- Email: [email protected]
Epidemiology of severe varicella–zoster virus infection in Spain
Vaccine 22 (2004) 3947–3951
Epidemiology of severe varicella–zoster virus infection in Spain Angel Gil a,∗ , Mar´ıa San-Mart´ın b , Pilar Carrasco a , Antonio González b a
Department of Health Sciences, Rey Juan Carlos University, Avda de Atenas s/n, 28922 Alcorcón, Madrid, Spain b Medical Department, Aventis Pasteur MSD, Po de la Castellana 141, 28046 Madrid, Spain Received 2 December 2002; accepted 7 April 2004 Available online 13 May 2004
Abstract Data of hospitalizations for varicella and herpes zoster in Spain during the 1999–2000 period were obtained from the national surveillance system for hospital data. A total of 3083 hospitalizations for varicella and 6324 for herpes zoster were identified, representing an annual incidence of 4.1 and 8.4 per 100,000 persons per year, respectively. Almost half of patients hospitalized for varicella were children under 5 years of age. In contrast, 78% of hospitalizations for zoster occurred in adults >50 years of age. Hospitalizations for varicella and herpes zoster resulted annually in 11,141 and 40,090 days of hospitalization and a cost of 3.2 and 7.0 million, respectively. © 2004 Elsevier Ltd. All rights reserved. Keywords: Varicella; Zoster; Hospitalizations
1. Introduction Primary Varicella–zoster virus (VZV) infection results in varicella (chickenpox), a common and extremely contagious acute infection that occurs in epidemics among pre-school and school-aged children [1,2]. The preponderance of uncomplicated childhood cases has tended to overshadow the morbidity and mortality associated with severe cases and the resultant hospitalizations [3,4]. Children bear the brunt of the health burden, however, the risk of severe complications and death is higher among susceptible adolescents, adults, and immunocompromised individuals [5]. Reactivation of latent VZV from dorsal root ganglia results in herpes zoster (shingles), which is more common and more severe in the elderly and immunocompromised persons [1,2]. Complications of zoster occur in 13–26% of cases, being post-herpetic neuralgia—the most common and debilitating [6]. The availability of an effective, live, and attenuated varicella vaccine underlines the need to better understand the burden of this disease. Population-based surveys carried out in the United States demonstrated the extent of varicella morbidity, complications and overall cost of this disease. These studies provided the rationale for adopting a policy of routine immunization of healthy children in 1996 [7–12]. How∗ Corresponding author. Tel.: +34-91-488-88-04; fax: +34-91-488-88-48. E-mail address: [email protected] (A. Gil).
0264-410X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2004.04.004
ever, epidemiologic data gathered in one part of the world may not reflect the situation in other parts of the world. The live and attenuated varicella vaccine has been licensed in many countries and some of them are currently considering whether to include varicella vaccine into their routine immunization schedule. To determine the most appropriate strategies and to evaluate the overall impact and cost-effectiveness of varicella immunization programs, a good understanding of the pre-vaccine epidemiology of both primary and reactivated varicella–zoster virus infection is crucial. 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. Additionally, hospitalization databases measure the most severe part of the disease spectrum [13]. The aim of this study was to obtain population-based estimates of varicella and zoster hospitalizations in Spain, and to estimate the annual costs of these hospital admissions.
2. Methods Varicella and zoster hospitalization in Spain during 1999–2000 were obtained from the national surveillance system for hospital data (Conjunto M´ınimo de Datos; CMBD), that collects information on all hospital discharges and uses clinical codes from the Spanish version of the
3948
A. Gil et al. / Vaccine 22 (2004) 3947–3951
Ninth International Classification of Diseases (Modificación Cl´ınica Clasificación Internacional de Enfermedades; CIE-9-MC). This nationwide system involves approximately 95% of public hospitals [14,15]. Information on private hospitals is available only for a few regions, but these hospitals account for only a small proportion of all hospital admissions, as compulsory health insurance covers almost 99.5% of the Spanish population (approximately 40 million) [14,16]. All hospitalizations for primary varicella (ICD-9-CM 052.0-052.9; in any diagnostic position) and herpes zoster (ICD-9-CM 053.0-053.9; in any diagnostic position) during the 2-year study period (January 1, 1999 through December 31, 2000) were extracted from the CMBD. Data obtained included dates of admission and discharge, age, sex, average length of stay, and outcome (survival to hospital discharge or death). All hospitalizations with a varicella or zoster diagnostic code in the first position were considered to be admissions due to VZV infection. A person was considered to have an underlying condition if there was a discharge diagnosis code for at least one of the conditions known to increase the risk of occurrence or severity of primary varicella or herpes zoster (Appendix A). A patient was considered to have a specific complication of varicella if there was one or more codes for potential varicella-related complications (Appendix A). 2.1. Statistical methods The age-specific average number of hospitalizations per year for primary varicella and herpes zoster, incidence of hospitalization (per 100,000 persons per year), average length of stay in hospital and case-fatality rate were calcu-
lated. Population data were obtained from the 1999–2000 Spanish census projection and adjusted to the 95% of the population covered by hospitals included in the CMBD database. It was assumed that the distribution by age of the population covered by these public hospitals was equal to the general population [16]. The average number of days of hospitalization per year for primary varicella and zoster during the 2-year period were calculated using the cumulative average number of cases per year and the average length of stay. The costs for the health care system attributed to primary varicella and zoster hospitalizations were calculated by considering the unit cost (1995 values updated for the 1999–2000 period) for 1-day of hospital care in a pediatric ward (365 ) and in a general ward (153 ) [17]. Statistical analyses were performed using SPSS software for personal computers (version 8.0; Chicago, Ill, USA).
3. Results A total of 3083 hospitalizations for primary varicella and 6324 herpes zoster-related hospital admissions were identified during the 2-year study period. Herpes zoster was the first-listed diagnosis in 1903 cases (428 had underlying conditions) and varicella in 2114 cases (113 with underlying conditions). The age-specific number of hospitalizations and hospitalization rates are shown in Tables 1 (primary varicella) and 2 (zoster). The average annual incidence of hospitalizations for varicella and zoster was 4.1 per 100,000 persons per year and 8.4 per 100,000 persons per year, respectively. Almost half of patients with an hospital discharge diagnosis of varicella were children under 5 years of age
Table 1 Age-specific average annual number of hospitalizations, deaths, incidence and case-fatality for primary varicella Age group (years)
Average number of hospitalizations
Incidence (100,000 persons)
Average number of deaths
Case-fatality rate
<1 1–2 3–5 6–10 11–20 21–30 31–50 >50
225 149 359 171 76 159 316 89
60.3 20.3 32.8 9.2 1.7 2.6 2.9 0.7
0 0 1 0.5 2 1 4.5 6.5
0 0 0.3 0.3 2.6 0.6 1.4 7.3
Total
1542
4.1
15.5
1.0
Table 2 Age-specific average annual number of hospitalizations, deaths, incidence and case-fatality for VZV reactivation Age group (years)
Average number of hospitalizations
Incidence (100,000 persons)
Average number of deaths
Case-fatality rate
0–14 15–20 21–30 31–50 >50
98 32 94 465 2474
1.7 1.1 1.5 4.3 20.8
0 0.5 0.5 11 103
0 1.6 0.5 2.4 4.16
Total
3162
8.4
115
3.6
A. Gil et al. / Vaccine 22 (2004) 3947–3951
(Table 1). Incidence of varicella in patients aged <1 year, 1–2 years and 3–5 years was 2–6 times higher than in older children and 19–35 times higher than in adolescents. In contrast, most hospitalizations for zoster occurred in adults, being 78% of them in persons >50 years of age (Table 2). The hospitalization rate in this age group was 5 and 14 times higher than in adults aged 31–50 years and 21–30 years, respectively. No significant differences were found between males and females, being the sex ratio (male/female) of 1.2/1 for varicella and 1.1/1 for zoster. Varicella or herpes zoster were reported as first-listed diagnosis (primary cause of hospitalization) in 69% and 30% of cases, respectively. Among all hospitalized patients for primary varicella, 10% had at least one reported underlying condition, being leukemia (43%) the most common condition. Twenty-seven percent of patients hospitalized for zoster presented at least one underlying condition, being “other malignancies” (35%) the most frequently reported. Almost 18% (275) of the patients had at least one varicella-specific complication, with “non specified varicella complications” being the most commonly reported (43%), followed by cellulitis (21%). During the 2-year study period, varicella hospitalizations resulted in 31 deaths (nine were patients with underlying conditions) and zoster hospitalizations resulted in 230 deaths (114 had underlying conditions). The average age-specific annual number of deaths and case-fatality rates for primary varicella and herpes zoster are shown in Tables 1 and 2. The overall case-fatality rate was 1.0% (CI 95%, 0.5–1.5) for primary varicella and 3.6 (CI 95%, 3.0–4.3) for zoster. Case-fatality rate was highly age dependent in both primary varicella and zoster; it was low in children but increased dramatically in adults. Adults accounted for 77% and 96% of deaths for primary varicella and zoster, respectively. Overall, hospital admissions for primary varicella resulted annually in an average of 11,141 days of hospitalization and a cost of 3.2 million. Pediatric patients (<14 years of age) accounted for 71% of this cost. Within this group, children <5 years of age accounted for 75% of the cost. The average annual number of days of hospitalization for herpes zoster was 40,090 days and the related costs of 7.0 million. Patients >50 years of age accounted for 80% of this cost.
4. Discussion The annual incidence of hospitalizations for primary varicella and herpes zoster in Spain was 4.1 per 100,000 population and 8.4 per 100,000 population, respectively. Varicella figures are similar to those obtained in studies carried out in the United States during a 10-year period from 1986 to 1995 (4.1 per 100,000 population) and in England and Wales during 1991–2000 (4.5 per 100,000 population). By contrast,
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the incidence of zoster-related hospitalizations varies widely within the different studies, being 16.1 per 100,000 population in the United States and 4.4 per 100,000 population in England and Wales [13,18]. These dissimilarities could be explained by different criteria for hospitalization of adult patients and differences in the structure of the health system [18]. The age distribution of both varicella and zoster cases was similar to that described in other countries [18–22]. Varicella hospitalizations occur mainly in children, being the highest rates in those aged <5 years; however, most varicella deaths occurred in adults [5,18,22]. In contrast, most of the burden of severe zoster is suffered by adults, specially those >50 years in age [5,22]. Persons with underlying conditions such as HIV infection, leukemia and other malignancies are at greater risk of varicella–zoster virus reactivation and of more serious complications. Patients hospitalized for herpes zoster had underlying conditions more frequently than persons hospitalized for varicella (27% versus 10%). However, this study confirms a strong association between the incidence of herpes zoster and age, and that most persons hospitalized for zoster do not have any underlying condition which could increase the risk of developing severe disease. These findings are consistent with previous observations showing that most severe zoster morbidity is the result of age-related waning immunity rather than the increase in underlying conditions, such as malignancy, that occurs with age [23]. This study provides an opportunity to compare the epidemiology, complications and cost of herpes zoster with its precursor disease, primary varicella. Our results showed that hospitalizations and costs were 2 and 2.2 times higher for zoster compared with varicella. A study carried out in the United States during the pre-vaccination era also showed that hospitalizations for zoster were more frequent than for varicella [13]. In our study, the mean length of stay in hospital and the mean cost of hospitalizations in zoster cases were two times higher than in primary varicella. In addition, the case-fatality rate in patients hospitalized for zoster was more than three times higher than in patients with varicella (3.6% versus 1.0%). Similar results were described in the US study [13]. Analysis of population-based hospital discharge data appear to be a feasible, simple and sensitive way to monitor the occurrence and costly complications of some diseases and their epidemiology. However, this kind of analysis of hospital data have some limitations. The first is that discharge diagnosis codes were not validated. It was not determined whether primary varicella or herpes zoster was the primary reason for initial hospitalization. Hospital discharge diagnosis as source of information, lacks of data on disease severity, medication, use of procedures, such as mechanical respiration, or intensive care stay all of which are important determinants of hospitalizations usage and costs [4]. Moreover, in studies that rely on discharge diagnoses, causality between disease and potential complications must
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be assumed, so that similar limitations apply to the data on complications of varicella [4]. This approach could result in some type of misclassification. However, an outpatient study of herpes zoster in which case finding was based on diagnostic codes, including ICD-9 codes, showed that the positive predictive value of a diagnostic code of herpes zoster was 89–96% [24]. Furthermore, a validation study of varicella-related hospital discharge data for persons aged ≥13 years in New York found that the positive predictive value of varicella as a discharge diagnosis was 87%, as an indicator for varicella-related hospitalizations [13]. In addition, both varicella and herpes zoster are common, recognizable entities, presumably less subject to miscoding than other diagnoses. The annual cost of hospitalizations for primary varicella and reactivated VZV infection reflects only a small part of the overall cost of this disease, as only a very limited number of cases require hospital admission [17,21].
Results of a recently published study, which assessed the economic impact of varicella in children attending primary care centers in Spain, shows that a non-hospitalized varicella case requires more than one visit to the primary care physician and at least one prescription [25]. The overall cost (including medical attention and social indirect cost) of one case attended in the primary care setting is estimated to be around 66 [25]. Our results are consistent with studies in other developed countries and provide evidence that primary varicella and reactivated VZV infection continues to cause severe disease and complications which require hospital admission in all age groups. These severe cases generate a considerable cost to the health care system. Widespread varicella vaccination programs may have an impact on the disease burden and associated costs, but it is the role of the local health authorities to determine whether health-care resources should be allocated to this or other preventive programs.
Appendix A Description
ICD-9-CM code(s)
Underlying conditions for varicella and herpes zoster Human immunodeficiency virus Leukemia Other malignancies Other blood dyscrasia Childhood immunodeficiencies Radiotherapy or chemotherapy Pregnancy
042.0–044.9, 795.8 200.0–208.9 140.0–199.9 284.0–284.9 288.0–288.2, 179.0–179.9 V58.0, V58.1, V07.2 634.0–634.9, 647.6, 647.9, 650.0–656.9
Varicella complications Septicemia Varicella with complications Viral hepatitis Meningitis due to other organism Meningitis of unspecified cause Encephalitis/encephalomyelitis/myelitis Acute infective polyneuritis Pneumonia due to other organism, unspecified organism Acute and subacute necrosis of the liver Other disorders of the liver Cellulitis Impetigo Endotoxic shock
038; 038.0–038.4 052.7;052–8 070; 070.4–070.9 321; 321.2–321.8 322 323.9 357.0 480; 480.8–480.9; 483; 485; 486 570 573; 573.1–573.3; 573.9 681; 681.0; 681.00;681.1; 681.9 682; 682.0–682.9 684 785.59
A. Gil et al. / Vaccine 22 (2004) 3947–3951
References [1] Gnann JW. Varicella–zoster Virus: atypical presentations and unusual complications. J Infect Dis 2002;186(Suppl 1):S91–8. [2] LaRussa P. The success of varicella vaccine. Pediatr Ann 2002;31:710–5. [3] Ratner AJ. Varicella-related hospitalisations in the vaccine era. Pediatr Infect Dis J 2002;21:927–30. [4] 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. [5] Meyer PA, Seward JF, Jumaan AO. Varicella mortality: trends before vaccine licensure in the United States, 1970–1994. J Infect Dis 2000;182:383–90. [6] Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster and potential cost-effectiveness of vaccination in England and Wales. Vaccine 2001;19:3076–90. [7] American Academy of Pediatrics. The 1997 red book. Elk Grove Village, Illinois: American Academy of Pediatrics; 1997. [8] Lieu TA, Cochi SL, Black SB, Halloran ME, Shinefield HR, Holmes SJ, et al. Cost-effectiveness of a routine varicella vaccination program for US children. JAMA 1994;271:375–81. [9] Huse DM, Meissner HC, Lacey MJ, Oster G. Childhood vaccination against chickenpox: an analysis of benefits and costs. J Pediatr 1994;124:869–74. [10] Peterson CL, Mascola L, Chao SM, Lieberman JM, Arcinue EL, Blumberg DA, et al. Children hospitalised for varicella: a prevaccine review. J Pediatr 1996;129:529–36. [11] Somekh E, Maharashak N, Shapira Y, Greenberg D, Dagan R. Hospitalization for primary varicella–zoster virus infection and its complications in patients form southern Israel. Infection 2000;28:200–4. [12] Centers for Disease Control. Summary of Notifiable Diseases, United States, 1994. MMWR 1995;43(53):1–55. [13] Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster hospitalisations: the pre-vaccination era. J Infect Dis 2000;181:1897– 905.
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[14] Visser LE, Cano Portero R, Gay NJ, Mart´ınez Navarro JF. Impact of rotavirus disease in Spain: an estimate of hospital admissions due to rotavirus. Acta Paediatr 1999;426(Suppl):72–6. [15] Pizarro A, Pachón I. Situación actual de tétanos y tos ferina. Bol Epidemiol Semanal 1998;6:300–3. Current situation of tetanus and pertussis. [16] Healthcare handbook. Vol. 4.2 Spain 1998–99. F., Favereau & Associates, editors. Lagon, France; 1998. p. 51–124. [17] Diez-Domingo J, Ridao M, Latour J, Ballester A, Morant A. A cost benefit analysis of routine varicella vaccination in Spain. Vaccine 1999;17:1306–11. [18] Brisson M., Edmunds W.J., Epidemiology of varicella–zoster virus in England and Wales, J. Med. Virol. 2003;Suppl 1:S9– S14. [19] Brisson M, Edmunds WJ, Law B, Gay NJ, Walld R, Brownell M, et al. Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemio Infect 2001;127:305– 14. [20] Choo PW, Donahue JG, Manson JE. The epidemiology of varicella and it complications. J Infect Dis 1995;172:706–12. [21] Coplan P, Black S, Rojas C, Shinefield H, Ray P, Lewis E, Guess H. 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;20:641–5. [22] Bramley JC, Jones IG. Epidemiology of chickenpox in Scotland: 1981 to 1998. Commun Dis Public Health 2000;3:282–7. [23] Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995;155:1605–9. [24] Miller E, Marshall R, Verdien J. Epidemiology, outcome and control of varicella–zoster infection. Rev Med Microbiol 1993;4:222– 30. [25] Diez-Domingo J, Aristegui J, Calbo F, Gonzalez-Hachero J, Moraga F, Peña-Guitian J, et al. Epidemiology and economic impact of varicella in immunocompetent children in Spain. A nation-wide study. Vaccine 2003;21:3236–9.
Epidemiology of severe varicella–zoster virus infection in Spain Angel Gil a,∗ , Mar´ıa San-Mart´ın b , Pilar Carrasco a , Antonio González b a
Department of Health Sciences, Rey Juan Carlos University, Avda de Atenas s/n, 28922 Alcorcón, Madrid, Spain b Medical Department, Aventis Pasteur MSD, Po de la Castellana 141, 28046 Madrid, Spain Received 2 December 2002; accepted 7 April 2004 Available online 13 May 2004
Abstract Data of hospitalizations for varicella and herpes zoster in Spain during the 1999–2000 period were obtained from the national surveillance system for hospital data. A total of 3083 hospitalizations for varicella and 6324 for herpes zoster were identified, representing an annual incidence of 4.1 and 8.4 per 100,000 persons per year, respectively. Almost half of patients hospitalized for varicella were children under 5 years of age. In contrast, 78% of hospitalizations for zoster occurred in adults >50 years of age. Hospitalizations for varicella and herpes zoster resulted annually in 11,141 and 40,090 days of hospitalization and a cost of 3.2 and 7.0 million, respectively. © 2004 Elsevier Ltd. All rights reserved. Keywords: Varicella; Zoster; Hospitalizations
1. Introduction Primary Varicella–zoster virus (VZV) infection results in varicella (chickenpox), a common and extremely contagious acute infection that occurs in epidemics among pre-school and school-aged children [1,2]. The preponderance of uncomplicated childhood cases has tended to overshadow the morbidity and mortality associated with severe cases and the resultant hospitalizations [3,4]. Children bear the brunt of the health burden, however, the risk of severe complications and death is higher among susceptible adolescents, adults, and immunocompromised individuals [5]. Reactivation of latent VZV from dorsal root ganglia results in herpes zoster (shingles), which is more common and more severe in the elderly and immunocompromised persons [1,2]. Complications of zoster occur in 13–26% of cases, being post-herpetic neuralgia—the most common and debilitating [6]. The availability of an effective, live, and attenuated varicella vaccine underlines the need to better understand the burden of this disease. Population-based surveys carried out in the United States demonstrated the extent of varicella morbidity, complications and overall cost of this disease. These studies provided the rationale for adopting a policy of routine immunization of healthy children in 1996 [7–12]. How∗ Corresponding author. Tel.: +34-91-488-88-04; fax: +34-91-488-88-48. E-mail address: [email protected] (A. Gil).
0264-410X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2004.04.004
ever, epidemiologic data gathered in one part of the world may not reflect the situation in other parts of the world. The live and attenuated varicella vaccine has been licensed in many countries and some of them are currently considering whether to include varicella vaccine into their routine immunization schedule. To determine the most appropriate strategies and to evaluate the overall impact and cost-effectiveness of varicella immunization programs, a good understanding of the pre-vaccine epidemiology of both primary and reactivated varicella–zoster virus infection is crucial. 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. Additionally, hospitalization databases measure the most severe part of the disease spectrum [13]. The aim of this study was to obtain population-based estimates of varicella and zoster hospitalizations in Spain, and to estimate the annual costs of these hospital admissions.
2. Methods Varicella and zoster hospitalization in Spain during 1999–2000 were obtained from the national surveillance system for hospital data (Conjunto M´ınimo de Datos; CMBD), that collects information on all hospital discharges and uses clinical codes from the Spanish version of the
3948
A. Gil et al. / Vaccine 22 (2004) 3947–3951
Ninth International Classification of Diseases (Modificación Cl´ınica Clasificación Internacional de Enfermedades; CIE-9-MC). This nationwide system involves approximately 95% of public hospitals [14,15]. Information on private hospitals is available only for a few regions, but these hospitals account for only a small proportion of all hospital admissions, as compulsory health insurance covers almost 99.5% of the Spanish population (approximately 40 million) [14,16]. All hospitalizations for primary varicella (ICD-9-CM 052.0-052.9; in any diagnostic position) and herpes zoster (ICD-9-CM 053.0-053.9; in any diagnostic position) during the 2-year study period (January 1, 1999 through December 31, 2000) were extracted from the CMBD. Data obtained included dates of admission and discharge, age, sex, average length of stay, and outcome (survival to hospital discharge or death). All hospitalizations with a varicella or zoster diagnostic code in the first position were considered to be admissions due to VZV infection. A person was considered to have an underlying condition if there was a discharge diagnosis code for at least one of the conditions known to increase the risk of occurrence or severity of primary varicella or herpes zoster (Appendix A). A patient was considered to have a specific complication of varicella if there was one or more codes for potential varicella-related complications (Appendix A). 2.1. Statistical methods The age-specific average number of hospitalizations per year for primary varicella and herpes zoster, incidence of hospitalization (per 100,000 persons per year), average length of stay in hospital and case-fatality rate were calcu-
lated. Population data were obtained from the 1999–2000 Spanish census projection and adjusted to the 95% of the population covered by hospitals included in the CMBD database. It was assumed that the distribution by age of the population covered by these public hospitals was equal to the general population [16]. The average number of days of hospitalization per year for primary varicella and zoster during the 2-year period were calculated using the cumulative average number of cases per year and the average length of stay. The costs for the health care system attributed to primary varicella and zoster hospitalizations were calculated by considering the unit cost (1995 values updated for the 1999–2000 period) for 1-day of hospital care in a pediatric ward (365 ) and in a general ward (153 ) [17]. Statistical analyses were performed using SPSS software for personal computers (version 8.0; Chicago, Ill, USA).
3. Results A total of 3083 hospitalizations for primary varicella and 6324 herpes zoster-related hospital admissions were identified during the 2-year study period. Herpes zoster was the first-listed diagnosis in 1903 cases (428 had underlying conditions) and varicella in 2114 cases (113 with underlying conditions). The age-specific number of hospitalizations and hospitalization rates are shown in Tables 1 (primary varicella) and 2 (zoster). The average annual incidence of hospitalizations for varicella and zoster was 4.1 per 100,000 persons per year and 8.4 per 100,000 persons per year, respectively. Almost half of patients with an hospital discharge diagnosis of varicella were children under 5 years of age
Table 1 Age-specific average annual number of hospitalizations, deaths, incidence and case-fatality for primary varicella Age group (years)
Average number of hospitalizations
Incidence (100,000 persons)
Average number of deaths
Case-fatality rate
<1 1–2 3–5 6–10 11–20 21–30 31–50 >50
225 149 359 171 76 159 316 89
60.3 20.3 32.8 9.2 1.7 2.6 2.9 0.7
0 0 1 0.5 2 1 4.5 6.5
0 0 0.3 0.3 2.6 0.6 1.4 7.3
Total
1542
4.1
15.5
1.0
Table 2 Age-specific average annual number of hospitalizations, deaths, incidence and case-fatality for VZV reactivation Age group (years)
Average number of hospitalizations
Incidence (100,000 persons)
Average number of deaths
Case-fatality rate
0–14 15–20 21–30 31–50 >50
98 32 94 465 2474
1.7 1.1 1.5 4.3 20.8
0 0.5 0.5 11 103
0 1.6 0.5 2.4 4.16
Total
3162
8.4
115
3.6
A. Gil et al. / Vaccine 22 (2004) 3947–3951
(Table 1). Incidence of varicella in patients aged <1 year, 1–2 years and 3–5 years was 2–6 times higher than in older children and 19–35 times higher than in adolescents. In contrast, most hospitalizations for zoster occurred in adults, being 78% of them in persons >50 years of age (Table 2). The hospitalization rate in this age group was 5 and 14 times higher than in adults aged 31–50 years and 21–30 years, respectively. No significant differences were found between males and females, being the sex ratio (male/female) of 1.2/1 for varicella and 1.1/1 for zoster. Varicella or herpes zoster were reported as first-listed diagnosis (primary cause of hospitalization) in 69% and 30% of cases, respectively. Among all hospitalized patients for primary varicella, 10% had at least one reported underlying condition, being leukemia (43%) the most common condition. Twenty-seven percent of patients hospitalized for zoster presented at least one underlying condition, being “other malignancies” (35%) the most frequently reported. Almost 18% (275) of the patients had at least one varicella-specific complication, with “non specified varicella complications” being the most commonly reported (43%), followed by cellulitis (21%). During the 2-year study period, varicella hospitalizations resulted in 31 deaths (nine were patients with underlying conditions) and zoster hospitalizations resulted in 230 deaths (114 had underlying conditions). The average age-specific annual number of deaths and case-fatality rates for primary varicella and herpes zoster are shown in Tables 1 and 2. The overall case-fatality rate was 1.0% (CI 95%, 0.5–1.5) for primary varicella and 3.6 (CI 95%, 3.0–4.3) for zoster. Case-fatality rate was highly age dependent in both primary varicella and zoster; it was low in children but increased dramatically in adults. Adults accounted for 77% and 96% of deaths for primary varicella and zoster, respectively. Overall, hospital admissions for primary varicella resulted annually in an average of 11,141 days of hospitalization and a cost of 3.2 million. Pediatric patients (<14 years of age) accounted for 71% of this cost. Within this group, children <5 years of age accounted for 75% of the cost. The average annual number of days of hospitalization for herpes zoster was 40,090 days and the related costs of 7.0 million. Patients >50 years of age accounted for 80% of this cost.
4. Discussion The annual incidence of hospitalizations for primary varicella and herpes zoster in Spain was 4.1 per 100,000 population and 8.4 per 100,000 population, respectively. Varicella figures are similar to those obtained in studies carried out in the United States during a 10-year period from 1986 to 1995 (4.1 per 100,000 population) and in England and Wales during 1991–2000 (4.5 per 100,000 population). By contrast,
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the incidence of zoster-related hospitalizations varies widely within the different studies, being 16.1 per 100,000 population in the United States and 4.4 per 100,000 population in England and Wales [13,18]. These dissimilarities could be explained by different criteria for hospitalization of adult patients and differences in the structure of the health system [18]. The age distribution of both varicella and zoster cases was similar to that described in other countries [18–22]. Varicella hospitalizations occur mainly in children, being the highest rates in those aged <5 years; however, most varicella deaths occurred in adults [5,18,22]. In contrast, most of the burden of severe zoster is suffered by adults, specially those >50 years in age [5,22]. Persons with underlying conditions such as HIV infection, leukemia and other malignancies are at greater risk of varicella–zoster virus reactivation and of more serious complications. Patients hospitalized for herpes zoster had underlying conditions more frequently than persons hospitalized for varicella (27% versus 10%). However, this study confirms a strong association between the incidence of herpes zoster and age, and that most persons hospitalized for zoster do not have any underlying condition which could increase the risk of developing severe disease. These findings are consistent with previous observations showing that most severe zoster morbidity is the result of age-related waning immunity rather than the increase in underlying conditions, such as malignancy, that occurs with age [23]. This study provides an opportunity to compare the epidemiology, complications and cost of herpes zoster with its precursor disease, primary varicella. Our results showed that hospitalizations and costs were 2 and 2.2 times higher for zoster compared with varicella. A study carried out in the United States during the pre-vaccination era also showed that hospitalizations for zoster were more frequent than for varicella [13]. In our study, the mean length of stay in hospital and the mean cost of hospitalizations in zoster cases were two times higher than in primary varicella. In addition, the case-fatality rate in patients hospitalized for zoster was more than three times higher than in patients with varicella (3.6% versus 1.0%). Similar results were described in the US study [13]. Analysis of population-based hospital discharge data appear to be a feasible, simple and sensitive way to monitor the occurrence and costly complications of some diseases and their epidemiology. However, this kind of analysis of hospital data have some limitations. The first is that discharge diagnosis codes were not validated. It was not determined whether primary varicella or herpes zoster was the primary reason for initial hospitalization. Hospital discharge diagnosis as source of information, lacks of data on disease severity, medication, use of procedures, such as mechanical respiration, or intensive care stay all of which are important determinants of hospitalizations usage and costs [4]. Moreover, in studies that rely on discharge diagnoses, causality between disease and potential complications must
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be assumed, so that similar limitations apply to the data on complications of varicella [4]. This approach could result in some type of misclassification. However, an outpatient study of herpes zoster in which case finding was based on diagnostic codes, including ICD-9 codes, showed that the positive predictive value of a diagnostic code of herpes zoster was 89–96% [24]. Furthermore, a validation study of varicella-related hospital discharge data for persons aged ≥13 years in New York found that the positive predictive value of varicella as a discharge diagnosis was 87%, as an indicator for varicella-related hospitalizations [13]. In addition, both varicella and herpes zoster are common, recognizable entities, presumably less subject to miscoding than other diagnoses. The annual cost of hospitalizations for primary varicella and reactivated VZV infection reflects only a small part of the overall cost of this disease, as only a very limited number of cases require hospital admission [17,21].
Results of a recently published study, which assessed the economic impact of varicella in children attending primary care centers in Spain, shows that a non-hospitalized varicella case requires more than one visit to the primary care physician and at least one prescription [25]. The overall cost (including medical attention and social indirect cost) of one case attended in the primary care setting is estimated to be around 66 [25]. Our results are consistent with studies in other developed countries and provide evidence that primary varicella and reactivated VZV infection continues to cause severe disease and complications which require hospital admission in all age groups. These severe cases generate a considerable cost to the health care system. Widespread varicella vaccination programs may have an impact on the disease burden and associated costs, but it is the role of the local health authorities to determine whether health-care resources should be allocated to this or other preventive programs.
Appendix A Description
ICD-9-CM code(s)
Underlying conditions for varicella and herpes zoster Human immunodeficiency virus Leukemia Other malignancies Other blood dyscrasia Childhood immunodeficiencies Radiotherapy or chemotherapy Pregnancy
042.0–044.9, 795.8 200.0–208.9 140.0–199.9 284.0–284.9 288.0–288.2, 179.0–179.9 V58.0, V58.1, V07.2 634.0–634.9, 647.6, 647.9, 650.0–656.9
Varicella complications Septicemia Varicella with complications Viral hepatitis Meningitis due to other organism Meningitis of unspecified cause Encephalitis/encephalomyelitis/myelitis Acute infective polyneuritis Pneumonia due to other organism, unspecified organism Acute and subacute necrosis of the liver Other disorders of the liver Cellulitis Impetigo Endotoxic shock
038; 038.0–038.4 052.7;052–8 070; 070.4–070.9 321; 321.2–321.8 322 323.9 357.0 480; 480.8–480.9; 483; 485; 486 570 573; 573.1–573.3; 573.9 681; 681.0; 681.00;681.1; 681.9 682; 682.0–682.9 684 785.59
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