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Mortality trend from sporadic Creutzfeldt-Jakob disease (CJD) in Italy, 1993–2000
Journal of Clinical Epidemiology 56 (2003) 494–499
Mortality trend from sporadic Creutzfeldt-Jakob disease (CJD) in Italy, 1993–2000 Maria Puopoloa, Anna Ladoganab, Susanna Almontib, Nathalie Daudeb, Simona Bevivinob, Rosella Petrarolib, Anna Poleggib, Liu Quanguob, Maurizio Pocchiarib,* a Laboratory of Pathophysiology, Istituto Superiore di Sanita`, Viale Regina Elena 299, 00161 Rome, Italy Laboratory of Virology, Istituto Superiore di Sanita`, Viale Regina Elena 299, 00161 Rome, Italy RP is now at Applera Italia, Viale A Ciamarra 209, 00173 Rome, Italy
b
Received 22 January 2002; received in revised form 4 July 2002; accepted 21 November 2002
Abstract The objective was to identify any possible cases of variant Creutzfeldt-Jakob disease (CJD) in Italy, and to estimate the trends in mortality from sporadic CJD for 1993–2000. CJD cases were ascertained through direct notification to the Registry; 382 definite or probable sporadic CJD patients, but no cases of variant CJD were identified. The average yearly mortality rate was 1.04 cases per million inhabitants, with an increase in deaths in the 60–69 and ⭓70 year age groups. Survival was shorter in male respect to female and in patients with an age at onset ⭓65 years. CJD cases were uneven distributed among different regions in the period 1993–1995, but not herein after. The rise in mortality from sporadic CJD in Italy likely reflects increased awareness and better diagnosis during the years. However, continuous notification and postmortem examination of all suspected cases are recommended for optimal surveillance. 쑖 2003 Elsevier Inc. All rights reserved. Keywords: Creutzfeldt-Jakob disease (CJD); Transmissible spongiform encephalopathy (TSE); Mortality rate; Molecular genetic; Epidemiology; Nation-wide surveillance
1. Introduction Prospective surveillance of Creutzfeldt-Jakob disease (CJD) and related disorders (Gerstmann-Stra¨usser-Scheinker syndrome, and fatal familial insomnia) has been active in Italy since 1993. The main objective of the survey was to determine any change with time in the clinical and epidemiologic characteristics of CJD following the epidemic of bovine spongiform encephalopathy (BSE) in the UK. Data collected from CJD cases in Italy have contributed to the studies on mortality rates in Europe [1–3]. Italian data have also been used for the analysis of risk factors for CJD [4,5], and for the identification, in 1996, of the first 10 cases of variant CJD in the UK [6] caused by exposure to the BSE agent [7–10]. We report on clinical and epidemiologic data of sporadic CJD in Italy during the period 1993–2000. We also examined the trends in age-specific and sex-specific death rates, the geographic distribution, and the frequency of genotypes of
codon 129 of the prion protein (PrP) gene (PRNP), between 1993 and 2000.
2. Patients and methods 2.1. CJD Register data Suspected cases of CJD are notified to the Register of CJD and related disorders at the Istituto Superiore di Sanita`, Rome, Italy, by neurologists and neuropathologists. After notification, follow-up of each patient is performed for a correct classification according to established diagnostic criteria for sporadic [3,11] and variant CJD [12]. In this period, about 50% of patients with suspected CJD came to necropsy. Cases classified as definite (neuropathologically confirmed) or probable sporadic CJD who died between January 1, 1993 and December 31, 2000, have been included in the analysis. Blood for DNA analysis of the polymorphic codon 129 of the PRNP gene [13] was obtained in 56% of all referred cases. 2.2. Statistical analysis
* Corresponding author. Tel.: +39-06-4990-3203; fax: +39-06-49903012. E-mail address: [email protected] (M. Pocchiari). 0895-4356/03/$ – see front matter 쑖 2003 Elsevier Inc. All rights reserved. doi: 10.1016/S0895-4356(02)00606-6
Crude, age- and sex-specific mortality rates were calculated using the annual estimates of the Italian population
M. Puopolo et al. / Journal of Clinical Epidemiology 56 (2003) 494–499
(Italian Census Bureau, ISTAT, Rome, Italy), excluding age class under 20 years old. Five age-interval classes (20–39, 40–49, 50–59, 60–69, 70 and over) were defined for the analysis. Differences in mortality from CJD among the 20 Italian regions were assessed by calculation of the standardized mortality ratio (SMR), based on the nationwide age- and sexspecific mortality rates. The SMR with 95% confidence intervals (CI) that did not include 1.0, were considered to be statistically significant [14]. The CIs were calculated under the assumption that the number of observed cases followed a Poisson’s distribution. This analysis was carried out on three periods 1993–1995, i.e., the beginning of activity of the Register, 1996–1998, i.e., the first 3 years after the report of variant CJD, and 1999–2000. The trend in number of deaths from CJD between 1993 and 2000 was analyzed using Poisson regression modeling. The trend was tested in each age class. Differences in age at onset between groups were assessed by t-test. Survival curves were estimated by the Kaplan-Meier method, and the comparisons were carried out by the generalized Wilcoxon test. The age at onset was dichotomized using the observed median age. The Cox proportional hazard model has then been carried out to assess the independent effects of the variables (sex and age at onset) in a multivariate analysis. Crude and adjusted relative risks with 95% confidence intervals (CI) were reported. The relationship between PRNP codon 129 polymorphism and the clinical phenotype of sporadic CJD patients was analyzed using the chi-square test. 3. Results There were 382 deaths from sporadic CJD in the period 1993–2000. The yearly number of death ranged from 27 in 1993 to 75 in 1999, corresponding to a mortality rate
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ranging from 0.61 to 1.63 per million inhabitants, with an average yearly crude mortality of 1.04 (Fig. 1). The yearly number of referred cases ranged between 51 and 77 up to 1996, followed by a sharp increase from 1997 onwards (Fig. 1). The distribution of the yearly age- and gender-specific mortality rates showed a low rate in the classes below 50 years of age, and a high rate in individuals aged 60 years and over in the three examined periods (1993–1995, 1996– 1998, and 1999–2000; Fig. 2). A higher rate of deaths among females was observed only for patients aged 60–69 in the period 1996–1998. More than 80% of the deaths occurred among individuals older than 60 years of age, while less than 3% (10 deaths) among individuals aged less than 50 years. Clinical or neuropathologic features (n ⫽ 154) of CJD patients aged 60 years and over did not seem to change during the period 1993–2000. There were no reported deaths under 20 years of age. Poisson regression analyses showed a significant increase in the number of deaths from sporadic CJD during the years (P ⬍ .001). This increase was confined to the 60–69 year age group (P ⫽ .005) and to the more than 70 year age group (P ⬍ .001). There was no increase in the number of deaths for the other age groups (Fig. 3). The SMRs and the 95% CI of SMRs for the 20 Italian regions in the three periods under examination are reported in Table 1. In the period 1993–1995, the number of deaths in Lazio (n ⫽ 17) was significantly higher than expected while in Sicily was significantly lower (n ⫽ 0). Lombardia, Trentino, and Marche showed a high mortality rate but did not reach a statistical significance. From 1996 onwards, none of the 20 Italian regions showed a SMR significantly different from 1, suggesting a homogeneous geographic distribution of cases all over Italy and an improvement in case ascertainment on a nationwide base.
Fig. 1. Number of referrals and deaths from sporadic CJD (left axis); annual mortality rates from sporadic CJD (right axis).
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Fig. 2. Age- and sex-specific average yearly death rates from sporadic CJD in Italy during 1993–1995 (a), 1996–1998 (b), and 1999–2000 (c).
The mean age at death of sporadic CJD patients was 65.3 ⫾ 8.5 year in men (n ⫽ 166) and 67.3 ⫾ 8.2 in women (n ⫽ 216). Clinical duration was 5.4 ⫾ 4.9 months in men and 7.0 ⫾ 6.1 in women. Univariate survival analyses of the cases with available data (n ⫽ 381) showed that the duration of illness is affected by gender (generalized Wilcoxon test, P ⫽ .0022; crude RR ⫽ 0.77, 95% CI ⫽ 0.63–0.94) (Fig. 4a) and age at onset (generalized Wilcoxon test, P ⫽ .0071; crude RR ⫽ 1.35, 95% CI ⫽ 1.10–1.66) (Fig. 4b). The multivariate analysis confirmed that survival is shorter in patients who were more than 65 years old at clinical onset (adjusted RR ⫽ 1.42, 95% CI ⫽ 1.16–1.75), and longer in females respect to males (adjusted RR ⫽ 0.73, 95% CI = 0.59–0.89).
Genetic data were available in 208 patients with definite or probable sporadic CJD. The overall distribution of the polymorphic PRNP genotype at codon 129 was 72.6% (n ⫽ 151) Met/Met, 14.4% (n ⫽ 30) Met/Val, and 13.0% (n ⫽ 27) Val/Val. Univariate survival analysis showed that methionine homozygous patients had a significant shorter clinical duration (median, 4 months) than valine homozygous (6 months) or heterozygous patients (7 months) (generalized Wilcoxon test, P ⫽ .0090; Met/Val vs. Met/Met crude RR ⫽ 0.83, 95%, CI ⫽ 0.56–1.24; Val/Val vs. Met/Met crude RR ⫽ 0.99, 95% CI ⫽ 0.65–1.50). When we included the genotype together with sex and age at onset into the Cox regression model (n ⫽ 208), the genotype did not affect
Fig. 3. Observed (dashed lines) and expected (Poisson regression modeling, full lines) number of deaths from sporadic CJD for different age groups.
M. Puopolo et al. / Journal of Clinical Epidemiology 56 (2003) 494–499
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Table 1 Standardized mortality ratios and 95% confidence intervals of sporadic Creutzfeldt-Jakob disease in each Italian region at different periods of surveillance Period of Surveillance Regions
1993–1995
1996–1998
1999–2000
Piemonte Valle d’Aosta Lombardia Trentino Alto Adige Veneto Friuli Liguria Emilia Toscana Umbria Marche Lazio Abruzzo Molise Campania Puglia Basilicata Calabria Sicilia Sardegna
0.80 0.00 1.52 1.51 1.17 0.47 0.61 0.56 0.94 1.35 1.99 2.18 0.00 0.00 0.87 1.14 0.00 0.35 0.00 0.46
0.53 2.90 1.04 2.52 1.38 0.80 0.69 1.02 1.24 0.76 0.89 1.14 2.21 2.09 0.64 1.25 0.63 0.60 0.56 1.01
1.41 0.00 1.13 0.99 1.53 0.31 0.20 1.27 0.51 1.30 2.05 1.00 0.63 1.21 0.57 0.86 0.00 0.69 0.94 1.19
(0.29–1.75) (0.00–19.13) (0.94–2.32) (0.18–5.47) (0.51–2.31) (0.01–2.63) (0.07–2.19) (0.15–1.42) (0.34–2.04) (0.16–4.87) (0.65–4.64) (1.27–3.50) (0.00–1.81) (0.00–6.81) (0.32–1.88) (0.42–2.48) (0.00–4.15) (0.01–1.98) (0.00–0.53) (0.01–2.57)
survival (Met/Val vs. Met/Met adjusted RR ⫽ 0.81, 95% CI ⫽ 0.54–1.21; Val/Val vs. Met/Met crude RR ⫽ 1.11, 95% CI ⫽ 0.73–1.70). Moreover, the adjusted RR for gender (RR ⫽ 0.60, 95% CI ⫽ 0.45–0.81) and age at onset (RR ⫽ 1.46, 95% CI ⫽ 1.10–1.94) obtained in this model were similar to those obtained in the larger samples reported above. There were no differences in the age at onset among different genotypes. Only 39% of valine homozygous CJD patients showed a typical periodic EEG compared to methionine homozygous (83%) or heterozygous (63%) patients (P ⬍ .001, Chi-square test). No cases of definite or probable variant CJD were observed between 1993 and 2000, despite that about 15% of referred cases were aged 50 years or less. In this age group there were 52 deaths; 20 of them were classified as familial CJD, Gerstmann-Stra¨ussler-Scheinker syndrome or fatal familial insomnia because carriers of a pathogenetic mutation of the PRNP gene. Two patients received a dura mater graft respectively 8 and 10 years before they developed CJD (i.e., iatrogenic CJD cases). Fourteen patients were classified as sporadic CJD (six definite, five probable, and three possible); none of them fulfilled the criteria for definite or clinically probable/possible variant CJD. The other 16 patients referred as suspected CJD received finally an alternative clinical or neuropathological diagnosis.
4. Discussion The most remarkable finding of this study is that between 1993 and 2000 we have observed in Italy an increase in deaths from sporadic CJD in people aged 60 years and over. A comparable age-specific increase in mortality rates has been
(0.21–1.08) (0.07–16.17) (0.68–1.52) (0.93–5.49) (0.80–2.21) (0.17–2.34) (0.19–1.77) (0.54–1.74) (0.68–2.08) (0.09–2.73) (0.24–2.28) (0.65–1.84) (0.95–4.35) (0.25–7.56) (0.28–1.26) (0.65–2.18) (0.02–3.52) (0.12–1.74) (0.23–1.16) (0.28–2.59)
(0.81–2.29) (0.00–12.62) (0.72–1.68) (0.12–3.59) (0.87–2.48) (0.01–1.74) (0.00–1.12) (0.69–2.13) (0.17–1.20) (0.27–3.80) (0.89–4.05) (0.52–1.75) (0.08–2.28) (0.03–6.72) (0.21–1.24) (0.35–1.77) (0.00–2.69) (0.14–2.02) (0.45–1.72) (0.32–3.04)
also reported in other countries (Austria [15], France [16], Spain [17], and the United Kingdom [18,19]) participating to the EU collaborative study group of CJD and sharing with Italy similar prospective surveillance programs [1–3]. Increased incidence rates in aged patients were revealed in Japan by a retrospective nation-wide mail survey study for the period 1985–1996 [20], but not in the United States[21]— the overall annual death rates have remained relatively stable since 1985—or Sweden [22]. The interpretation of the increased mortality rate observed in Italy, and in other countries as well, remains unclear: it may represent an improvement in case ascertainment or the rising of unknown risk factors for sporadic CJD [23]. The last hypothesis is fairly speculative: a large case–control study conducted in Europe [4] and a recent reanalysis of previous case–control studies [24] failed to identify a convincing putative risk factors for sporadic CJD, including diet, past medical history, occupation, and animal exposure. Iatrogenic transmission of disease, mainly caused by substitutive therapy with human growth hormone of cadaveric origin or dura mater implants, can be dismissed as well: they are rare events—about 3%of cases— and usually affect young people [25]. The possibility that the number of surgical procedures increases the risk of CJD remains unsettled [5,26–29]. Further research is necessary to establish whether this association is accurate or depends on recall bias due to surrogate respondents (i.e., relatives of cases), but if confirmed, it is consistent with the selective rise of deaths in aged people. The most accepted interpretation for the annual increase in CJD mortality rates remains, therefore, the continuous improvement in case ascertainment—especially among old people—during the surveillance period [19]. Data from Italy confirm this assumption. First, the number of referred cases
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Fig. 4. Survival curves for sporadic CJD by gender (a) and age at onset (b). In (b), the two age classes were based on the median age at onset of all cases (65 years).
to the CJD register at the Istituto Superiore di Sanita` doubled in the 3-year period 1996–1998 and tripled in 1999 and 2000 compared to the first 3 years of surveillance. This suggests a greater attention of neurologists to the disease, an increase care to refer suspicious CJD cases to the CJD Register, or both. This increased awareness is also documented by the distribution of sporadic CJD cases in the Italian regions. During the period 1993–1995, three regions did not report any case, and in another five regions the number of observed cases was about 50% of expected. We had previously estimated an underreporting of 26.7% in 1993 [30], and it is likely that a similar proportion of underreporting was present in 1994 and 1995 (currently under investigation). This uneven geographic distribution declined in the 3 years 1996–1998 and even more in the period 1999–2000, suggesting a better accomplishment of the surveillance during the last 5 years. The introduction of the 14-3-3 immunoassay in the diagnostic criteria for probable CJD also helped to improve the identification of cases [11] (especially valine homozygous and, at a lower extent, heterozygous patients at codon 129 of the PRNP gene) who do not present a periodic EEG with
typical features of CJD and before 1998, if not autopsied, were excluded from the study. A similar finding was also reported in other European countries, but at variance with Italy, France, Germany, and the UK, found a significant excess of valine homozygous CJD cases aged less than 50 years at onset [31]. The reason for this discrepancy remains unknown, but it is unlikely that this depends on a bias in the Italian surveillance system for the identification of younger atypical cases of sporadic CJD. In fact, more than 130 cases aged less than 50 years were referred to the CJD Register at the Istituto Superiore di Sanita` during the 8 years of surveillance. None of those who died in the period 1993–2000 had a pathologic or clinical diagnosis of variant CJD [12], suggesting that in Italy the exposure to the BSE agent was, at least in past years, lower than in the UK or France. The first case of variant CJD in Italy had clinical onset in May 2001 [32]. Predicting how many people in Italy, and elsewhere [33,34], are incubating variant CJD is difficult. Only a continuous surveillance program within the frame of international collaboration may answer these questions in the years to come. The Italian Ministry of Health introduced in February 2001, mandatory notification of all suspected cases of CJD and, at death, mandatory neuropathologic examination. These measurements will likely improve the ascertainment of CJD cases and, hopefully, result in a better estimate of CJD incidence in Italy. Finally, we report that clinical duration of CJD is independently influenced by age at onset and sex. The observation that clinical duration of CJD is longer in younger patients confirms a common assumption that was, however, only based upon limited and handful data [35,36]. This event is likely related to better general health conditions in younger patients. The finding that duration of disease is shorter in males with respect to females, however, was unexpected, and we have no pathogenetic interpretation for that. It would be interesting to know whether females survive longer than males in other countries as well, and if so, to further investigate the reason for this occurrence. In addition, larger studies are needed to better investigate the effect of genotype on the survival of sporadic CJD patients.
Acknowledgments Surveillance of CJD is dependent on the cooperation of neurologists and neuropathologists throughout Italy. We thank the relatives of the patients and hospital medical records officers for their cooperation. We also thank Antonino Bella and Roberto Bugarini (Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanita`) for advice in the statistical analysis, and Alessandra Garozzo for editorial assistance. The Italian Ministry of Health and the Istituto Superiore di Sanita` supports the Registry of CJD.
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Mortality trend from sporadic Creutzfeldt-Jakob disease (CJD) in Italy, 1993–2000 Maria Puopoloa, Anna Ladoganab, Susanna Almontib, Nathalie Daudeb, Simona Bevivinob, Rosella Petrarolib, Anna Poleggib, Liu Quanguob, Maurizio Pocchiarib,* a Laboratory of Pathophysiology, Istituto Superiore di Sanita`, Viale Regina Elena 299, 00161 Rome, Italy Laboratory of Virology, Istituto Superiore di Sanita`, Viale Regina Elena 299, 00161 Rome, Italy RP is now at Applera Italia, Viale A Ciamarra 209, 00173 Rome, Italy
b
Received 22 January 2002; received in revised form 4 July 2002; accepted 21 November 2002
Abstract The objective was to identify any possible cases of variant Creutzfeldt-Jakob disease (CJD) in Italy, and to estimate the trends in mortality from sporadic CJD for 1993–2000. CJD cases were ascertained through direct notification to the Registry; 382 definite or probable sporadic CJD patients, but no cases of variant CJD were identified. The average yearly mortality rate was 1.04 cases per million inhabitants, with an increase in deaths in the 60–69 and ⭓70 year age groups. Survival was shorter in male respect to female and in patients with an age at onset ⭓65 years. CJD cases were uneven distributed among different regions in the period 1993–1995, but not herein after. The rise in mortality from sporadic CJD in Italy likely reflects increased awareness and better diagnosis during the years. However, continuous notification and postmortem examination of all suspected cases are recommended for optimal surveillance. 쑖 2003 Elsevier Inc. All rights reserved. Keywords: Creutzfeldt-Jakob disease (CJD); Transmissible spongiform encephalopathy (TSE); Mortality rate; Molecular genetic; Epidemiology; Nation-wide surveillance
1. Introduction Prospective surveillance of Creutzfeldt-Jakob disease (CJD) and related disorders (Gerstmann-Stra¨usser-Scheinker syndrome, and fatal familial insomnia) has been active in Italy since 1993. The main objective of the survey was to determine any change with time in the clinical and epidemiologic characteristics of CJD following the epidemic of bovine spongiform encephalopathy (BSE) in the UK. Data collected from CJD cases in Italy have contributed to the studies on mortality rates in Europe [1–3]. Italian data have also been used for the analysis of risk factors for CJD [4,5], and for the identification, in 1996, of the first 10 cases of variant CJD in the UK [6] caused by exposure to the BSE agent [7–10]. We report on clinical and epidemiologic data of sporadic CJD in Italy during the period 1993–2000. We also examined the trends in age-specific and sex-specific death rates, the geographic distribution, and the frequency of genotypes of
codon 129 of the prion protein (PrP) gene (PRNP), between 1993 and 2000.
2. Patients and methods 2.1. CJD Register data Suspected cases of CJD are notified to the Register of CJD and related disorders at the Istituto Superiore di Sanita`, Rome, Italy, by neurologists and neuropathologists. After notification, follow-up of each patient is performed for a correct classification according to established diagnostic criteria for sporadic [3,11] and variant CJD [12]. In this period, about 50% of patients with suspected CJD came to necropsy. Cases classified as definite (neuropathologically confirmed) or probable sporadic CJD who died between January 1, 1993 and December 31, 2000, have been included in the analysis. Blood for DNA analysis of the polymorphic codon 129 of the PRNP gene [13] was obtained in 56% of all referred cases. 2.2. Statistical analysis
* Corresponding author. Tel.: +39-06-4990-3203; fax: +39-06-49903012. E-mail address: [email protected] (M. Pocchiari). 0895-4356/03/$ – see front matter 쑖 2003 Elsevier Inc. All rights reserved. doi: 10.1016/S0895-4356(02)00606-6
Crude, age- and sex-specific mortality rates were calculated using the annual estimates of the Italian population
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(Italian Census Bureau, ISTAT, Rome, Italy), excluding age class under 20 years old. Five age-interval classes (20–39, 40–49, 50–59, 60–69, 70 and over) were defined for the analysis. Differences in mortality from CJD among the 20 Italian regions were assessed by calculation of the standardized mortality ratio (SMR), based on the nationwide age- and sexspecific mortality rates. The SMR with 95% confidence intervals (CI) that did not include 1.0, were considered to be statistically significant [14]. The CIs were calculated under the assumption that the number of observed cases followed a Poisson’s distribution. This analysis was carried out on three periods 1993–1995, i.e., the beginning of activity of the Register, 1996–1998, i.e., the first 3 years after the report of variant CJD, and 1999–2000. The trend in number of deaths from CJD between 1993 and 2000 was analyzed using Poisson regression modeling. The trend was tested in each age class. Differences in age at onset between groups were assessed by t-test. Survival curves were estimated by the Kaplan-Meier method, and the comparisons were carried out by the generalized Wilcoxon test. The age at onset was dichotomized using the observed median age. The Cox proportional hazard model has then been carried out to assess the independent effects of the variables (sex and age at onset) in a multivariate analysis. Crude and adjusted relative risks with 95% confidence intervals (CI) were reported. The relationship between PRNP codon 129 polymorphism and the clinical phenotype of sporadic CJD patients was analyzed using the chi-square test. 3. Results There were 382 deaths from sporadic CJD in the period 1993–2000. The yearly number of death ranged from 27 in 1993 to 75 in 1999, corresponding to a mortality rate
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ranging from 0.61 to 1.63 per million inhabitants, with an average yearly crude mortality of 1.04 (Fig. 1). The yearly number of referred cases ranged between 51 and 77 up to 1996, followed by a sharp increase from 1997 onwards (Fig. 1). The distribution of the yearly age- and gender-specific mortality rates showed a low rate in the classes below 50 years of age, and a high rate in individuals aged 60 years and over in the three examined periods (1993–1995, 1996– 1998, and 1999–2000; Fig. 2). A higher rate of deaths among females was observed only for patients aged 60–69 in the period 1996–1998. More than 80% of the deaths occurred among individuals older than 60 years of age, while less than 3% (10 deaths) among individuals aged less than 50 years. Clinical or neuropathologic features (n ⫽ 154) of CJD patients aged 60 years and over did not seem to change during the period 1993–2000. There were no reported deaths under 20 years of age. Poisson regression analyses showed a significant increase in the number of deaths from sporadic CJD during the years (P ⬍ .001). This increase was confined to the 60–69 year age group (P ⫽ .005) and to the more than 70 year age group (P ⬍ .001). There was no increase in the number of deaths for the other age groups (Fig. 3). The SMRs and the 95% CI of SMRs for the 20 Italian regions in the three periods under examination are reported in Table 1. In the period 1993–1995, the number of deaths in Lazio (n ⫽ 17) was significantly higher than expected while in Sicily was significantly lower (n ⫽ 0). Lombardia, Trentino, and Marche showed a high mortality rate but did not reach a statistical significance. From 1996 onwards, none of the 20 Italian regions showed a SMR significantly different from 1, suggesting a homogeneous geographic distribution of cases all over Italy and an improvement in case ascertainment on a nationwide base.
Fig. 1. Number of referrals and deaths from sporadic CJD (left axis); annual mortality rates from sporadic CJD (right axis).
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Fig. 2. Age- and sex-specific average yearly death rates from sporadic CJD in Italy during 1993–1995 (a), 1996–1998 (b), and 1999–2000 (c).
The mean age at death of sporadic CJD patients was 65.3 ⫾ 8.5 year in men (n ⫽ 166) and 67.3 ⫾ 8.2 in women (n ⫽ 216). Clinical duration was 5.4 ⫾ 4.9 months in men and 7.0 ⫾ 6.1 in women. Univariate survival analyses of the cases with available data (n ⫽ 381) showed that the duration of illness is affected by gender (generalized Wilcoxon test, P ⫽ .0022; crude RR ⫽ 0.77, 95% CI ⫽ 0.63–0.94) (Fig. 4a) and age at onset (generalized Wilcoxon test, P ⫽ .0071; crude RR ⫽ 1.35, 95% CI ⫽ 1.10–1.66) (Fig. 4b). The multivariate analysis confirmed that survival is shorter in patients who were more than 65 years old at clinical onset (adjusted RR ⫽ 1.42, 95% CI ⫽ 1.16–1.75), and longer in females respect to males (adjusted RR ⫽ 0.73, 95% CI = 0.59–0.89).
Genetic data were available in 208 patients with definite or probable sporadic CJD. The overall distribution of the polymorphic PRNP genotype at codon 129 was 72.6% (n ⫽ 151) Met/Met, 14.4% (n ⫽ 30) Met/Val, and 13.0% (n ⫽ 27) Val/Val. Univariate survival analysis showed that methionine homozygous patients had a significant shorter clinical duration (median, 4 months) than valine homozygous (6 months) or heterozygous patients (7 months) (generalized Wilcoxon test, P ⫽ .0090; Met/Val vs. Met/Met crude RR ⫽ 0.83, 95%, CI ⫽ 0.56–1.24; Val/Val vs. Met/Met crude RR ⫽ 0.99, 95% CI ⫽ 0.65–1.50). When we included the genotype together with sex and age at onset into the Cox regression model (n ⫽ 208), the genotype did not affect
Fig. 3. Observed (dashed lines) and expected (Poisson regression modeling, full lines) number of deaths from sporadic CJD for different age groups.
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Table 1 Standardized mortality ratios and 95% confidence intervals of sporadic Creutzfeldt-Jakob disease in each Italian region at different periods of surveillance Period of Surveillance Regions
1993–1995
1996–1998
1999–2000
Piemonte Valle d’Aosta Lombardia Trentino Alto Adige Veneto Friuli Liguria Emilia Toscana Umbria Marche Lazio Abruzzo Molise Campania Puglia Basilicata Calabria Sicilia Sardegna
0.80 0.00 1.52 1.51 1.17 0.47 0.61 0.56 0.94 1.35 1.99 2.18 0.00 0.00 0.87 1.14 0.00 0.35 0.00 0.46
0.53 2.90 1.04 2.52 1.38 0.80 0.69 1.02 1.24 0.76 0.89 1.14 2.21 2.09 0.64 1.25 0.63 0.60 0.56 1.01
1.41 0.00 1.13 0.99 1.53 0.31 0.20 1.27 0.51 1.30 2.05 1.00 0.63 1.21 0.57 0.86 0.00 0.69 0.94 1.19
(0.29–1.75) (0.00–19.13) (0.94–2.32) (0.18–5.47) (0.51–2.31) (0.01–2.63) (0.07–2.19) (0.15–1.42) (0.34–2.04) (0.16–4.87) (0.65–4.64) (1.27–3.50) (0.00–1.81) (0.00–6.81) (0.32–1.88) (0.42–2.48) (0.00–4.15) (0.01–1.98) (0.00–0.53) (0.01–2.57)
survival (Met/Val vs. Met/Met adjusted RR ⫽ 0.81, 95% CI ⫽ 0.54–1.21; Val/Val vs. Met/Met crude RR ⫽ 1.11, 95% CI ⫽ 0.73–1.70). Moreover, the adjusted RR for gender (RR ⫽ 0.60, 95% CI ⫽ 0.45–0.81) and age at onset (RR ⫽ 1.46, 95% CI ⫽ 1.10–1.94) obtained in this model were similar to those obtained in the larger samples reported above. There were no differences in the age at onset among different genotypes. Only 39% of valine homozygous CJD patients showed a typical periodic EEG compared to methionine homozygous (83%) or heterozygous (63%) patients (P ⬍ .001, Chi-square test). No cases of definite or probable variant CJD were observed between 1993 and 2000, despite that about 15% of referred cases were aged 50 years or less. In this age group there were 52 deaths; 20 of them were classified as familial CJD, Gerstmann-Stra¨ussler-Scheinker syndrome or fatal familial insomnia because carriers of a pathogenetic mutation of the PRNP gene. Two patients received a dura mater graft respectively 8 and 10 years before they developed CJD (i.e., iatrogenic CJD cases). Fourteen patients were classified as sporadic CJD (six definite, five probable, and three possible); none of them fulfilled the criteria for definite or clinically probable/possible variant CJD. The other 16 patients referred as suspected CJD received finally an alternative clinical or neuropathological diagnosis.
4. Discussion The most remarkable finding of this study is that between 1993 and 2000 we have observed in Italy an increase in deaths from sporadic CJD in people aged 60 years and over. A comparable age-specific increase in mortality rates has been
(0.21–1.08) (0.07–16.17) (0.68–1.52) (0.93–5.49) (0.80–2.21) (0.17–2.34) (0.19–1.77) (0.54–1.74) (0.68–2.08) (0.09–2.73) (0.24–2.28) (0.65–1.84) (0.95–4.35) (0.25–7.56) (0.28–1.26) (0.65–2.18) (0.02–3.52) (0.12–1.74) (0.23–1.16) (0.28–2.59)
(0.81–2.29) (0.00–12.62) (0.72–1.68) (0.12–3.59) (0.87–2.48) (0.01–1.74) (0.00–1.12) (0.69–2.13) (0.17–1.20) (0.27–3.80) (0.89–4.05) (0.52–1.75) (0.08–2.28) (0.03–6.72) (0.21–1.24) (0.35–1.77) (0.00–2.69) (0.14–2.02) (0.45–1.72) (0.32–3.04)
also reported in other countries (Austria [15], France [16], Spain [17], and the United Kingdom [18,19]) participating to the EU collaborative study group of CJD and sharing with Italy similar prospective surveillance programs [1–3]. Increased incidence rates in aged patients were revealed in Japan by a retrospective nation-wide mail survey study for the period 1985–1996 [20], but not in the United States[21]— the overall annual death rates have remained relatively stable since 1985—or Sweden [22]. The interpretation of the increased mortality rate observed in Italy, and in other countries as well, remains unclear: it may represent an improvement in case ascertainment or the rising of unknown risk factors for sporadic CJD [23]. The last hypothesis is fairly speculative: a large case–control study conducted in Europe [4] and a recent reanalysis of previous case–control studies [24] failed to identify a convincing putative risk factors for sporadic CJD, including diet, past medical history, occupation, and animal exposure. Iatrogenic transmission of disease, mainly caused by substitutive therapy with human growth hormone of cadaveric origin or dura mater implants, can be dismissed as well: they are rare events—about 3%of cases— and usually affect young people [25]. The possibility that the number of surgical procedures increases the risk of CJD remains unsettled [5,26–29]. Further research is necessary to establish whether this association is accurate or depends on recall bias due to surrogate respondents (i.e., relatives of cases), but if confirmed, it is consistent with the selective rise of deaths in aged people. The most accepted interpretation for the annual increase in CJD mortality rates remains, therefore, the continuous improvement in case ascertainment—especially among old people—during the surveillance period [19]. Data from Italy confirm this assumption. First, the number of referred cases
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Fig. 4. Survival curves for sporadic CJD by gender (a) and age at onset (b). In (b), the two age classes were based on the median age at onset of all cases (65 years).
to the CJD register at the Istituto Superiore di Sanita` doubled in the 3-year period 1996–1998 and tripled in 1999 and 2000 compared to the first 3 years of surveillance. This suggests a greater attention of neurologists to the disease, an increase care to refer suspicious CJD cases to the CJD Register, or both. This increased awareness is also documented by the distribution of sporadic CJD cases in the Italian regions. During the period 1993–1995, three regions did not report any case, and in another five regions the number of observed cases was about 50% of expected. We had previously estimated an underreporting of 26.7% in 1993 [30], and it is likely that a similar proportion of underreporting was present in 1994 and 1995 (currently under investigation). This uneven geographic distribution declined in the 3 years 1996–1998 and even more in the period 1999–2000, suggesting a better accomplishment of the surveillance during the last 5 years. The introduction of the 14-3-3 immunoassay in the diagnostic criteria for probable CJD also helped to improve the identification of cases [11] (especially valine homozygous and, at a lower extent, heterozygous patients at codon 129 of the PRNP gene) who do not present a periodic EEG with
typical features of CJD and before 1998, if not autopsied, were excluded from the study. A similar finding was also reported in other European countries, but at variance with Italy, France, Germany, and the UK, found a significant excess of valine homozygous CJD cases aged less than 50 years at onset [31]. The reason for this discrepancy remains unknown, but it is unlikely that this depends on a bias in the Italian surveillance system for the identification of younger atypical cases of sporadic CJD. In fact, more than 130 cases aged less than 50 years were referred to the CJD Register at the Istituto Superiore di Sanita` during the 8 years of surveillance. None of those who died in the period 1993–2000 had a pathologic or clinical diagnosis of variant CJD [12], suggesting that in Italy the exposure to the BSE agent was, at least in past years, lower than in the UK or France. The first case of variant CJD in Italy had clinical onset in May 2001 [32]. Predicting how many people in Italy, and elsewhere [33,34], are incubating variant CJD is difficult. Only a continuous surveillance program within the frame of international collaboration may answer these questions in the years to come. The Italian Ministry of Health introduced in February 2001, mandatory notification of all suspected cases of CJD and, at death, mandatory neuropathologic examination. These measurements will likely improve the ascertainment of CJD cases and, hopefully, result in a better estimate of CJD incidence in Italy. Finally, we report that clinical duration of CJD is independently influenced by age at onset and sex. The observation that clinical duration of CJD is longer in younger patients confirms a common assumption that was, however, only based upon limited and handful data [35,36]. This event is likely related to better general health conditions in younger patients. The finding that duration of disease is shorter in males with respect to females, however, was unexpected, and we have no pathogenetic interpretation for that. It would be interesting to know whether females survive longer than males in other countries as well, and if so, to further investigate the reason for this occurrence. In addition, larger studies are needed to better investigate the effect of genotype on the survival of sporadic CJD patients.
Acknowledgments Surveillance of CJD is dependent on the cooperation of neurologists and neuropathologists throughout Italy. We thank the relatives of the patients and hospital medical records officers for their cooperation. We also thank Antonino Bella and Roberto Bugarini (Laboratory of Epidemiology and Biostatistics, Istituto Superiore di Sanita`) for advice in the statistical analysis, and Alessandra Garozzo for editorial assistance. The Italian Ministry of Health and the Istituto Superiore di Sanita` supports the Registry of CJD.
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