Original Paper Neuroepidemiology 2014;43:1–8 DOI: 10.1159/000362688
Received: January 5, 2014 Accepted: March 24, 2014 Published online: June 24, 2014
Trends in Encephalitis-Associated Deaths in the United States, 1999–2008 Danielle M. Tack a, b Robert C. Holman b Arianne M. Folkema b Jason M. Mehal b Jesse D. Blanton b James J. Sejvar b a
Epidemic Intelligence Service and b Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Ga., USA
Abstract Background: While encephalitis may be caused by numerous infectious, immune and toxic processes, the etiology often remains unknown. Methods: We analyzed multiple cause-of-death mortality data during 1999–2008 for the USA, using the 10th revision of International Classification of Diseases codes for encephalitis, listed anywhere on the death record, including ‘specified’ and ‘unspecified’ encephalitis. Annual and average annual age-adjusted and age-specific death rates were calculated. Results: For 1999–2008, 12,526 encephalitis-associated deaths were reported with 68.5% as unspecified encephalitis. The average annual ageadjusted encephalitis-associated death rate was 4.3 per 1 million persons, 1.3 for specified and 2.9 for unspecified encephalitis. Annual encephalitis-associated death rates had a significant downward trend (p < 0.01). The most common specified encephalitis deaths were herpesviral encephalitis (36.7%), Toxoplasma meningoencephalitis (27.8%) and Listeria meningitis/meningoencephaltis (6.8%). HIV was colisted with 15.0% of encephalitis-associated deaths, 58.4% of these with a specified code. Conclusion: Encephalitis-asso-
© 2014 S. Karger AG, Basel 0251–5350/14/0431–0001$39.50/0 E-Mail [email protected] www.karger.com/ned
ciated death rates decreased during 1999–2008, and herpesvirus was the most commonly identified infectious agent associated with encephalitis deaths. The high proportion of unspecified encephalitis deaths highlights the continued challenge of laboratory confirmation for causes of encephalitis and the importance of monitoring trends to assess the impact of new diagnostics and guide potential interventions. © 2014 S. Karger AG, Basel
Introduction
Encephalitis, an inflammatory process of brain parenchyma, may be caused by numerous infectious, toxic and immunologic etiologies. Signs and symptoms typically include fever, headache and altered consciousness, often with focal neurologic deficits and seizures [1, 2]. Definitive treatment for encephalitis is limited to a few specific pathogens, and clinical management generally involves symptom control and supportive care only. Clinical outcomes of encephalitis vary, but many cases result in severe ongoing morbidity and death [3, 4]. Infectious etiologies represent the most common causes of encephalitis, with viruses the most frequently James J. Sejvar, MD Centers for Disease Control and Prevention 1600 Clifton Rd, Mailstop A–30 Atlanta, GA 30333 (USA) E-Mail zea3 @ cdc.gov
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 4:43:21 AM
Key Words Encephalitis · Mortality · Unspecified encephalitis
2
Neuroepidemiology 2014;43:1–8 DOI: 10.1159/000362688
cephalitis deaths due to varicella-zoster) and removed others (i.e. HIV encephalitis) [15]. Despite these changes, other etiologies remain without specific diagnostic codes. This is particularly true for noninfectious etiologies such as limbic and paraneoplastic encephalitis, which have been increasingly recognized as encephalitic etiologies [16]. In this study, we describe trends in encephalitis-associated death rates in the USA during 1999–2008 and determine differences in death rate trends between encephalitis attributable to a specific cause and encephalitis without an identified etiology.
Methods Multiple cause-of-death mortality data for the USA for 1999– 2008 were obtained from the National Center for Health Statistics, Centers for Disease Control and Prevention [17]. Encephalitis-associated deaths were defined as deaths among US residents with ICD-10 codes for encephalitis anywhere on the coded death record [15]. Cause-of-death information is coded from a specific section on death certificates completed by the person certifying the death. The ICD-10 codes used to identify encephalitis-associated deaths were selected to be consistent with ICD-9 codes from previous encephalitis mortality studies (table 1) [7, 8]. Encephalitis deaths were categorized into two groups: ‘specified encephalitis’ using the specified encephalitis causes (ICD-10 codes) and ‘unspecified encephalitis’ which included the remaining encephalitis death records (table 1) [15]. An encephalitis-associated death in an HIVinfected person was defined as a death with any encephalitis code(s) and at least one of the HIV ICD-10 codes of B20–B24. An unspecified encephalitis death could have been cocoded with a non-encephalitis-specific code potentially explaining the etiology of the encephalitis death. To further explore this possibility, the top 5 infectious disease codes (A00–B99) and top 5 neoplastic codes (codes C00–D48) colisted with unspecified encephalitis (A86 and G04.9 codes) were determined. Encephalitis-associated death rates were expressed as the number of deaths per 1 million persons from the corresponding population using annual national census data for the US resident population [19]. Annual and average annual encephalitis-associated death rates were calculated overall and by age group, sex, race and US Census Bureau geographic division for the encephalitis groups [20]. Age-adjusted death rates were calculated by the direct method using the year 2000 projected census US population [21]. Comparisons of death rates between groups were made using Poisson regression analysis with rate ratios (RRs) and 95% confidence intervals (CIs) [22]. Trends for rates over the study period were conducted using Poisson regression both for overall deaths (controlling for age) and by age group for each encephalitis category [22]. The trend of the annual proportion of unspecified encephalitis deaths and of encephalitis deaths associated with HIV during the study period was analyzed using the χ2 due to linear trend test. The proportion of encephalitis-associated deaths listing encephalitis as the underlying cause of death was also provided. Statistical tests were considered significant at the p < 0.05 level.
Tack /Holman /Folkema /Mehal /Blanton / Sejvar
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identified pathogens. However, about one third of cases are thought to be immune-mediated, such as acute disseminated encephalomyelitis or limbic encephalitis, with a clinical presentation similar to infectious encephalitis [1, 5]. Despite extensive laboratory diagnostic testing for infectious or other etiologies of encephalitis, the underlying cause often remains unknown [6]. Previous studies in North America, Europe and Australia have estimated the encephalitis incidence between 3.4 and 7.4 per 100,000 patient-years with up to 86% of cases attributed to an unknown cause [2, 7–10]. Encephalitis surveillance in most countries is passive and is generally pathogen specific. Understanding trends in encephalitis death rates can help determine whether diagnostics and treatment regimens are improving, and identify changes in encephalitis epidemiology which might reflect pathogen-specific factors. Recent development of more sensitive diagnostic modalities, including molecular techniques, has improved the diagnostic capacities for identification of encephalitic pathogens [11]. In the USA, the rate of encephalitis-associated deaths based on multiple cause-of-death mortality data was stable at approximately 5.1 and 5.3 per 1 million population for 1979–1988 and 1989–1998, respectively [8]. However, significant differences in encephalitis death rate trends among persons with and without human immunodeficiency virus (HIV) were identified; the rate for non-HIV encephalitis-associated deaths declined in all categories while the rate for encephalitis-associated deaths among HIV-positive persons increased. In Australia, where similar studies were conducted, the rate of encephalitis deaths was 2.3 per 1 million persons for 1979–2006 with an average annual decline of 2.3%, primarily associated with identified causes [7]. This Australian assessment was based on encephalitis as the primary cause-of-death, whereas the US study reported multiple cause-of-death mortality, which presumably contributes to the lower rate reported in Australia [7, 8]. Several significant changes in medical care, reporting and encephalitis epidemiology have occurred since 1998, when the last retrospective review of encephalitis mortality in the USA was completed. Highly active antiretroviral therapy became a standard of care for HIV patients by the late 1990s, resulting in improved chronic health status among those infected [12, 13]. West Nile virus (WNV) was introduced to the USA in 1999 and quickly spread throughout North America [14]. The 10th revision of the International Classification of Diseases (ICD-10) was also implemented, which introduced some agent-specific codes for the first time (i.e. toxoplasmic encephalitis, en-
Table 1. Encephalitis-associated deaths by cause of death category, USA, 1999 – 2008
Category
ICD-10 code(s)1
Encephalitisassociated deaths2 n
Specified encephalitis Listeria meningitis and meningoencephalitis Subacute sclerosing panencephalitis Rabies Mosquito-borne viral encephalitis3 Tick-borne encephalitis Enteroviral encephalitis Adenoviral encephalitis Other specified viral encephalitis Herpesviral encephalitis Varicella encephalitis Zoster encephalitis Measles encephalitis Mumps encephalitis Toxoplasma meningoencephalitis Naegleriasis Sequelae of viral encephalitis Acute disseminated encephalitis and encephalomyelitis Bacterial meningoencephalitis and meningomyelitis, not elsewhere classified Other encephalitis, myelitis and encephalomyelitis Hemorrhagic leukoencephalomyelitis Unspecified encephalitis Mosquito-borne viral encephalitis, unspecified Tick-borne encephalitis, unspecified Arthropod-borne viral encephalitis, unspecified Unspecified viral encephalitis Encephalitis, myelitis and encephalomyelitis, unspecified All encephalitis
%
Encephalitis with a specified code A32.1 A81.1 A82.0-9 A83.0-8 A84.0-8 A85.0 A85.1 A85.8 B00.4 B01.1 B02.0 B05.0 B26.2 B58.2 B60.2 B94.1 G04.0
3,945 270 37 20 65 0 9 2 41 1,448 63 220 8 1 1,097 15 144 105
31.5 2.2 0.3 0.2 0.5 0.0 0.1 0.02 0.3 11.6 0.5 1.8 0.1 0.01 8.8 0.1 1.2 0.8
G04.2 G04.8 G36.1 Encephalitis with unspecified encephalitis code A83.9 A84.9 A85.2 A86 G04.9 Unspecified and specified encephalitis
89 315 14 8,581
0.7 2.5 0.1 68.5
7 0 1 1,373 7,220 12,526
0.1 0.0 0.01 11.0 57.6 100
1
The G05 code was not included since it is not used in the USA [18]. Percent of all encephalitis-associated deaths during the given study period. More than one cause of death with an encephalitis code was listed for 0.4% (n = 17) of the ‘specified encephalitis’ deaths and 0.2% (n = 20) of ‘unspecified encephalitis’ deaths. Consequently, the sum of deaths in each category exceeds the total, and the sum of percentages exceeds 100%. 3 Does not include WNV, no specific WNV encephalitis code. 2
During 1999–2008, 12,526 encephalitis-associated deaths were reported in the USA (table 1). Of these, 5,835 (46.6%) listed encephalitis as the underlying cause-ofdeath. The overall average annual age-adjusted encephalitis-associated death rate for 1999–2008 was 4.3 per 1 million and was higher for males than females (RR = 1.3, 95% CI = 1.3–1.4, table 2). Although the majority of enEncephalitis-Associated Deaths
cephalitis-associated deaths occurred among whites (76.3%), the age-adjusted death rate was higher for blacks than for whites (RR = 2.1, 95% CI = 1.5–2.9). The agespecific rate was highest for decedents ≥65 years of age (15.5). These demographic differences were consistent for both specified and unspecified encephalitis deaths. Minor geographic differences were identified by census division (table 2).
Neuroepidemiology 2014;43:1–8 DOI: 10.1159/000362688
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Results
Table 2. Encephalitis-associated age-adjusted and age-specific death rates per 1,000,000 deaths, by encephalitis category, USA, 1999 –
2008 Category
All encephalitis n
Total 12,526 Sex Male 6,708 Female 5,818 Race White 9,561 Black 2,564 Other 401 Age group
Received: January 5, 2014 Accepted: March 24, 2014 Published online: June 24, 2014
Trends in Encephalitis-Associated Deaths in the United States, 1999–2008 Danielle M. Tack a, b Robert C. Holman b Arianne M. Folkema b Jason M. Mehal b Jesse D. Blanton b James J. Sejvar b a
Epidemic Intelligence Service and b Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Ga., USA
Abstract Background: While encephalitis may be caused by numerous infectious, immune and toxic processes, the etiology often remains unknown. Methods: We analyzed multiple cause-of-death mortality data during 1999–2008 for the USA, using the 10th revision of International Classification of Diseases codes for encephalitis, listed anywhere on the death record, including ‘specified’ and ‘unspecified’ encephalitis. Annual and average annual age-adjusted and age-specific death rates were calculated. Results: For 1999–2008, 12,526 encephalitis-associated deaths were reported with 68.5% as unspecified encephalitis. The average annual ageadjusted encephalitis-associated death rate was 4.3 per 1 million persons, 1.3 for specified and 2.9 for unspecified encephalitis. Annual encephalitis-associated death rates had a significant downward trend (p < 0.01). The most common specified encephalitis deaths were herpesviral encephalitis (36.7%), Toxoplasma meningoencephalitis (27.8%) and Listeria meningitis/meningoencephaltis (6.8%). HIV was colisted with 15.0% of encephalitis-associated deaths, 58.4% of these with a specified code. Conclusion: Encephalitis-asso-
© 2014 S. Karger AG, Basel 0251–5350/14/0431–0001$39.50/0 E-Mail [email protected] www.karger.com/ned
ciated death rates decreased during 1999–2008, and herpesvirus was the most commonly identified infectious agent associated with encephalitis deaths. The high proportion of unspecified encephalitis deaths highlights the continued challenge of laboratory confirmation for causes of encephalitis and the importance of monitoring trends to assess the impact of new diagnostics and guide potential interventions. © 2014 S. Karger AG, Basel
Introduction
Encephalitis, an inflammatory process of brain parenchyma, may be caused by numerous infectious, toxic and immunologic etiologies. Signs and symptoms typically include fever, headache and altered consciousness, often with focal neurologic deficits and seizures [1, 2]. Definitive treatment for encephalitis is limited to a few specific pathogens, and clinical management generally involves symptom control and supportive care only. Clinical outcomes of encephalitis vary, but many cases result in severe ongoing morbidity and death [3, 4]. Infectious etiologies represent the most common causes of encephalitis, with viruses the most frequently James J. Sejvar, MD Centers for Disease Control and Prevention 1600 Clifton Rd, Mailstop A–30 Atlanta, GA 30333 (USA) E-Mail zea3 @ cdc.gov
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 4:43:21 AM
Key Words Encephalitis · Mortality · Unspecified encephalitis
2
Neuroepidemiology 2014;43:1–8 DOI: 10.1159/000362688
cephalitis deaths due to varicella-zoster) and removed others (i.e. HIV encephalitis) [15]. Despite these changes, other etiologies remain without specific diagnostic codes. This is particularly true for noninfectious etiologies such as limbic and paraneoplastic encephalitis, which have been increasingly recognized as encephalitic etiologies [16]. In this study, we describe trends in encephalitis-associated death rates in the USA during 1999–2008 and determine differences in death rate trends between encephalitis attributable to a specific cause and encephalitis without an identified etiology.
Methods Multiple cause-of-death mortality data for the USA for 1999– 2008 were obtained from the National Center for Health Statistics, Centers for Disease Control and Prevention [17]. Encephalitis-associated deaths were defined as deaths among US residents with ICD-10 codes for encephalitis anywhere on the coded death record [15]. Cause-of-death information is coded from a specific section on death certificates completed by the person certifying the death. The ICD-10 codes used to identify encephalitis-associated deaths were selected to be consistent with ICD-9 codes from previous encephalitis mortality studies (table 1) [7, 8]. Encephalitis deaths were categorized into two groups: ‘specified encephalitis’ using the specified encephalitis causes (ICD-10 codes) and ‘unspecified encephalitis’ which included the remaining encephalitis death records (table 1) [15]. An encephalitis-associated death in an HIVinfected person was defined as a death with any encephalitis code(s) and at least one of the HIV ICD-10 codes of B20–B24. An unspecified encephalitis death could have been cocoded with a non-encephalitis-specific code potentially explaining the etiology of the encephalitis death. To further explore this possibility, the top 5 infectious disease codes (A00–B99) and top 5 neoplastic codes (codes C00–D48) colisted with unspecified encephalitis (A86 and G04.9 codes) were determined. Encephalitis-associated death rates were expressed as the number of deaths per 1 million persons from the corresponding population using annual national census data for the US resident population [19]. Annual and average annual encephalitis-associated death rates were calculated overall and by age group, sex, race and US Census Bureau geographic division for the encephalitis groups [20]. Age-adjusted death rates were calculated by the direct method using the year 2000 projected census US population [21]. Comparisons of death rates between groups were made using Poisson regression analysis with rate ratios (RRs) and 95% confidence intervals (CIs) [22]. Trends for rates over the study period were conducted using Poisson regression both for overall deaths (controlling for age) and by age group for each encephalitis category [22]. The trend of the annual proportion of unspecified encephalitis deaths and of encephalitis deaths associated with HIV during the study period was analyzed using the χ2 due to linear trend test. The proportion of encephalitis-associated deaths listing encephalitis as the underlying cause of death was also provided. Statistical tests were considered significant at the p < 0.05 level.
Tack /Holman /Folkema /Mehal /Blanton / Sejvar
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 4:43:21 AM
identified pathogens. However, about one third of cases are thought to be immune-mediated, such as acute disseminated encephalomyelitis or limbic encephalitis, with a clinical presentation similar to infectious encephalitis [1, 5]. Despite extensive laboratory diagnostic testing for infectious or other etiologies of encephalitis, the underlying cause often remains unknown [6]. Previous studies in North America, Europe and Australia have estimated the encephalitis incidence between 3.4 and 7.4 per 100,000 patient-years with up to 86% of cases attributed to an unknown cause [2, 7–10]. Encephalitis surveillance in most countries is passive and is generally pathogen specific. Understanding trends in encephalitis death rates can help determine whether diagnostics and treatment regimens are improving, and identify changes in encephalitis epidemiology which might reflect pathogen-specific factors. Recent development of more sensitive diagnostic modalities, including molecular techniques, has improved the diagnostic capacities for identification of encephalitic pathogens [11]. In the USA, the rate of encephalitis-associated deaths based on multiple cause-of-death mortality data was stable at approximately 5.1 and 5.3 per 1 million population for 1979–1988 and 1989–1998, respectively [8]. However, significant differences in encephalitis death rate trends among persons with and without human immunodeficiency virus (HIV) were identified; the rate for non-HIV encephalitis-associated deaths declined in all categories while the rate for encephalitis-associated deaths among HIV-positive persons increased. In Australia, where similar studies were conducted, the rate of encephalitis deaths was 2.3 per 1 million persons for 1979–2006 with an average annual decline of 2.3%, primarily associated with identified causes [7]. This Australian assessment was based on encephalitis as the primary cause-of-death, whereas the US study reported multiple cause-of-death mortality, which presumably contributes to the lower rate reported in Australia [7, 8]. Several significant changes in medical care, reporting and encephalitis epidemiology have occurred since 1998, when the last retrospective review of encephalitis mortality in the USA was completed. Highly active antiretroviral therapy became a standard of care for HIV patients by the late 1990s, resulting in improved chronic health status among those infected [12, 13]. West Nile virus (WNV) was introduced to the USA in 1999 and quickly spread throughout North America [14]. The 10th revision of the International Classification of Diseases (ICD-10) was also implemented, which introduced some agent-specific codes for the first time (i.e. toxoplasmic encephalitis, en-
Table 1. Encephalitis-associated deaths by cause of death category, USA, 1999 – 2008
Category
ICD-10 code(s)1
Encephalitisassociated deaths2 n
Specified encephalitis Listeria meningitis and meningoencephalitis Subacute sclerosing panencephalitis Rabies Mosquito-borne viral encephalitis3 Tick-borne encephalitis Enteroviral encephalitis Adenoviral encephalitis Other specified viral encephalitis Herpesviral encephalitis Varicella encephalitis Zoster encephalitis Measles encephalitis Mumps encephalitis Toxoplasma meningoencephalitis Naegleriasis Sequelae of viral encephalitis Acute disseminated encephalitis and encephalomyelitis Bacterial meningoencephalitis and meningomyelitis, not elsewhere classified Other encephalitis, myelitis and encephalomyelitis Hemorrhagic leukoencephalomyelitis Unspecified encephalitis Mosquito-borne viral encephalitis, unspecified Tick-borne encephalitis, unspecified Arthropod-borne viral encephalitis, unspecified Unspecified viral encephalitis Encephalitis, myelitis and encephalomyelitis, unspecified All encephalitis
%
Encephalitis with a specified code A32.1 A81.1 A82.0-9 A83.0-8 A84.0-8 A85.0 A85.1 A85.8 B00.4 B01.1 B02.0 B05.0 B26.2 B58.2 B60.2 B94.1 G04.0
3,945 270 37 20 65 0 9 2 41 1,448 63 220 8 1 1,097 15 144 105
31.5 2.2 0.3 0.2 0.5 0.0 0.1 0.02 0.3 11.6 0.5 1.8 0.1 0.01 8.8 0.1 1.2 0.8
G04.2 G04.8 G36.1 Encephalitis with unspecified encephalitis code A83.9 A84.9 A85.2 A86 G04.9 Unspecified and specified encephalitis
89 315 14 8,581
0.7 2.5 0.1 68.5
7 0 1 1,373 7,220 12,526
0.1 0.0 0.01 11.0 57.6 100
1
The G05 code was not included since it is not used in the USA [18]. Percent of all encephalitis-associated deaths during the given study period. More than one cause of death with an encephalitis code was listed for 0.4% (n = 17) of the ‘specified encephalitis’ deaths and 0.2% (n = 20) of ‘unspecified encephalitis’ deaths. Consequently, the sum of deaths in each category exceeds the total, and the sum of percentages exceeds 100%. 3 Does not include WNV, no specific WNV encephalitis code. 2
During 1999–2008, 12,526 encephalitis-associated deaths were reported in the USA (table 1). Of these, 5,835 (46.6%) listed encephalitis as the underlying cause-ofdeath. The overall average annual age-adjusted encephalitis-associated death rate for 1999–2008 was 4.3 per 1 million and was higher for males than females (RR = 1.3, 95% CI = 1.3–1.4, table 2). Although the majority of enEncephalitis-Associated Deaths
cephalitis-associated deaths occurred among whites (76.3%), the age-adjusted death rate was higher for blacks than for whites (RR = 2.1, 95% CI = 1.5–2.9). The agespecific rate was highest for decedents ≥65 years of age (15.5). These demographic differences were consistent for both specified and unspecified encephalitis deaths. Minor geographic differences were identified by census division (table 2).
Neuroepidemiology 2014;43:1–8 DOI: 10.1159/000362688
3
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Results
Table 2. Encephalitis-associated age-adjusted and age-specific death rates per 1,000,000 deaths, by encephalitis category, USA, 1999 –
2008 Category
All encephalitis n
Total 12,526 Sex Male 6,708 Female 5,818 Race White 9,561 Black 2,564 Other 401 Age group
