value of varicella listed as a discharge
diagnosis was 87%, indicating that discharge data provide
a valid measurement of varicella-related hospitalization [7].
In addition, hospitalization databases provide documentation of the severe and costly end of the disease spectrum,
and it is here that vaccination is likely to have its great Corresponding author. Tel.: +34-91-488-8804; fax: +34-91-488-8848.
E-mail address: a.gildemiguel@cs.urjc.es (A. Gil).
est impact. This epidemiological retrospective survey was

undertaken to obtain population-based estimates of hospitalization rates for primary varicella in Spain during a
4-year period (19951998), to determine the epidemiology
of these hospitalizations, and to obtain estimates of the
overall cost of hospitalizations due to primary varicella.
2. Material and methods

This retrospective study was based on the national
surveillance system for hospital data (Conjunto Mnimo
de Datos; CMBD) maintained by the Ministry of Health
[8]. This system uses clinical codes for the Spanish version of the 9th International Classification of Diseases
(Modificacin Clnica Clasificacin Internacional de Enfermedades; CIE-9-MC) and covers an estimated 83% of
public hospitals [8,9]. Information on private hospitals is
available only for a few autonomous regions, but these
hospitals account for only a small proportion of all hospital
admissions throughout Spain [8]. Compulsory health insurance covers an estimated 99.5% of the Spanish population,
but even persons not covered by health insurance can be
treated in hospitals of the National Health System [10].
All hospital discharges for primary varicella (ICD-9-CM
052.0052.9; first listed diagnosis) were analyzed for the
4-year study period (1 January 1995 through 31 December
1998). For each case of varicella, data were gathered on age,
0264-410X/01/$ see front matter 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 2 6 4 - 4 1 0 X ( 0 1 ) 0 0 3 7 0 - X
296
A. Gil et al. / Vaccine 20 (2002) 295298
sex, underlying conditions, average length of stay, and outcome (survival to hospital discharge or died). A person was
considered to have an underlying condition if there was a
discharge diagnosis code for a condition known to increase
the risk of occurrence or severity of primary varicella.
These conditions included immunosuppression secondary
to radiotherapy or chemotherapy (ICD-9-CM V58.0, V58.1
and V07.2), leukemia (ICD-9-CM 200.0208.9), human immunodeficiency virus (ICD-9-CM 042.0044.9 and 795.8),
childhood immunodeficiencies (ICD-9-CM 288.0288.2,
179.0179.9), other malignancies (ICD-9-CM 140.0199.9)
or other blood dyscrasia (ICD-9-CM 284.0284.9).
Table 2
Underlying conditions among persons hospitalized with primary varicella
during the 19951998 period
Cases (%)
Human immunodefiency virus

Leukemia
Chidlhood immunodeficiencies
Radiotherapy/chemotherapy
Other malignancies
Other blood dyscrasia
130
114
32
1
2
18
Total
297 (100)
(44)
(38)
(11)
(0.3)
(0.6)
(6)
of 908 per year (range: 7801037). The annual incidence

of hospitalization was 2.8 per 100,000 population. Table 1
shows the average number of hospitalizations and incidence
by age group and by year. A total of 58% of the primary varicella hospitalizations were children 10 years of age, and
33% were adults between 21 and 50 years of age. Overall,
58.6% of patients were females. The ALOS for all patients
was of 6.8 7.4 days: 5.6 5.6 days for children 10 years
in age and 9.08.7 days for persons >10 years in age. Overall, varicella was responsible for 6174 (range: 55617395)
days of hospitalizations per year; 2969 (range: 23093459)
and 3400 (range: 29753459) days in persons 10 and >10
years in age, respectively. The number of primary varicella
hospitalizations increased substantially in 1997 and 1998
compared with the 19951996 period. Among all patients,
297 (8%) had an underlying condition recorded (Table 2),
among which human immunodeficiency virus (HIV) infection and leukemia accounted for 244 (82%) of cases. There
were six hospital deaths related to primary varicella, averaging 1.5 deaths per year, and 1.6 deaths for every 1000
varicella hospitalizations. Four of those who died were >30
years of age and none of the deaths were in patients with
underlying illness. During this 4-year period, the mean annual cost of primary varicella hospitalizations for centers
participating in the National Health System was 1.6 million euros (1.1 million euros for children <10 years in age
and 0.5 million euros in older children, adolescents and
adults).
2.1. Statistical methods

The average number of cases of primary varicella per year
(overall and stratified by age groups), annual hospitalization rate (per 100,000 population), average length of stay in
the hospital (ALOS) and case-fatality ratio were calculated.
Population data obtained were from the 19951998 Spanish
census projection and adjusted to the 83% of the population
covered by hospitals included in the CMBD surveillance
system. It was assumed that the distribution by age of the
population covered by these public hospitals was equal to
the general population [10]. The average annual number of
days of hospitalization during the 4-year period was calculated using the cumulative average number of cases per year
and the ALOS. The costs to the health care system due to primary varicella hospitalizations were calculated by considering the unit cost (1995 values) for 1-day of hospital care in a
pediatric ward (365 euros) and in a general ward (153 euros)
[11]. These values were updated for the 19961998 period.
Statistical analyses were performed using SPSS software
for personal computers (version 8.0; Chicago, IL, USA).
3. Results
Over the 4-year study period, there were 3632 primary
varicella-related hospital discharges in Spain, for average
Table 1
Average number of hospitalizations and incidence (per 100,000) of primary varicella by group of age and by year
Age group (years)
1995
1996
1997
1998
1995-98
na
Incidence
Incidence
01
12
35
610
1120
2130
3150
>50
151
71
172
85
37
138
121
27
24.0
22.4
17.7
4.9
0.8
2.6
1.4
0.3
117
65
196
61
27
126
148
40
18.4
21.1
20.2
3.6
0.6
2.3
1.6
0.4
168
78
245
119
48
128
206
45
26.6
24.4
25.7
7.2
1.1
2.4
2.3
0.4
151
102
242
98
47
119
208
46
23.9
32.1
25.6
6.0
1.1
2.2
2.3
0.5
587
316
855
363
159
511
683
158
23.2
25.0
22.3
5.4
0.9
2.3
1.9
0.4
Total
802
2.5
780
2.4
1037
3.2
1013
3.1
3632
2.8
n: cases.
Incidence
Incidence
Incidence
4. Discussion
From 1995 to 1998, the annual incidence of hospitalization by primary varicella in Spain was about 2.8 cases per
100,000 population. This rate remained relatively stable during the 19951996 period (2.52.4/100,000), but increased
in 19971998 (3.23.1/100,000). A total of 960,740 cases
of varicella were officially notified to health authorities during the study period, giving a hospital admission rate of 38
cases per 10,000 [1214]. These data are similar to those
reported from Scotland, Canada and the USA, where rates
of hospitalization have ranged from 29 to 55 per 10,000
reported primary varicella cases [1518].
A study carried out in several areas of Spain in 1995
showed that the prevalence of varicella antibodies reached 80
and 91% in 69- and 1014-year-old children, respectively
[19]. More recent studies carried out in Madrid and Catalonia found an antibody prevalence of 94% in adolescents
[20,21]. According to these data, it seems clear that in Spain
varicella predominantly affects pre-school and early primary
school children. Our results show that the incidence of hospitalization among children 5 years of age was >15-fold
higher than that among adolescents and adults. However,
>35% of the hospitalizations for primary varicella were in
adults >20 years of age, and 4% were in persons >50 years
of age. Primary varicella in adults is not common, but the
disease is usually more severe and complications are more
frequent, so adults will be more likely to require hospitalization [21]. Our data indicate there is an appreciable morbidity and mortality due to varicella among adolescents and
adults, many of these cases could probably be prevented
with effective vaccination programs for children.
In May 1995, the American Academy of Pediatrics (AAP)
recommended universal childhood vaccination against varicella and in June 1996, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control
and Prevention issued a similar recommendation [22,23]. In
Europe, many still consider varicella a benign disease for
which routine vaccination is of questionable benefit. There
are also concerns that the duration of immunity conferred by
vaccination may be shorter than expected, that vaccination
may create a susceptible older population at risk of severe
complications, and that decreased circulation of varicella
virus could results in an increase in herpes zoster [2426]. In
the US, licensing of varicella vaccine was delayed for many
years due to similar concerns. However, after collection of
data on the cost of severe varicella and evaluation of data
collected on duration of immunity and possible vaccine relationship to herpes zoster, it was decided that the vaccine was
safe and would be cost effective for routine childhood immunization [25,7,24]. Despite concerns on the part of many
physicians, recommendations to vaccinate children routinely
were made by the AAP and the ACIP, shortly after vaccine
licensing [2226]. Within 4 years, in sites where high vaccination levels were achieved, incidence of both mild and severe varicella had dropped by nearly 80% in all age groups.
297
Our findings provide evidence that primary varicella

continues to result in the hospitalization of children, adolescents and adults in Spain. Most of these cases (92%) did
not have any underlying condition. The mean annual cost of
these hospitalizations (1.6 million euros) reflects only the
most severe manifestations of the disease, as only a limited
percentage of varicella cases required hospital admission
[11]. Besides, the cost of hospitalization from herpes zoster
was not included. In studies carried out in the US and Australia, this has been found to be 46-fold higher than the
overall cost of hospitalization from primary varicella.
It has been estimated that the overall cost of varicella
in Spain, including direct and indirect costs, will be about
20.6 million euros [11]. Although, this figure is considerably lower than the estimated costs for major health
problems, such as chronic respiratory diseases (100 million euros), ischemic heart disease (245 million euros) and
cerebro-vascular disease (255 million euros), it is a cost
that could be potentially reduced by widespread varicella
immunization [10]. However, before deciding to establish
local immunization programs, additional population-based
studies would be needed for assessing the community burden of varicella and estimating the cost-effectiveness of the
different strategies for varicella vaccination.
References
[1] Gershon AA. Viral vaccines of the future. Pediatr Clin North Am
1990;37:689707.
[2] American Academy of Pediatrics. The 1997 Red Book. Elk Grove
Village, Illinois: American Academy of Pediatrics, 1997.
[3] Lieu TA, Cochi SL, Black SB, et al. Cost-effectiveness of a
routine varicella vaccination program for US children. JAMA
1994;271:37581.
[4] Huse DM, Meissner HC, Lacey MJ, Oster G. Childhood vaccination
against chickenpox: an analysis of benefits and costs. J Pediatr
1994;124:86974.
[5] Peterson CL, Mascola L, Chao SM, et al. Children hospitalised for
varicella: a prevaccine review. J Pediatr 1996;129:52936.
[6] Centers for Disease Control. Summary of notifiable diseases, United
States, 1994. MMWR 1995;43(53):155.
[7] Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster
hospitalisations: the pre-vaccination era. J Infect Dis 2000;181:1897
905.
[8] Visser LE, Cano Portero R, Gay NJ, Martnez Navarro JF. Impact
of rotavirus disease in Spain: an estimate of hospital admissions due
to rotavirus. Acta Paediatr 1999;426(Suppl):726.
[9] Ministerio de Sanidad y Consumo. Clasificacin Internacional de
Enfermedades 9 Revisin, Modificacin Clnica (9th International
Classification of Diseases, Clinical Modification), 1994.
[10] Favereau, F. and Associates, editors. Healthcare Handbook, vol. 4.2
Spain 19981999. France: Lagon, 1998. p. 51124.
[11] Diez-Domingo J, Ridao M, Latour J, Ballester A, Morant A. A cost
benefit analysis of routine varicella vaccination in Spain. Vaccine
1999;17:130611.
[12] Centro Nacional de Epidemiologa. Enfermedades de declaracin
obligatoria. Espaa, 1995 y 1996. Bol Epidemiol Semanal 1997;5:2.
obligatoria. Incidencia notificada en Espaa, 1996 y 1997. Bol
Epidemiol Semanal 1998;6:2.
298

obligatoria. Incidencia notificada en Espaa, 1997 y 1998. Bol
Epidemiol Semanal 1999;7:2.
[15] Fairley CK, Miller E. Varicella-zoster virus epidemiology; a changing
scene? J Infect Dis 1996;174(Suppl 3):S314319.
[16] Varughese PV. Chickenpox in Canada 19241987. Can Med Assoc
J 1988;138:1334.
[17] Choo PW, Donahue JG, Manson JE, Platt R. The epidemiology of
varicella and its complications. J Infect Dis 1995;172:70612.
[18] Yawn BP, Yawn RA, Lydick E. Community impact of childhood
varicella infection. J Pediatr 1997;130:75965.
[19] Pachn I, Amela C, de Ory F, Leon P, Alonso M. Encuesta nacional
de seroprevalencia de enfermedades inmunoprevenibles Ao 1996.
Bol Epidemiol Sem 1998;6:93104.
[20] Gil A, Gonzlez A, Dal-Re R, Ortega P, Domnguez V. Prevalence
of antibodies against varicella-zoster, herpes simple (type 1 and 2),
hepatitis B and hepatitis A viruses among Spanish adolescents. J
Infect 1998;36:536.
[21] Salleras L, Domnguez A, Vidal J, Plans P, Salleras M, Taberner

JL. Seroepidemiology of varicella-zoster virus infection in Catalonia
(Spain). Rationale for universal vaccination programmes. Vaccine
2001;19:1838.
[22] Committee on Infectious Disease, American Academy of Pediatrics.
Recommendations for the use of live attenuated varicella vaccine.
Pediatrics 1995;95:7916.
[23] Centers for Disease Control and Prevention. Prevention of varicella:
recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR 1996;45(RR-1l):136.
[24] Plotkin SA. Varicella vaccine. Pediatrics 1996;97:2513.
[25] Newman RD, Taylor JA. Reactions of pediatricians to the
recommendations for universal varicella vaccination. Arch Pediatr
Adolesc Med 1998;152:7926.
[26] MacFarlane LL, Sanders ML, Carek PJ. Concerns regarding universal
varicella immunization: time will tell. Arch Fam Med 1997;6:
53741.
Acta Pdiatrica ISSN 08035253
REGULAR ARTICLE
Epidemiology of hospital admissions for chickenpox in children: an Italian

multicentre study in the pre-vaccine era
S Marchetto1 , F M de Benedictis2 , M de Martino (maurizio.demartino@unifi.it)1 , A Versace3 , E Chiappini1 , C Bertaine3 , P Osimani2 , R Cordiali2 ,
C Gabiano3 , L Galli1
1.Department of Paediatrics, University of Florence, Florence, Italy
2.Department of Paediatrics, University Hospital, Ancona, Italy
3.Department of Paediatrics, University of Turin, Turin, Italy
Keywords
Chickenpox, Complications, Epidemiology, Vaccine
Correspondence
Prof. Maurizio de Martino, MD, Department of
Paediatrics, University of Florence,
Anna Meyer Childrens Hospital,
Via Luca Giordano 13, 50132 Florence, Italy.
Tel: +39-055-5662494 |
Fax: +39-055-570380 |
Email: maurizio.demartino@unifi.it
Received
2 May 2007; revised 12 July 2007;
accepted 13 July 2007.
DOI:10.1111/j.1651-2227.2007.00465.x
Abstract
Aim: To describe the chickenpox complications in children in Italy.
Methods: Hospital discharge data from 1 January 2002 to 15 June 2006 were queried for patients
less than 18 years of age in three Italian paediatric university hospitals.
Results: During the study period, 349 children (189 males, 160 females) were admitted. Thirteen
out of 349 (3.7%) of them had serious underlying diseases. Two hundred and sixty-one (74.8%)
children (median age: 41 months, range: 6 days to 200 months) had complicated chickenpox.
Among complications, neurological disorders were the most common (100/261 = 38.3%), followed
by skin and soft tissue infections (63/261 = 24.1%), lower respiratory tract infections (57/261 =
21.8%) and haematological disorders (24/261 = 9.2%). Children with neurological complications
were significantly older and had a longer hospital stay than those with other complications. Three
children with encephalitis and cerebellitis had developed long-term sequelae by the 6-month
follow-up. The mortality rate was 0.4% (1/261 children with complicated chickenpox).
Conclusion: Chickenpox is a disease that can provoke serious complications and long hospital stays, even in
healthy children. Our findings may be useful as background to evaluate the impact of a tetravalent
measles-mumps-rubella-varicella vaccine (MMRV) which is going to be introduced in Italy.
INTRODUCTION
Chickenpox is considered a mild or moderate illness in immunocompetent children (1). Nevertheless, serious complications, including central nervous system involvement,
pneumonia and secondary bacterial infections, can arise (1).
As a consequence, rates of admission to hospital due to
chickenpox in developed countries are considerably high,
the majority of hospitalized patients being children. Furthermore, a mortality rate of 23 cases per 100000 affected
people has been reported (1). An accurate estimate of chickenpox complications is not clearly established, ranging from
40.7% to 83.3% of children hospitalized for this illness (26).
In Italy, rates and characteristics of complicated chickenpox
have not been clearly defined (7,8).
In order to obtain more accurate information, we collected data retrospectively in children hospitalized for
complicated or uncomplicated chickenpox during a 4-year
period in three paediatric hospitals. The results obtained
may provide a background to assess the impact of the imminent immunization programme with tetravalent measlesmumps-rubella-varicella vaccine (MMRV) in Italian
children.
PATIENTS AND METHODS
A retrospective study was conducted to analyse data from
all children admitted for chickenpox to three Italian tertiary care paediatric hospitals (Anna Meyer University
1490
Childrens Hospital, Florence, Salesi University Childrens

Hospital, Ancona and Regina Margherita Childrens Hospital, University of Turin) between 1 January 2002 and 15 June
2006. Overall, the territorial area covered by these hospitals represents about 5% of the Italian paediatric population
(www.demo.istat.it).
Cases were identified locally by reviewing hospital discharge charts and by using the International Classification
of Diseases ninth (ICD-9) diagnostic codes for chickenpox infection or chickenpox-associated complications, as in
other epidemiological studies (2,9,10). The following codes
for chickenpox complications were reviewed: neurological
(including encephalitis [ICD-9 0520], meningitis [ICD-9
3220], cerebral degeneration [ICD-9 3319], post-infective
encephalitis [ICD-9 3236], cerebellar ataxia [ICD-9 3343]
or any alteration of movement or body coordination [ICD9 7812 or 7813]), respiratory (ICD-9 3829, 463, 485,
486), renal (ICD-9 5809, 5819, 5839, 5849, 5997), osteoarticular (ICD-9 7169, 7194, 7202), haematological (ICD-9
2859, 2874, 2875, 2880) or infective complications (ICD9 0389, 0410, 04110, 3760, 0340, 6822, 684).
The diagnosis of encephalitis was based on clinical features (decreased consciousness, seizures, focal neurologic
defects), cerebrospinal fluid pleocytosis and on the results of
specific investigations, such as neuroimaging and electroencephalogram study (11). Cerebellitis was defined by clinical findings (ataxia, tremulousness of the head and trunk
in upright position and of the extremities when attempting

C 2007 The Author(s)/Journal Compilation
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 14901493
Marchetto et al.
to move them against gravity). Presumptive bacterial or viral pneumonia were defined by means of clinical, laboratory
and radiological investigations (11).
As international guidelines do not clearly establish
whether immunocompetent children with cerebellitis or
encephalitis should receive intravenous acyclovir and/or
steroids, treatment of these conditions was decided independently by paediatricians at each centre (12,13).
Data concerning treatment with intravenous steroids (dexamethasone 0.6 mg/Kg/day) and intravenous acyclovir
(1500 mg/m2 body surface area, daily) were recorded and
analysed.
Data from children with serious underlying diseases (i.e.
congenital or acquired immunodeficiency, chronic renal disease, chronic liver disease, thalassaemia and infantile cerebral palsy) were analysed separately.
Statistical analysis
Age of the patients (months) and length of hospitalization
(days) were expressed as median and ranges. The following
age classes were considered: 024 months, 2560 months,
>60 months. Length of hospitalization was stratified as 05
days and >5 days. Comparison among the groups were performed using the 2 or Fishers exact test, when appropriate.
MannWhitney test was used for non-normally distributed
data. A p-value <0.05 was considered statistically significant. Data were analysed using SPSS software (11.0 version;
SPSS Inc, Chicago, IL, USA).
RESULTS
Three hundred and forty-nine children were admitted for
complicated or uncomplicated chickenpox. One hundred
and sixty-five (47.3%) children were hospitalized in Florence,
106 (30.4%) in Ancona and 78 (22.3%) in Turin. Their median age was 40 months (range: 6 days to 206 months). One
hundred and eighty-nine (54.2%) children were male. The
median length of hospitalization was 5 days (range: 128).
Two hundred and sixty-one (74.8%) children had complicated chickenpox. Their median age was 41 months (range:
6 days to 200 months).
The number and rates of complications are shown in
Table S1. Neurological complications (encephalitis, cerebellitis, seizures and facial nerve palsy) were the most common,
followed by skin and soft tissue infections, lower respiratory
tract infections and haematological complications.
Two extremely severe complications occurred in immunocompetent children. A 12-year-old boy had abdominal pain
and haemorrhagic vesicles 3 days after the onset of rash.
During hospitalization he developed thrombocytopaenia,
intravascular disseminated coagulopathy and hepatitis. A
16-year-old girl had purpura and haemorrhagic vesicles
3 days after the diagnosis of chickenpox. She rapidly developed respiratory and renal failure with marked hypotension.
Despite aggressive treatment, she died of septic shock on
28th day. This was the only fatal outcome of a total mortality
rate of 0.4% (1/261 children with complicated chickenpox).
Age and length of hospitalization in children with chickenpox complications are shown in Table S2. Children with neu-
Epidemiology of chickenpox admissions in children
rological complications were significantly older (p < 0.005

vs. those with respiratory complications; p < 0.0001 vs. those
with skin and soft tissue complications) and were admitted
for a significantly longer period (p < 0.005 vs. respiratory
complications; p < 0.005 vs. skin and soft tissue complications) than those with other complications.
Table S3 shows the distribution of patients according to
age classes and length of hospitalization. The median ages
of children with encephalitis or cerebellitis were 65 (range:
9166) and 41 (range: 11117) months, respectively (p =
0.26). Among children with encephalitis or cerebellitis, 49
out of 64 (76.5%) received systemic steroids, and 45 out of
64 (68.7%) received acyclovir intravenously (Table S4).
Children with encephalitis and cerebellitis treated with
systemic steroids were hospitalized for a significantly lower
number of days than those who did not receive steroids
(p = 0.048). Children treated both with and without acyclovir displayed the same hospitalization lengths (p = 0.20).
Three children with encephalitis and cerebellitis, who
were treated with intravenous acyclovir and dexamethasone, presented long-term sequelae at 6-month follow-up. A
3-year-old male and an 8-year-old male with encephalitis developed squint and dysarthria. A 3-year-old male with cerebellitis developed epilepsy.
Eighty-eight (88/349 = 25.2%) children had no complications and were hospitalized for miscellaneous reasons:
age less than 1 year (26/349 = 7.5%), immunodepression
(8/349 = 2.3%), gastrointestinal disorders (11/349 = 3.1%)
and high fever (43/349 = 12.3%).
Eight per cent (28/349) of the children (20 males, 8 females) were younger than a month old. All these children
were immunocompetent and their mothers were VaricellaZoster virus (VZV) seronegative. Among them, five had
complicated chickenpox (2 pneumonia, 2 impetigo and one
anaemia). The time from onset of rash and admission was
1 day in 21 (21/28 = 75%) children. Twenty-seven out of
28 (96.4%) children received acyclovir intravenously and/or
orally.
Thirteen out of 349 (3.7%) children had serious underlying
diseases (nephrosis [3/349 = 0.8%], cerebral tumour [3/349
= 0.8%], bone cancer [1/349 = 0.3%], selective IgA deficiency [1/349 = 0.3%], human immunodeficiency virus-type
1 (HIV-1) infection [1/349 = 0.3%], infantile cerebral palsy
[2/349 = 0.6%], thalassaemia [1/349 = 0.3%] and acute
lymphatic leukaemia [1/349 = 0.3%]). Children with underlying diseases were more likely to be older (median age:
50 months [range: 26166] vs. 41 months [range: 6 days
to 200 months]; p = 0.03) and to be hospitalized longer
(6 days [range: 320] vs. 5 days [range: 128]; p = 0.03)
than children without underlying diseases. Twelve out of
13 (92.3%) children with underlying diseases received acyclovir (orally or intravenously) concomitant with the diagnosis of chickenpox. The time from rash onset to hospital
admission was 1 day (range: 13). Five out of 13 (38.5%)
children with underlying diseases had complicated chickenpox. In particular, a child with infantile cerebral palsy
and a child with thalassaemia had encephalitis. Another
one with cerebral tumour and a child with bone cancer had

1491
Marchetto et al.
thrombocytopaenia. A child with infantile cerebral palsy had

viral pneumonia. None of these children developed longterm sequelae.
DISCUSSION
This is the first Italian multicentre study analysing causes
of hospitalization for complicated or uncomplicated chickenpox in recent years. Our dataset is considerable, because
the involved centres cover about 5% of the Italian paediatric
population.
The proportion of complications reported in literature
among children hospitalized for chickenpox vary from
40.7% to 83.3% (26). Such great variation may depend on
the characteristics of the study population (different ages
and underlying diseases) and the methods by which data
were collected (26). An intermediate value of complications (74.8% of cases) was found in our study.
The main purpose of our study was to describe the causes
of hospitalizations related to chickenpox. The distribution
of complications in our study was similar to that reported
in other paediatric series, with neurological, skin and respiratory involvement occurring most commonly (3,4,9,1417).
Neurological complications were more frequent in children
older than 2 years, while younger children were most likely
to be admitted for respiratory, skin or soft tissue complications (2,5,15,17).
In our study, the most frequent complications were neurological. Among children with encephalitis or cerebellitis,
5% developed neurological sequelae. About 70% of these
patients received intravenous acyclovir with and without
steroids, but our retrospective study is not appropriate to
evaluate the efficacy of any treatment.
A recent review of treatment for chickenpox in healthy
children supports the benefit of acyclovir in reducing the
number of days with fever and the number of lesions, when
treatment is initiated within 24 hours from the rash onset
(12). The number or severity of complications associated
with chickenpox did not differ between patients receiving
acyclovir or placebo (12).
The effect of steroid therapy in children with encephalitis and cerebellitis has not been established (9,11,13,18). In
our study, due to the low number of sequelae, it was not
possible to analyse differences among children according to
type of treatment, but steroid treatment was associated with
a shorter hospitalization length. Further randomized studies
are required to evaluate the possible bias.
A main finding of our study is that 8% of the hospital
admissions for chickenpox occurred in children less than
a month old. This finding can be explained by the fact that
newborns are at higher risk of mortality and serious morbidity from chickenpox (11). Immunisation of the female population prior to pregnancy could prevent these admissions
(11).
Chickenpox can cause greater morbidity in children with
underlying diseases than in the general population (11). In
immunocompromised children, standard management includes their hospitalization (20,21). Intravenous acyclovir is
recommended for treatment of chickenpox in HIV-infected
1492
children with moderate or severe immunosuppression or

with high fever or numerous skin lesions, and in immunocompromised cancer patients (20,21).
Our study may have some limitations. It relies on hospitalization data, and therefore children with mild or moderate complications may have been excluded. However, the
most severe complications requiring hospitalization should
emerge from our survey. Discharge diagnoses codes used for
data collection might be biased, but studies investigating the
accuracy of ICD-9 codes for several types of diseases in different countries, including Italy, suggested that this is a useful
tool for epidemiological studies (3,22,23). Indeed, chickenpox is a common and easily recognisable disease, rarely subject to miscoding (24). Therefore, the use of ICD-9 codes in
the present study should be appropriate.
Immunization against chickenpox has been used routinely
in the United States since 1995 (25). Among the European
countries, it is currently recommended for routine administration in healthy children only in Germany (2527). In
Italy, a tetravalent MMRV is going to be licensed. In the
United States, the introduction of chickenpox vaccine resulted in a substantial decrease in morbidity and mortality rates (28,29), with a reported consequent reduction of
chickenpox-associated medical expenditures (29). A similar
decline is expected to follow the imminent vaccination programme in Italy. Moreover, likewise to what is suggested for
pertussis, the development of herd immunity for VZV may be
useful to protect those subjects, as newborns and immunocompromised children, even if not vaccinated, are at high
risk of chickenpox complications (30). As a matter of fact,
effectiveness of immunization should result in a reduction
of VZV-related hospitalizations. Therefore, we believe that
our study may be useful as a basis to evaluate a modification over time in hospitalization due to chickenpox in our
country.
References
1. Boelle PY, Hanslik T. Varicella in non-immune persons:
incidence, hospitalization and mortality rates. Epidemiol
Infect 2002; 129: 599606.
2. Galil K, Brown C, Lin F, Seward J. Hospitalizations for
varicella in the United States, 1988 to 1999. Pediatr Infect Dis
J 2002; 21: 9315.
3. Lin F, Hadler JL. Epidemiology of primary varicella and
herpes zoster hospitalizations: the pre-varicella vaccine era.
J Infect Dis 2000; 181: 1897905.
4. Carapetis JR, Russell DM, Curtis N. The burden and cost of
hospitalised varicella and zoster in Australian children.
Vaccine 2004; 23: 75561.
5. Mandelcwajg A, Quinet B, Castello B, Parez N, Grimprel E.
Causes of hospitalization of patients with ongoing varicella in
a French children hospital: evolution between 1990 and 2001.
Arch Pediatr 2006; 13: 42935.
6. Dubos F, Grandbastien B, Hue V, Martinot A. Epidemiology
of hospital admissions for paediatric varicella infections: a
one-year prospective survey in the pre-vaccine era. Epidemiol
Infect 2007; 135: 1318.
7. Gabutti G, Penna C, Rossi M, Salmaso S, Rota MC, Bella A,
et al. The seroepidemiology of varicella in Italy. Epidemiol
Infect 2001; 126: 43340.

Marchetto et al.
8. Losurdo G, Bertoluzzo L, Canale F, Timitilli A, Bondi E,

Castagnola E, et al. Varicella and its complications as cause of
hospitalisation. Infez Med 2005; 13: 22935.
9. Bonhoeffer J, Baer G, Muehleisen B, Aebi C, Nadal D, Schaad
UB, et al. Prospective surveillance of hospitalisations
associated with varicella-zoster virus infections in children
and adolescents. Eur J Pediatr 2005; 164: 36670.
10. Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil K, Seward JF.
Incidence of herpes zoster, before and after varicella
vaccination-associated decreases in the incidence of varicella,
19922002. J Infect Dis 2005; 191: 20027.
11. Gnann JW. Varicella-zoster virus: atypical presentations
and unusual complications. J Infect Dis 2002; 186(Suppl. 1):
918.
12. Klassen TP, Hartling L, Wiebe N, Belseck EM. Acyclovir for
treating varicella in otherwise healthy children and
adolescents. The Cochrane Library, Issue 4, 2005.
13. Gilden D. Varicella zoster virus and central nervous system
syndromes. Herpes 2004; 11(Suppl. 2): 8994.
14. Tseng HW, Liu CC, Wang SM, Yang YJ, Huang YS.
Complications of varicella in children: emphasis on skin and
central nervous system disorders. J Microbiol Immunol Infect
2000; 33: 24852.
15. Ziebold C, von Kries R, Lang R, Weigl J, Schmitt HJ. Severe
complications of varicella in previously healthy children in
Germany: a 1-year survey. Pediatrics 2001; 108: E79.
16. Mallet E, Maitre M, Delalande-Dutilleul L, Marguet C,
Mouterde O. Evaluation of varicella complications through a
retrospective hospital survey in a paediatric center over 16
years in France. Arch Pediatr 2004; 11: 114551.
17. Koturoglu G, Kurugol Z, Cetin N, Hizarcioglu M, Vardar F,
Helvaci M, et al. Complications of varicella in healthy children
in Izmir, Turkey. Pediatr Int 2005; 47: 2969.
18. Koskiniemi M, Piiparinen H, Rantalaiho T, Eranko P, Farkkila
M, Raiha K, et al. Acute central nervous system complications
in varicella zoster virus infections. J Clin Virol 2002; 25:
293301.
19. Hausler M, Schaade L, Kemeny S, Schweizer K,
Schoenmackers C, Ramaekers VT. Encephalitis related to
primary varicella-zoster virus infection in immunocompetent
children. J Neurol Sci 2002; 195: 1116.
20. Mofenson LM, Oleske J, Serchuck L, Van Dyke R, Wilfert C.
Treating opportunistic infections among HIV-exposed and
infected children: recommendations from CDC, the National
Institutes of Health, and the Infectious Diseases Society of
America. Clin Infect Dis 2005; 40(Suppl. 1): 184.
21. Carcao MD, Lau RC, Gupta A, Huerter H, Koren G, King SM.
Sequential use of intravenous and oral acyclovir in the therapy
of varicella in immunocompromised children. Pediatr Infect
Dis J 1998; 17: 62631.
22. Quan H, Parsons GA, Ghali WA. Validity of procedure codes
in International Classification of Disease 9th revision, clinical
modification administrative data. Med Care 2004; 42: 8019.
23. Frenos S, Galli L, Chiappini E, de Martino M. An increasing

incidence of chickenpox central nervous system complications
in children: whats happening in Tuscany? J Clin Virol 2007;
38: 35861.
24. Gil A, San-Martin M, Carrasco P, Gonzalez A. Epidemiology
of severe varicella-zoster virus infection in Spain. Vaccine
2004; 22: 394751.
25. Heininger U, Seward JF. Varicella. Lancet 2006; 368: 136576.
26. Shinefield H, Black S, Williams WR, Marchant C, Reisinger K,
Stewart T, et al. Dose-response study of a quadrivalent
measles, mumps, rubella and varicella vaccine in healthy
children. Pediatr Infect Dis J 2005; 24: 6705.
27. Heininger U, Desgrandchamps D, Schaad UB. Seroprevalence
of Varicella-Zoster virus IgG antibodies in Swiss children
during the first 16 months of age. Vaccine 2006; 24: 325860.
28. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due
to varicella after implementation of varicella vaccination in
the United States. N Engl J Med 2005; 352: 4508.
29. Zhou F, Harpaz R, Jumaan AO, Winston CA, Shefer A. Impact
of varicella vaccination on health care utilization. JAMA 2005;
294: 797802.
30. Centers for Disease Control and Prevention. Pertussis
vaccination: use of acellular pertussis vaccines among infants
and young children. Recommendations of the Advisory
Commitee on Immunization Practices (ACIP). MMWR
Recomm Rep 1997; 46(RR-7): 125.
Supplementary material
The following supplementary material is available for this
article:
Table S1 Chickenpox-related complications leading to hospitalization.
Table S2 Chickenpox-related complications: age of patients
and length of hospitalization.
Table S3 Distribution of children with complicated chickenpox, according to age classes and length of hospitalization.
Table S4 Distribution of children hospitalized for neurological complications by centre and characteristics.
This material is available as part of the online article from:
http://www.blackwell-synergy.com/doi/abs/10.1111/j.16512227.2007.00465.x
(This link will take you to the article abstract.)
Please note: Blackwell Publishing is not responsible for the
content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the
article.

1493
Epidemiol. Infect. (2002), 129, 599606. f 2002 Cambridge University Press

DOI : 10.1017/S0950268802007720 Printed in the United Kingdom
Varicella in non-immune persons: incidence, hospitalization

and mortality rates
P. Y. B O E L L E 1
AND
T. HA N S L IK 2*
Department of Public Health, Hopital Saint Antoine, Universite Pierre et Marie Curie, Assistance PubliqueHopitaux de Paris, INSERM U444
2
Department of Internal Medicine, Hopital Ambroise Pare, Universite Paris 5, Assistance Publique-Hopitaux de
Paris, INSERM U444
(Accepted 8 August 2002)

SUMMARY
This study was conducted to estimate the varicella morbidity and mortality rates per age group
among the non-immune population in France. Morbidity and mortality data for the years 19909
were derived from nationwide databases and surveillance systems. An incidence/prevalence model
was designed to quantify the non-immune population per age group. The incidence of varicella
in the non-immune population peaks during childhood and again in the 2535 years age group.
For children aged 1 4 years, adults aged 2534 years and those older than 65 years, the
hospitalization rates are respectively 235, 1438 and 8154 per 100 000 cases, and the death rates
are respectively 7, 104 and 5345 per million cases. Case fatality or case hospitalization rates were
not evenly distributed among adults and increased dramatically with age.
INTRODUCTION
Varicella is usually a mild disease. Nevertheless, it
may cause death, although rarely in adults, pregnant
women and immunosuppressed patients [13]. An
ecient live attenuated vaccine has been licensed in
many countries, but few have adopted routine childhood immunization. Today, it is only practised in the
United States (since 1995), and in Japan and Korea
[1]. Widespread childhood immunization should
greatly reduce the number of primary cases. However,
it may also favour an increase in complications, as
a result of the shift in the age distribution of the remaining cases towards older persons, because of the
waning of vaccine-induced immunity or the reduction of exposure to infection [4]. This is all the more
concerning since during the pre-vaccine period in the
* Author for correspondence : Federation de Medecine Interne,

CHU Ambroise Pare, 9 Avenue Charles de Gaulle, 92104 Boulogne
Billancourt cedex, France.
United States and United Kingdom, the average age

of cases has already risen [57]. Targeting vaccination to non-immune adults or adolescents therefore has a strong appeal in countries where routine
childhood immunization has not yet been considered. Such targeting may be expected to prevent
a signicant portion of complicated or lethal cases of
varicella, while at the same time avoiding an increase
in its incidence among adolescents and adults.
To assess the benet of this strategy, it is necessary
to determine the epidemiology of complications from
primary varicella in the pre-vaccine era, and the frequency of severe and costly complications. Providing
health professionals and the lay public with estimates
of these factors before any vaccination programme is
implemented may help to gain condence and support
for the programme. Estimates of the incidence of
varicella and of its hospitalization and mortality
rates in the general population have been reported in
countries where the vaccine is not currently in use,
and in the United States for the pre-vaccine era [2, 3,
600
Table 1. Average annual number of varicella-related deaths in France (19907 ) and hospitalizations (19979),
by age group
Age group (years)
Varicella related deaths
Varicella related hospitalization
Varicella meningitis
or encephalitis
Varicella pneumonia
Total number of
hospitalization
<1
2.0
1 4
2.4
12.3
35
17.9
10.3
1240
819
514
1524
2534
1.8
1.3
2.5
30.7
6.7
3.7
13
51
172
348
401
5, 717]. However, none of these reports dealt directly

with the risks for non-immune persons, which are
crucial in deciding for or against the immunization
of an adolescent or adult.
In France, the epidemiology of varicella has not
been changed by the vaccine, as the latter is only licensed for children with leukaemia or cancer, for persons in household contact with immunocompromised
persons and for their care-givers. Using a substantial
database of varicella cases collected by a French
national system of surveillance for communicable
diseases over the last 10 years, and an age-specic
incidence/prevalence model for varicella, we estimated
its age-specic incidence rates in non-immune persons, and computed their varicella-related age-specic
hospitalization and mortality rates.
METHODS
Available surveillance data for varicella consist of
case descriptions that do not allow direct calculation
of its incidence in non-immune individuals. To make
this calculation possible, we constructed an incidence/
prevalence mathematical model for the epidemiology
of varicella, and applied it to a population similar to
that of France. We rst modelled the history of infection in a birth cohort in relation to ageing, and included 100 lagged birth cohorts, in order to re-create
the age structure of the general French population.
The age-specic risks were then obtained by dividing
the numbers of incident cases, hospitalizations and
deaths by the number of living non-immune individuals.
The overall incidence of varicella was obtained
from the French general practitioners Sentinelles surveillance network [18]. The members of this network,
4564
o65
o15
( % all ages)
1.5
2.0
5.8
13.1 (69)
19.1
8.3
7.7
36.7 (32)
114.7
9.7
108.4 (78)
139.7
35 44
20.7
124
14
111
90
845 (26)
All
ages
3306
about 500 voluntary unpaid Sentinel General Practitioners (1 % of all GPs), report cases of communicable diseases every week. Incidence estimates for
the whole country are produced by extrapolation of
the cases reported. It was previously shown that the
characteristics of the GPs in the Sentinel network are
comparable to those of all French GPs as regards
regional distribution, the proportion in rural practice, the type of practice and the distribution of the
main clinical skills [19]. The age distribution of incident varicella cases in general practice was estimated
on the basis of all the varicella cases reported and
described between 1 January 1991 and 31 December
1998 (n=28 453).
All-causes age-specic mortality rates were obtained from the French National Mortality Database
(INSERM SC8). Data concerning mortality for varicella were obtained from the French National Mortality Database, for deaths between 1 January 1990,
and 31 December 1997, as were all deaths coded
varicella (International Classication of Disease, 9th
revision, code 052), and information on underlying
medical conditions (Tables 1, 2).
Hospitalization data were obtained by reviewing
all hospital discharge reports from 1 January 1997 to
31 December 1999 (PMSI Data Processing Centre).
These reports constitute a national collection of all
discharges from all short-stay/acute-care hospitals
since 1997. The national hospital discharge register
of information is abstracted by physicians from information found in the patients medical record, using
the International Classication of Diseases, 10th Revision. Varicella hospitalization was dened as hospital discharges with code B01.0-9 for varicella and its
complications, and code P35.8 for congenital varicella. Information on underlying medical conditions
known to increase the severity or risk of occurrence of
601
Table 2. Percentage of deaths and cases hospitalized in France with underlying conditions known to
increase the severity or risk of occurrence of varicella
International classication of diseases,

9th revision, codes used to
determine underlying conditions
Percentage of
hospitalizations for
varicella
Percentage of
deaths from
varicella
Human immunodeciency virus/AIDS

Leukaemia and other malignancies
Other forms of blood dyscrasia
Immune deciencies
Pregnancy
042.0044.9, 795.8
140.0208.9
284.0284.9
279.0279.9, 288.0288.2
634.0634.9, 647.6, 647.9, 650.0656.9
1.5
3.3
0.5
0.9
1.2
7.5
9.8
17.6
0.7
2
0
Total
varicella was also obtained (Tables 1, 2). The gures

in the Results section include all hospitalizations and
deaths of subjects with varicella-related diagnoses,
either principal or associated.
Data gathered through the Sentinelles network
makes possible the estimation of the number of new
varicella cases per age group per year (denoted Vi,
where i is the age class) ; it is the extrapolated total
number of cases of varicella (V ) in France, over 1 year,
as derived from the Sentinelles data, apportioned
to the observed age-distribution ( fi) of the varicella
cases compiled through the Sentinelles network
(Vi=V * fi ). Assuming the epidemiology of varicella
has been stationary over time, the counts Vi are the
age-specic incidence experienced by a birth cohort
throughout life. The history of varicella in a birth
cohort was therefore simulated as follows : starting
from a totally susceptible birth cohort of size
L0=720 000, counts of living individuals were calculated in relation to age by progressively discounting
deaths (Li=Lix1 * (1xdix1), where Li is the number
of living individuals in age class i and di the all causes
death rate in this age class). The age-specic number
of living non-immune (denoted Ni) was calculated
accordingly, by applying the age-specic incidence of
varicella Vi to the counts of non-immune, starting
from the rst age class (Ni=(Nix1xVix1) * (1xdix1);
N0=L 0=size of the birth cohort). We used 1-year
age classes up to age 20 and 5 years age classes
afterwards.
Using the model, we calculated age-specic incidence rates per population, per living non-immune
(or force of infection ) and determined the lifetime
risk of varicella from the predicted percentage of
immune in the uppermost age class. To assess the
variability of the results due to random uctuations, we replicated all calculations with source data
30
(number of incident cases, hospitalization and deaths,

and age distribution of cases) systematically varied
over a range reecting the degree of uncertainty of
the original data. We performed 1000 independent
simulations, each time using a dierent combination
of resampled source data. We report the results as the
mean and range obtained from the simulations, and
also exhibit the special case where the lifetime risk
of varicella is 100%. Source data were resampled as
follows :
Using data from the Sentinelles network, the extrapolated annual incidence of varicella (V ) diagnosed by GPs in France between 1991 and 1998
was estimated at 680 400 cases (http ://www.u444.
jussieu.fr/sentiweb). It led to a lifetime risk of 96 %
(we restate that the lifetime risk calculation is based
on the percentage of immune individuals in the
uppermost age class predicted by the model). To
account for underestimation, this gure was considered the lower limit of the incidence. To explore
the range of lifetime risk from 96 to 100 % in the
sensitivity analysis, we chose, in each simulation, the
value of V at random between 680 400 and the
annual incidence leading to a lifetime risk of 100 %.
This last gure was determined for each simulation
because it was dependent on the resampled age
distribution of cases ; to study the special case of a
100 % lifetime risk, the above-determined value was
used for V.
The age distribution of cases ( fi) was resampled
by creating, each time, a surrogate series of cases
by resampling with replacement the original series of
cases described to the Sentinelles network (n=28 453
over the period 19918), over which the age distribution was then calculated.
For varicella-related hospital and mortality counts,
the original data were resampled, assuming that these
602
Table 3. Average age-specic incidence rates of varicella per year in the general population and in non-immune
persons, France, 1991 8. For the incidence in non-immune persons, the lifetime risk ranged from 96 to 100 %, with
a mean case corresponding to 98 %. The special case of a 100 % lifetime risk is reported in a separate column
Incidence
per 100 000 general population
Incidence per 100 000 non-immune population
Age group
(years)
Mean (range)
Lifetime risk 96 %x100 %

Mean (range)
Lifetime risk 100 %

Mean (range)
<1
14
514
1524
2534
3544
4564
o65
<15
o15
4 973
12 124
3 600
342
344
92
12
10
5 974
128
4 973
15 015
17 329
3 620
5 751
3 324
691
769
14 168
3 229
5 093
15 439
19 351
4 632
8 557
8 135
2 747
4 829
14 953
5 943
(44875521)
(14 38315 676)
(15 31119 991)
(27104936)
(39048860)
(15099121)
(1853378)
(1617567)
(13 33415 128)
(19016185)
10 866 (896513 497)
Incidence
(per 100 000 non immune)
1 255 (12281285)
Incidence
(per 100 000 population)
Total
(44875521)
(11 70212 534)
(34413764)
(305377)
(309386)
(72110)
(819)
(515)
(58266143)
(119138)
25 000
10 000
0
0
20
40
Age
60
80
(46005552)
(15 09215 802)
(18 62120 058)
(41815087)
(77019330)
(692210 186)
(16824768)
(25538936)
(14 68915 214)
(55146836)
13 287 (12 98213 643)
25 000
10 000
0
0
20
40
Age
60
80
Fig. 1. Incidence in the general French population (left) and the non-immune population (right). Solid line corresponds
to the mean case (lifetime risk of 98 %), dotted lines to the minimum (lifetime risk 96 %) and maximum (lifetime risk 100 %)
from the sensitivity analysis.
counts conformed to the Poisson distribution. For

each age group, the original count was used as an
estimate of the mean number of cases.
R ES U L T S
The incidence of varicella diagnosed by GPs for 1991
4, was not dierent from the incidence for 19958.
There was no sex-related dierence in this incidence.
In the general population, the incidence of varicella
cases seen by GPs peaked among children aged 4
years, and then decreased regularly (Table 3, Fig. 1).
Among individuals aged more than 15 years, the overall incidence was 47 times lower than in children, and
in addition, decreased markedly with age. An annual
estimated average of 57 881 cases were diagnosed by
French GPs in subjects aged 15 years and more

(range : 53 98762 221), i.e. 8.3% of the total annual
number of cases of varicella (range : 7.78.9 %). In a
birth cohort, 10.8 % of subjects remained susceptible
at age 15 (range : 6.414.9%).
The force of infection of varicella, i.e. its incidence
among non-immune persons, peaked during childhood, at age 5, and also displayed a second peak
among subjects 30 years old. Thus, the incidence for
the 2529 years age group was 42 % higher than for
the 2024 years age group, and the incidence in those
aged 3539 years was 36% less than in those aged
3034 years. This feature was found regardless of the
assumed lifetime risk of varicella. However, the risk
starts increasing again in the old when 100 % lifetime
risk is assumed.
603
Table 4. Average hospitalization and mortality rates for varicella per year, in the general French population
and in non-immune persons by age group, France
Hospitalization (19979)
Mortality (19907)
Age group
(years)
per 100 000

population
per 100 000

non-immune
per 100 000

cases
per 1 000 000

population
per 1 000 000

non-immune
per 1 000 000

cases
<1 year
14 years
514 years
1524 years
2534 years
3544 years
4564 years
o65 years
<15 years
o15 years
172
28
5.6
2.4
4.9
1.8
0.8
0.8
23.0
1.9
5.9
172
35
27
25
82
64
46
60
54
47
3467
235
156
707
1438
1945
6902
8154
383
1464
2.86
0.83
0.24
0.18
0.36
0.22
0.15
0.54
0.58
0.29
0.35
2.86
1.03
1.17
1.92
5.98
7.81
8.13
40.2
1.37
7.32
3.00
57
7
7
53
104
235
1219
5345
10
228
Total
(156189)
(2533)
(4.86.6)
(1.93.1)
(4.35.7)
(1.32.2)
(0.61.2)
(0.61.2)
(21.524.4)
(1.72.1)
(5.66.3)
(156189)
(3140)
(2233)
(1737)
(53138)
(26184)
(14194)
(14536)
(4958)
(1792)
51 (3363)
(30754032)
(209269)
(134186)
(528962)
(12001751)
(12252602)
(380412 233)
(468715 183)
(357416)
(12641670)
473 (441504)
Each year, varicella and its complications were

responsible for an average of 3306 hospitalizations, and
19 deaths (Table 1). About 78% of the varicella patients
hospitalized for pneumonia and 70% of the deaths
attributed to varicella concerned persons of 15 years or
more (Table 1). Congenital varicella accounted for an
average of 29 hospitalizations each year. Among nonimmune persons, the risk of varicella-related hospitalization was highest among infants. It was lower
and approximately constant in other age-groups, and
exhibited a marked increase at 30 years (Table 4). The
death rate was U-shaped, decreasing in childhood and
increasing with age thereafter.
The hospitalization and case fatality rates for varicella were highest among adults, and then infants, and
the lowest rates were for children. The risk of hospitalization was 4 50 times higher in adults than in children 514 years old. The case fatality rate showed a
risk of death 7.5 times higher in subjects aged from 15
to 24 years than in children of 514 years, and was
more than 174 times higher in adults aged 45 years or
more. There was a higher risk of death and hospitalization in infants than in children aged 1 4 years.
Underlying conditions known to increase the severity
or risk of occurrence of varicella accounted for 30 %
of varicella-related deaths and for 7.5 % of varicellarelated hospitalizations (Table 2).
Ranges for incidence rates among the general population were narrow. On the contrary, estimates of the
force of infection spanned a wide range around the
mean value for those over 15. For younger individuals however, a 10% range around the mean value
(011.1)
(02.78)
(00.98)
(01.12)
(01.14)
(01.01)
(00.61)
(01.38)
(01.30)
(0.070.62)
(0.200.66)
(011.1)
(03.4)
(04.6)
(010.1)
(024.2)
(053.1)
(093.9)
(2.43501)
(0.03.18)
(1.3721.4)
(1.225.54)
(0221)
(024)
(027)
(0357)
(0338)
(01072)
(04971)
(015 395)
(022)
(53484)
28 (1154)
was observed (Table 3). These variations were mainly

a consequence of the assumed lifetime risk, and indeed
the force of infection increased with the lifetime risk.
Nevertheless, even with a lifetime risk of 100 %,
there were substantial variations resulting from the
age distribution of cases. These increases accounted
in turn for much of the variability in the hospitalization and mortality rates for non-immune persons.
The hospitalization and mortality rates in the general
population and among varicella cases were not
sensitive to the overall incidence of varicella. For
these rates, the main source of variability was in the
counts of hospitalizations or deaths by age group,
which were modelled on the basis of the Poisson
distribution. The lowest bound estimates for mortality were indeed 0, because with this distribution, a
0 death count in an age group was common in the
replicated samples.
DISCUSSION
This work provided estimates of the force of infection
of varicella, and of varicella-related hospitalization
and death rates according to age in France, a country
where no mass immunization has been implemented.
It showed that the force of infection increased in
30-year-old adults, and that although the incidence of
varicella among non-immune individuals decreased
with age, the hospitalization and fatality rates increased exponentially with age.
Estimates of the age-related force of varicella infection, hospitalization and death rate in non-immune
604
persons were obtained on a nationwide level. Certain

previously published estimates of the force of infection were obtained by dividing the yearly incidence of
varicella by the percentage of susceptible adults [20],
with results similar to those reported here. However,
their estimates were limited to young adults. The prevaccination force of varicella infection estimated in
Canada [21] was based on mathematical modelling,
data for antibody prevalence, and billings. This procedure yielded higher rates than those we obtained,
except when the lifetime risk was set to 100 %. For
example, the force of infection in subjects 25 44 years
old ranged from 2 to 8 % in this work for a lifetime
risk increasing from 96 to 100 % ; the upper limit compared to the 8% of the Canadian study. Likewise,
the force of infection ranged from 0.1 to 7 % in individuals older than 65, and the special case of 100 %
lifetime risk yielded an average value of 4%, in
accordance with the Canadian study.
One surprising feature of the force of infection
reported here is that besides the expected peak during
childhood, a second peak appeared in the 2535 years
age group. The occurrence of this peak had previously
been postulated [22], but never actually observed.
Presumably, individuals in this age group are naturally in contact with young children through parenthood, and are therefore likely to be infected if they
are not already immune. This implies that the risk
of varicella may be very heterogeneous among adults,
and that familial or occupational exposure must
be taken into account in the individual risk/benet
analysis of vaccination. On the whole, the 30-year
incidence peak provides a strong justication for
screening young adults before they have their rst
child.
The age-specic yearly incidence rates of varicella
observed in France in the general population and
reported here correspond to those previously published for the United States [1, 3, 20, 23, 24], and
so do the French mortality and hospitalization rates,
per population and per number of cases [1, 3, 10,
11, 23].
It is well known that the complications of varicella
tend to be more severe in adults than in children.
Thus, in previous studies conducted in the United
States, the risks of hospitalization and death were
highest among those aged 20 years or more [1, 3, 8, 10,
23]. For instance, the risk of dying of varicella was 25
times greater in adults than in children aged 1 4 years
[1, 10], and the risk of hospitalization 14 times greater
[3, 23]. Our estimates show a similar trend, as the risk
of death was 30 times greater in subjects over 15 years

than in children aged 1 4 years, but the risk of hospitalization was only 7 times greater. Note that in
previous studies all subjects aged 20 years or more
were considered as adults for the calculation of
varicella-related risks of death and hospitalization
[3, 10, 23]. However, our results show that case fatality or case hospitalization rates, far from being
uniformly distributed in adults, are greatly dependent
on age.
Adults o25 years old accounted for 62 % of all
varicella deaths in France, a higher proportion than
in the United States, where this gure was estimated
at about 54 % [1, 10]. Most of those who died of, or
were hospitalized for, varicella were previously healthy
individuals. We found that an underlying condition,
often immunosuppression, was a factor contributing
to death in 30% of our adult cases, as reported in
other countries [9, 10, 25]. In two studies, 15% of the
persons hospitalized for varicella were reported to
have had an underlying condition known to increase
the severity or risk of occurrence of varicella [2, 11].
The rate we calculated was lower, despite a comparable case hospitalization rate.
In temperate countries, it is often admitted that the
annual incidence of varicella almost equals the size of
the birth cohort. Seroprevalence studies, which are the
gold standard for establishing previous infection by
varicella, showed that the lifetime risk of varicella was
indeed close to 100 %, but published estimates have
generally yielded smaller values : for example, the lifetime risk was estimated at 97.8 % in a recent study
from Spain [26]. The Sentinelles network estimates
that there are approximately 680 400 cases of varicella per year, which leads to a lifetime risk of 96%.
This is likely underestimated, because data is reported by GPs only, hence patients who consulted a
paediatrician, or dermatologist, or went to a hospital
emergency unit were not accounted for. Furthermore, parents may seek medical advice for the index
case in the family but less frequently for subsequent
cases. Nevertheless, the estimated lifetime risk of acquiring varicella was over 95 %, indicating that only
a small percentage of patients are likely to be missed
by the Sentinelles network. We investigated this underestimation in two ways : rst, the sensitivity analysis
took into account the fact that the lifetime risk could
be between 96 and 100%, and we also investigated
the special case of a 100 % lifetime risk. This analysis
showed that there was strong uncertainty regarding
the actual level of the force of infection after age 50,

due to the small percentage of the population still
vulnerable beyond that age.
Our hospitalization and mortality data were certainly closer to reality than those in certain other
reports, because they were obtained from the full set
of hospital discharge reports and death certicates.
Although hospitalization data, unlike those concerning mortality, describe episodes of care and thus are
not person-based, varicella is not a recurrent disease,
and repeated hospitalization seems improbable [27].
The retrospective nature of the present study might
raise the question of the accuracy of the mortality and
hospital discharge data, and of the actual nature of
the cases diagnosed as varicella during a visit with a
physician. Nevertheless, the clinical denition of varicella is simple enough for it to be diagnosed with
precision in clinical practice, and it is unlikely to be
confused with other conditions causing vesicles. At
the same time, we cannot completely rule out the possibility that certain cases of disseminated herpes zoster
in elderly adults might have been misclassied as primary varicella. We also admit that adult cases may
have been more likely to have received medical attention than milder cases in children.
In conclusion, the estimates provided by our study
show that the force of infection of varicella increases
in 30-year-old adults, and conrm the strong dependence of varicella-related mortality and hospitalization rates on age. In countries where no routine
childhood immunization is implemented, targeted
vaccination of non-immune adolescents and adults
could still reduce the current medical and nancial
burden constituted by varicella. Medicoeconomic
evaluation of the benet of such vaccination is therefore needed for decision making.
REFERENCES
1. CDCs. Prevention of varicella. Recommendations of
the Advisory Committee on Immunization Practices.
MMWR 1996 ; 45 : RR-11.
2. Preblud SR. Age-specic risks of varicella complications. Pediatrics 1981 ; 68 : 147.
3. Guess HA, Broughton DD, Melton LJ, Kurland LT.
Population based studies of varicella complications.
Pediatrics 1986 ; 78 (Suppl) : 7237.
4. Halloran ME. Epidemiologic eects of varicella
vaccination. Infect Dis Clin North Am 1996 ; 10 :
63155.
5. Bovill B, Bannister B. Review of 26 years hospital
admissions for chickenpox in North London. J Infect
1998 ; 36 (Suppl 1) : 1723.
605
6. Gray GC, Palinkas LA, Kelley PW. Increasing

incidence of varicella hospitalization in United States
army and Navy personnel : are todays teenagers more
susceptible ? Should recruits be vaccinated ? Pediatrics
1990 ; 86 : 86773.
7. Fairley CK, Miller E. Varicella-zoster virus epidemiology a changing scene ? J Infect Dis 1996 ; 174
(Suppl 3) : S3149.
8. Wharton M. The epidemiology of varicella-zoster
virus infections. Infect Dis Clin North Am 1996 ; 10 :
57181.
9. Joseph CA, Noah ND. Epidemiology of chickenpox in England and Wales, 196785. BMJ 1988 ; 296 :
6736.
10. Meyer PA, Seward JF, Jumman AO, Wharton M.
Varicella mortality : trends before vaccine licensure in
the United States, 19701994. J Infect Dis 2000 ; 182 :
38390.
11. Lin F, Hadler JL. E. Epidemiology of primary varicella
and herpes zoster hospitalizations : the pre-varicella
vaccine era. J Infect Dis 2000 ; 181 : 1897905.
12. Paul E, Thiel T. Epidemiology of varicella zoster infection. Results of a prospective study in the Ansbach area.
Hautarzt 1996 ; 8 : 6049.
13. Salleras L, Dominguez A, Vidal J, Plans P, Salleras M,
Taberner JL. Seroepidemiology of varicella-zoster
virus infection in Catalonia (Spain). Rationale for
universal vaccination programmes. Vaccine 2001 ; 19 :
1838.
14. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella zoster virus infection in Canada
and the United Kingdom. Epidemiol Infect 2001 ;
127 : 30514.
15. Bramley JC, Jones IG. Epidemiology of chickenpox in
Scotland : 1981 to 1998. Commun Dis Public Health
2000 ; 3 : 2827.
16. Coplan P, Black S, Rojas C, et al. Incidence and hospitalization rates of varicella and herpes zoster before
varicella vaccine introduction : a baseline assessment
of the shifting epidemiology of varicella disease. Pediatr
Infect Dis J 2001 ; 20 : 6415.
17. Gil A, Oyaguez I, Carrasco P, Gonzalez A. Epidemiology of primary varicella hospitalizations in Spain.
Vaccine 2002 ; 20 : 2958.
18. Deguen S, Chau NP, Flahault A. Epidemiology of
chickenpox in France (19911995). J Epidemiol
Commun Health 1998 ; 52 (Suppl 1) : 46S 49S.
19. Chauvin P, Valleron AJ. Attitude of French general
practitioners to the public health surveillance of
communicable diseases. Int J Epidemiol 1995 ; 24 :
435 40.
20. Smith KJ, Roberts MS. Cost eectiveness of vaccination strategies in adults without a history of
chickenpox. Am J Med 2000 ; 108 : 7239.
21. Brisson M, Edmunds WJ, Gay NJ, Law B, De Serres G.
Modelling the impact of immunization on the epidemiology of varicella zoster virus. Epidemiol Infect
2000 ; 125 : 65169.
22. Garnett GP, Grenfell BT. The epidemiology of
varicella-zoster virus infections : the inuence of
606
varicella on the prevalence of herpes zoster. Epidemiol

Infect 1992 ; 108 : 51328.
23. Choo PW, Donahue JG, Manson JAE, Platt R. The
epidemiology of varicella and its complications. J Infect
Dis 1995 ; 172 : 70612.
24. Lieu TA, Cochi SL, Black SB, et al. Cost-eectiveness
of a routine varicella vaccination program for US
children. JAMA 1994 ; 271 : 37581.
25. Miller E, Vurdien J, Farington P. Shift in age in

chickenpox. Lancet 1993 ; 341 : 3089.
26. Munoz MP, Dominguez A, Salleras L. Estimated varicella incidence on the basis of a seroprevalence survey.
Epidemiol Infect 2001 ; 127 : 5017.
27. Wallace MR, Chamberlin CJ, Zerboni L, et al. Reliability of a history of previous varicella infection in
adults. JAMA 1997 ; 278 : 15202.

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ORIGINALES

Hospitalizaciones por varicela

HOSPITALIZATIONS FOR VARICELLA

Patients and methods

Correspondencia: Dra. M.C. Otero Reigada.

An Pediatr (Barc) 2005;63(2):120-4

Piqueras AI, et al. Hospitalizaciones por varicela

the leading cause was Streptococcus pyogenes (n 13)

The high morbidity associated with varicella and its

De enero de 2001 a junio de 2004, 101 nios (43 nias y

An Pediatr (Barc) 2005;63(2):120-4

Piqueras AI, et al. Hospitalizaciones por varicela

Figura 1. Distribucin por

TABLA 1. Tipo de enfermedad subyacente

*3 casos con trasplante renal y 1 caso trasplante heptico.

TABLA 2. Nmero y tipo de complicaciones

Infeccin de piel y tejidos blandos

*Un caso fulminante, que falleci por fallo multiorgnico.

An Pediatr (Barc) 2005;63(2):120-4

Piqueras AI, et al. Hospitalizaciones por varicela

El coste total del tratamiento fue de 22.336,24 1 y el de

Figura 2. Distribucin de los nios segn el ao de ingreso y la causa de hospitalizacin.

TABLA 3. Coste de la hospitalizacin

En Estados Unidos, tras la introduccin de la vacuna de

An Pediatr (Barc) 2005;63(2):120-4

Piqueras AI, et al. Hospitalizaciones por varicela

3. Peterson CL, Mascola L, Chao SM, Lieberman JM, Arcinue EL,

16. Doctor A, Harper MB, Fleisher GR. Group A -hemolytic

7. Ziebold C, Von Kries R, Lang R, Weigl J, Schmitt HJ. Severe

9. Choo PW, Donahue JG, Manson JE, Platt R. The epidemiology

19. Hardy I, Gershon A, Steinberg S, LaRussa P. The incidence of

20. Moraga F, Campins M. Vacuna de la varicela. An Pediatr Contin. 2003;1:101-4.

11. Gil A, San-Martn M, Carrasco P, Gonzlez A. Epidemiology of

An Pediatr (Barc) 2005;63(2):120-4

Epidemiol. Infect. (2002), 129, 599606. f 2002 Cambridge University Press

Varicella in non-immune persons: incidence, hospitalization

(Accepted 8 August 2002)

* Author for correspondence : Federation de Medecine Interne,

United States and United Kingdom, the average age

P. Y. Boelle and T. Hanslik

5, 717]. However, none of these reports dealt directly

Varicella in non-immune persons

International classication of diseases,

Human immunodeciency virus/AIDS

varicella was also obtained (Tables 1, 2). The gures

(number of incident cases, hospitalization and deaths,

P. Y. Boelle and T. Hanslik

Incidence per 100 000 non-immune population

Lifetime risk 96 %x100 %

Lifetime risk 100 %

10 866 (896513 497)

13 287 (12 98213 643)

counts conformed to the Poisson distribution. For

French GPs in subjects aged 15 years and more

Varicella in non-immune persons

per 100 000

per 100 000

per 100 000

per 1 000 000

per 1 000 000

per 1 000 000

Each year, varicella and its complications were

was observed (Table 3). These variations were mainly

P. Y. Boelle and T. Hanslik