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Meningococcal meningitis and meningococcemia : epidemiological study, France (1985–1991)
EPIDEMIOLOGIE
M6d Mal Infect. 1995 ; 25,584-93
Meningococcal meningitis and meningococcemia : epidemiological study, France (1985-1991)* N. BRASSIER**,
A. LEPOUTRE**, C. MOYSE**
M. GUIBOURDENCHE***,
e t J.Y. R I O U * * *
SUMMARY
In France, meningococcal meningitis and meningococcemia occur at an incidence of 0.8 per 100.000. As about 10 % of cases are fatal, these two diseases pose a serious threat to public health. Doctors are obliged to declare cases to the French Direction G6ndrale de la Sant6 (DGS). Cases (2817) declared at the DGS from 1985 to 1991 reveal that the death rate from meningitis and meningococcemia is elevated in young children and young adults (with a predominance of serogroup C in the latter) when meningitis is associated with meningococcemia or extensive purpura fulminans, and when certain serogroups are present (A and C). For such cases, the use of rifampicin appears to have become normal practice since distribution of a circular by the French Ministry of Health (Department of Health) in February 1990; however, it is necessary to improve vaccinal practice against meningococci A and C. In addition, analysis of the meningococcal strains (1569) addressed to the Centre National de R6f6rence des Meningocoques et Neisseria apparentdes (CNRM) from 1989 to 1992 for complementary examination (serotypes, subtypes) revealed a stronger incidence of serogroup B in extremely heterogeneous antigenic formulae of which the strains B:15:P1.7,16 are encountered most frequently. Also noted, were progressions of serogroup C (42 % of isolates in 1992; major antigenic formula, C:2a:P1.1,2) and serogroup Y (2-3 %). The clinical evolution of cases associated with 556 strains examined at both the DGS and the CNRM revealed elevated death rates associated with serotype 2a and subtype P1.1,2 and a low death rate associated with serotype 4. Improved channels for declaration of cases (more exhaustive, more rapid) and research on other antigenic markers ought to enhance prevention of secondary cases and allow better monitoring of epidemic and/or virulent strains.
Key-words : Meningococci - Meningitis - Meningococcemia - Antigenic formula - Risk factors - Epidemiology Prophylaxis.
Meningococcal meningitis and meningococcemia are subject to obligatory declaration in many countries. Of major studies undertaken, the most prominent are those that seek new disease risk factors, and new epidemiological markers among strains of Neisseria meningitidis. Since 1946, m e n i n g o c o c c a l meningitis and meningococcemia have posed a serious threat to public health in France. T h e i n c i d e n c e s o f these diseases varied between 1946 and 1980 (between 1 and 4 per 100 000); in 1980, the i n c i d e n c e b e g a n to * Re~u le 07.11.1994. Acceptation ddfinitive le 16.11.1994. ** Direction Gdndrale de la Sant6, Bureau des maladies transmissibles, Minist6re des Affaires Sociales, de la Sant6 et de la Ville, Bureau VS 2, 1 Place de Fontenoy - F-75350 Paris 07 SP. *** Centre National de Rdfdrence des M6ningocoques et Neisseria apparentdes, Institut Pasteur, 25 et 28 rue du Docteur Roux F-75724 Paris Cedex.
584
diminish to 0.76 per 100 000 in 1991, with a death rate of 10 % (1). However, a study conducted in 1990 by H u b e r t (2) used the " c a p t u r e - r e c a p t u r e " m o d e l to estimate the level o f u n d e r d e c l a r a t i o n in F r a n c e at around 20 to 30 %. The aim of our study was to review the epidemiological status of meningococcal meningitis and/or m e n i n g o c o c c e m i a in France, to identify risk factors based on the cases studied, to seek virulence factors for these germs (notably in the structure o f their envelopes), and to study the prophylaxis. Prophylaxis was modified following distribution o f a circular from the French Ministry of Health (Department of Health) dated 5 February 1990. This concerned the measures to take in case o f m e n i n g o c o c c a l infection, and the prevention of secondary cases. Prophylaxis
recommends, notably, the use of rifampicin (even spiramycin in case of contra-indications) for chemoprophylaxis (all serogroups), and of vaccination (serogroups A and C).
MATERIALS AND METHODS Data collection In France, meningococcal meningitis and meningococcemia must be strictly monitored (3). The Direction Grnrrale de la Sant6 (DGS) and the Centre National de Rrfrrence des Mrningocoques et Neisseria apparentres (CNRM), Institut Pasteur, Paris, are the two organizations responsible for centralizing declarations from all over France. Doctors at all the Direction Drpartementale des Affaires Sanitaires et Sociales (DDASS) provide the DGS with the declaration form concerning the details of each case, including prophylactic measures taken; the strains received from different French laboratories are analyzed at the CNRM.
Populations Descriptive analysis of cases and of strains of N. meningitidis concerned DGS data for the period 1985 to 1991 (2817 cases), and CNRM data for the period 1989 to 1992 (1569 strains). Cases common to the DGS and to the CNRM (556 cases) were examined to seek relations between (a) the severity of a case and its antigenic structures (serogroups, serotypes, and subtypes), and (b) the severity of a case and its characteristics (age, gender, type of infection, etc.). Prophylactic measures taken in cases of meningococcemiathat occurred between 1987 and 1991 (1859 cases) were reviewed. The following declaration criteria were selected: isolation of N. meningitidis in the cerebrospinal fluid (CSF) and/or in the blood, or the presence of soluble antigens of N. meningitidis in the CSF or urine.
RESULTS
Descriptive analysis of cases (DGS) Descriptive analysis was performed for the 2817 cases of meningococcal meningitis and/or meningococcemia declared at the DGS between 1985 and 1991; these corresponded to the selection criteria defined earlier. • Incidence and seasonal variations : the level of incidence decreased smoothly from 1.55 per 100 000 inhabitants in 1985 to stabilize at around 0.76 per 100 000 in 1991. But account must be taken of the level of underdeclaration in France, which has been estimated at 20-30 % (2). Also, as the level of incidence since 1945 has been marked by a succession of increases and decreases, the reduction to 1985 remains to be confirmed. Figure 1 shows that seasonal variations are characterized by variable-amplitude peaks in the first quarter of each year. • Distribution by age and gender : from 1985 to 1991, the gender ratio varied only slightly (1-1.4; mean, 1.2). This corresponds approximately to the gender ratio in the French population. The age of patients infected ranged from 12 days to 81 years; 46.5 % of patients were aged less than 5 years, and 86.5 % less than 25 years (19.3 % between 15 and 25 years). These results confirm that this type of infection affects predominantly young children and young adults. • Distribution by serogroup : according to DGS data, the distribution of serogroups identified on declaration forms over the period of study was as follows: serogroup B, 51.1% of declarations; serogroup C, 25.8 %; and serogroup A, 3.3 %. The other serogroups
Number of cases 9° t ...........................................................................................................
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii12111111111111111 i12 iiiiiiiiiiiiiiiiii12iiiiiiiiii
Data analysis All data were treated using Epi-Info software (CDC, Atlanta, USA) and the statistical analysis software BMDP-LR. Data held at the CNRM had been keyboarded on ORACLE; these were retranscribed for use with Epi-Info. Univariate analysis was performed to identify major death risk factors in terms of cases (age, gender, clinical form, purpura fulminans) and meningococci (serogroups, serotypes, subtypes). Logistic regression was used to study the relation between strain characteristics and death.
585
10 ................................................................................................................. o -I-FII II II I~I I~I ',~ H It III HI~II~'~II
85
86
87
I III I H III I I N~FI III I I1~I ',It III III II III III I~+~-I
~t
89
90
91
Fig. 1 : Monthly distribution of 2817 cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991)
identified (X, Y, 29E, W135) comprised 1.8 % of declarations. Nongroupable and nongrouped strains were observed in 18 % of cases - such a high figure can be explained by the fact that many declaration forms are completed before the result of serotyping is available.
80%
16%
70%
14%
60%
12%
\
50%
• Distribution by type of infection and evolution : meningococcemia (alone or in association with meningitis) was observed in 24.7 % of cases, and meningitis only; in 54 %, 21,3 % of cases were not defined. The death rate varied according to the clinical form of the infection: 19.6 % for meningococcemia (alone or in association with meningitis), and 6.8 % for meningitis only. Extensive purpura fulminans was indicated as being present or absent in 2655 cases (24 % incidence). The incidence of purpura fulminans decreased from 20 % in 1985 to 13.6 % in 1986; the incidence then rose again to 31.2 %. Levels began to decrease in 1991. After-effects - largely neurological and hearing difficulties - were noted in 3 to 5 % of cases. Over the 7-year period, the death rate was 9.7 % (range: 8.1-11.8 %). It varied as a function of type of infection, and, as was seen previously, of serogroup (table I) and of age (figure 2).
10%
40%
5%
30%
6%
20%
4%
10%
2%
• Geographic distribution : figure 3 shows the geographic distribution by region of the level of incidence (0.2-1.05 per 100.000) of meningococcal meningitis and meningococcemia in France. Mean levels are indicated, as great disparities are found in each region. In addition, cases were not always declared where contagion occurred.
Descriptive analysis of strains (CNRM) From 1989 to 1992, 1569 strains of N. meningitidis were isolated from blood or CSF at the CNRM. Various
0%
0% 100-011
101-05]
105-101
110-15]
I!!Illi A
115-201
B
~Tffff~ Y
~
120-251
I
Other
1;Z5-501
150-001
C
•
Death rate
Fig. 2 : Age distribution of 1569 cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991). The death rate corresponding to each age group is also indicated French (or foreign) microbiology laboratories serogrouped the strains prior to delivering them to the CNRM for typing. Serogroups A, B, and C were often identified correctly; for other serogroups (X, Y, Z, 29E, and W135), results were less good due to technical constraints. • Distribution by serogroup : analysis of strains by serogroup confirmed that serogroup B predominates in France, followed, respectively, by serogroups C, Y, and A. Trends in incidence from 1989 were as follows:
TABLE I : Clinical evolution, as a function of serogroup, of 2817 cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991) Serogroup
Death
Recovery
After-effects
Unknown
A B C Other* NG-NR**
(n= 92) (n=1439) (n= 728) (n= 50) (n= 508)
14.1% 8.1% 12.9 % 20.0 % 7.3 %
69.6 % 76.9 % 69.1% 66.0 % 66.4 %
1.1: % 4.3 % 6.0 % 6.0 % 3.5 %
15.2 10.7 12.0 8.0 22.8
Total
(n=2817)
9.7 %
73.4 %
4.6 %
12.3 %
* Strains with another serogroup (X, Y, Z, 29E, W135). ** Strains not grouped or for witch no information was supplied on the declaration forms.
586
% % % % %
Total 100.0 100.0 100.0 100.0 100.0
% % % % %
100.0 %
serogroup A, decreased from 3.5 to 0.6 %; serogroup C, increased from 27.1 to 41.9 %; serogroup B, decreased from 66.4 to 54.2 %; and serogroup Y, oscillated between 1.5 and-2.8 %. These results provide a more accurate estimate of the distribution of serogroups than was possible with the results from the DGS, and also complete analysis of the "nongrouped" strains - these belonged to serogroups X, Y, Z, and W135. • Distribution by serotype : of the 1569 strains studied
at the CNRM from 1989 to 1992, 1490 were typed. The serotypes most frequently encountered were 2a (29.4 %), 15 (12.8 %), and undetermined serotypes (33.5 %). Serotypes 4 (8.9 %) and 2b (6.8 %) were the next most common. Serotype 2a was increasingly (6.8 %) isolated from 1989, whereas serotype 16 was not studied after 1991. The incidences of other serogroups remained relatively stable, with the exception of that of serotype 4, which fell sharply between 1989 and 1990 (from 20 to 5 %). O.Z - 8 . 5 1 0.57_
-
0.63
0.64
-
e.67
0.68
-
0.81
8.82
-
1.05
Table II confirms the associations that exist between serogroup B and serotype 15, serogroup C and serotype 2a, and serogroup A and serotype 4. Forty-two percent of serogroup B strains and 63 % of serogroup Y strains were nontypable. With serogroup B, serotypes 2b, 2a, 4, and 14 were encountered at approximately the same frequencies; serotypes 1 and 16 were encountered at lower frequencies. Serogroup C was mostly associated with serotype 2a, but associations with serotypes 2b and 4 were also encountered.
[ ~
i
Fig. 3 : Geographic distribution, in terms of level of incidence (per 100 000), of cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991)
TABLE II : Distribution, as a function of serogroup and serotype, of 1490 strains of received at the C N R M from 1989 to 1992
Serotype
1
14 15 16 2a 2b 4 NT** Total
A (n = 31)
B (n --- 915)
C (n = 504)
0.0 %
3.0 %
0.2 %
0.0 0.0 0.0 0.0 0.0 93.5 6.5
% % % % % % %
8.3 % 20.3 % 1.5 % 9.8 % 7.4 % 8.6 % 41.1%
100.0 %
100.0 %
1.0 0.6 0.0 68.9 6.7 3.6 19.0
X (n = 3) 0.0 0.0 0.0 0.0 0.0 0.0 66.7 33.3
% % % % % % %
100.0 %
% % % % % % % %
100.0 %
* nongroupable strains. ** nonserotypable strains.
587
Y (n = 30) 0.0 13.3 6.7 3.3 3.3 0.0 10.0 63.4
% % % % % % % %
100.0 %
N. meningitidis
Z (n = 6) 0.0 %
0.0 0.0 0.0 0.0 0.0 16.6 83.4
% % % % % % %
100.0 %
Other* (n = 1) 0.0 %
0.0 0.0 0.0 0.0 0.0 100.0 0.0
% % % % % % %
100.0 %
* Distribution by subtype : the principal subtype of N. meningitidis was P1.1,2 (19.4 % of strains), followed
133 strains of serotype 4 in combination with Pl.15 (20 %), P1.9 (19 %), and nonsubtypable strains (21%);
by subtypes P1.2 .(6.7 %), P1.7,16 (6.7 %), Pl.15 (5.4 %), P1.15,16 (4.4 %), and P1.6 (4.1%); 28.1% of strains of N. meningitidis were nonsubtypable. But these figures are averages over all strains. In reality, subtypes and serotypes were found associated to different degrees. The major combinations were as follows:
499 nonserotypable strains in combination with P l . l , 2 (9 %), Pl.15 (8 %), and nonsubtypable strains (38 %).
- 438 strains of serotype 2a in combination with P l . l , 2 (45 %), P1.2 (17 %), and nonsubtypable strains (23 %); - 190 strains of serotype 15 in combination with P l . l , 2 (15 %) and P1.7,16 (41%); - 102 strains of serotype 2b in combination with P1.1,2 (28 %), PI.10 (24 %), and nonsubtypable strains (26 %);
T A B L E III : Overall distribution of the antigenic f o r m u l a e of 1490 strains of N. meningitidis (serogroup B or C) received at the C N R M f r o m 1989 to 1992
Antigenic formula
B B B B B B B B B
: NT : NST : 15 : P1.7,16 : NT : P1.15,16 : NT : Pl.15 : NT : P l . l , 2 : 2a : P l . l , 2 : 15 : NST : NT : PI.14 : Other
Total
Number of strains
131 78 39 39 35 35 27 27 504
Strains of serogroupB
Typed strains
(%)
(%)
14.3 % 8.5 % 4.3 % 4.3 % 3.8 % 3.8 % 3.0 % 3.0 % 55.0 %
8.8 % 5.2 % 2.6 % 2.6 % 2.3 % 2.3 % 1.8 % 1.8 % 33.8 %
915
160 91 52 45 15 15 126
61.4 %
Total
504
31.7 % 18.1% 10.3 % 8.9 % 3.0 % 3.0 % 25.0 %
serotype/subtype associations, there are serogroup/ serotype/subtype associations. For example, 31.7 % of serogroup C strains had antigenic formula C:2a:P1.1,2, and 8.5 % of serogroup B strains antigenic formula B:15:P1.7,16 (table III). Of serogroup A strains (32), 74.2 % had antigenic formula A:4:P1.9, and 12.9 %, formula A:4:NST. A n a l y s i s o f risk f a c t o r s
In this study, different death risk factors - known or suspected - were considered: age, gender, clinical form, purpura fulminans, serogroup, serotype, and subtype. The results indicated that age, clinical form, and the presence of purpura fulminans were correlated with death. For virulence factors, although no significant difference was found between serogroups, serotype 2a and subtype P l . l , 2 correlated significantly with a high death rate. In contrast, serotype 4 appeared to be linked with a lower death rate. The results of the univariate analysis are shown in table IV. Analysis of the 556 cases common to both the DGS and the CNRM did not appear to reveal a link between serogroups B or C and a high death rate; this contrasts with the results of the analysis of the 2817 cases declared at the DGS from 1985 to 1991. Analysis of the larger sample set revealed that serogroups C (p < 0.001) and B (p < 0.01) were linked with a higher than average death rate. All serogroups were tested separately, and only serotype 2a and the association 2a + 2b were found to be correlated with a higher than average mortality. In contrast, serotype 4 appeared to be related to a lower mortality rate over all strains, but not when serogroups B and C were studied separately.
.. of serogroup C (%) C : 2a : Pl.l,2 C : 2a : NST C : 2a : P1.2 C : NT : NST C : 2a : P1.7,16 C : 2b : Pl.l,2 C : Other
• Distribution by antigenic formula : in addition to
10.7 % 6.1% 3.5 % 3.0 % 1.0 % 1.0 % 8.5 %
Analysis of the prophylaxis
Information relating to prophylaxis provided by the 1859 declaration forms concerning the period 1987-1991 was used to review the prescription of antibiotics and vaccination for community and/or family prophylaxis. The results - which vary according to serogroup (table V) show that family chemoprophylaxis was practiced in 75 % of cases, and community prophylaxis in 24.8 %. Trends were' more marked for family prophylaxis (practice
33.8 %
588
TABLE IV : Risk factors associated with death based on 556 cases of meningococcal meningitis and/or meningococcemia registered in France at the DGS and the CNRM from 1989 to 1991 Risk factors
Number of cases
Age [0-5[ [5-15[ [15-25[ [25-90[
Death
100%
90%
Significance
80%
...........................................................
70~
..........................................................
60%
...........................................................
50%
...........................................................
...........................................................
40%
233 128 124 71
23 (9.9 %) 8 (6.3 %) 20 (16.1%) 8 (11.3 %)
NS
30%
...........................................................
20%
..........................................................
10q~
0% 87 TI
Age [15-25[ Yes No
124 432
20 (16.1%) 34 (7.9 %)
p < 0.01
Sexe Male Female
289 240
32 (11.1%) 27 (11.3 %)
NS
Clinical factors Septicemia (_+m6ningitis) M6ningitis alone
130 230
26 (20.0 %) 19 (8.3 %)
p < 0.01
Purpura Yes No
133 310
49 (36.8 %) 8 (2.6 %)
p < 0.001
T2
T3
T4
88 TI
T2
T3
T4
89
I"2
TI
T3
T4
90 TI
"1"2
"1'3
T4
91 TI
T2
T3
1"4
T : Trimestre Rifampicine A
Spiramycine
Other
Fig. 4 : Trends in prophylactic measures applied in cases of meningococcal meningitis and/or meningococcemia declared in France (1987-1991) being spiramycin (42.7 % of prescriptions) and rifampicin (15.8 % of prescriptions). Other antibiotics used included betalactamines, macrolides or tetracyclines. The trend in antibioprophylaxis is clearly to reduce use of spiramycin and to increase use of rifampicin.
increased from 54 to 87 %) than for community prophylaxis (practice increased from 30 to 32 %) (figure 4). Between 1987 and 1991, numerous antibiotics were prescribed, the two major ones
When meningococcal strains A or C were present, vaccinations were restricted to the family in 20.8 % of cases (14.6 % in 1987; 27.5 % in 1991), and practiced in the community in 18.1% of cases (11.5 % in 1987; 22.9 % in 1991).
TABLE V : Distribution by serogroup of chemoprophylaxis practiced in the family or community based on 1859 cases of meningococcal meningitis and/or meningococcemia declared in France (1987-1991) S erogroup
A C B Other* NG-NR**
Chemoprophylaxie
(n= 75) (n=512) (n=976) (n= 38) (n=258)
Vaccination
Family
Community
Family
Community
73.3 % 71.1% 77.8 % 64.7 % 73.7 %
28.0 % 31.6 % 21.5 % 33.3 % 22.1%
24.0 % 20.3 % 0.6 % 11.1% 3.6 %
13.3 % 18.8 % 0.4 % 11.1% 3.6 %
* Strains with another serogroup (X, Y, Z, 29E, W135). ~* Strains not grouped or for which no information was supplied on the declaration forms.
589
DISCUSSION Our results confirm that the reduction in incidence of meningococcemia, which began in the early 1980s, is a long-term trend. The incidence in France is relatively low compared with other European countries (4). Death rates have remained constant in France since 1985; however, this information depends largely on the quality of the declaration. Spanjaard (5) has shown that in The Netherlands, from 1953 to 1983, the death rate was 5.1%. In Canada, on average, 10 % of cases between 1980 and 1986 were fatal (6) - a reduction from the pre-1970's level of 28 %. In England, the death rate was 10 % in 1989 (7), and in Belgium, between 1975 and 1979, 6 . 1 % in 309 patients less than 15 years old (8). The seasonal variations observed in this study confirm that there is a sharp increase in incidence during winter/spring (December-May). A study of 248 cases declared in France between 1980 and 1984 revealed that 64.6 % bad been declared between December and May (9). Identical seasonal variations have been observed for other countries (e.g., the United States, 1975-1980) (10). The higher incidence in young adults and young children has also been observed in other countries, notably Italy (11), Dakar (12), Russia (13), and Belgium (8). In France at present, serogroup B is the most frequently isolated serogroup (54.2 % of strains); however, the level is decreasing in parallel with an increase in isolation of serogroup C. Serogroup Y is encountered fairly often, whereas serogroups W135 and A are rare. Serogroup A is predominant in epidemics (e.g., Morocco, 1990 (14), and Mecca, 1987). Riou et al (15, 16) were able to demonstrate - largely through interviews with patients - that 20 cases of serogroup A N. meningitidis infection in France were linked with strains of the 1987 Mecca epidemic. The following hypothesis is one of several that have been proposed to explain the distribution of serogroups as a function of age. When young children are not fully immunized, they are liable to be struck by serogroup B meningococci (the most frequently encountered serogroup in the population); once immunized against serogroup B, they then go down with infections due to the serogroup C strains that are associated with a higher than average mortality in young adults.
majority (72.2 % of strains, 1985-1987). In Dakar, until 1977, serogroup A predominated (74.5 % of cases), but since 1978, its incidence has diminished to the benefit of serogroup C, which, in 1980, represented 68.4 % o f cases (12). In Africa, serogroup A is the major serogroup, especially in the endemic zones of subtropical Africa (serogroup B is very rare). Analysis of the distribution of serogroups by age revealed a greater frequency of serogroup C in patients between 10 and 25 years old, and of serogroup B, in patients less than 10 years old and older than 25 years. This distribution is similar to those reported by Band et al (10) for the USA between 1975 and 1980. The relationship between the distribution of serogroups and age class has also been revealed for The Netherlands (17). The two major serotypes found in France are 2a (29.6 %) and 15 (12.7 %). Serotype 2a has been isolated increasingly since 1989 in parallel with an increase in serogroup C strains. The serogroup C/serotype 2a association is very common, often in combination with subtype Pl.l,2. Besides France (18), it is also very common in countries such as The Netherlands (19, 20), Belgium (21), and England and Scotland (7). The diversity of the serotypes and subtypes associated with serogroup B is much greater than that for C, but the association B:15 is the most common, often in combination with subtype P1.7,16; B: 15 meningococci were responsible for an epidemic in Gloucester, UK, which occurred between 1981 and 1986 (22) (major subtype, PI.16). In Holland (5), the associations B:2b (44 %), B:15, C:2a (21%), and W135:2a (60 %) are most commonly encountered; B:2a (4 %), C:2b (21%), and W135:2b (3 %) are rarer. In Canada (6), the most common antigenic formulae are B:15:P1.7,16 (18 %), B:nt:Pl.15 (13 %), and B:2b:PI.10 (13 %). The emergence of strains B:4:P1.4 (4 %) is relatively recent. The N. meningitidis strains B:2a:P1.2 and B:2b:P1.2 (23) have often been associated with infection peaks - in The Netherlands (1966), Iceland (1976-1977), and England and Scotland (1973-1975). Strains B:15:PI.16 have been associated with infection peaks in northern Norway (1974-1975) and in the Faroe Islands (19801981).
Within the factors of risk and of virulence, the extensive purpura fulminans, which are particularly serious are The distribution of serogroups in most other European associated with death. A relative risk of 5.6 in our study countries and in the USA, is identical to that in France. • confirms previous results (24). Septicemia - either in However, in Italy, serogroup C is present in large association with meningitis or alone - provides bad 590
prognosis. Studies conducted elsewhere - in France (24) and in western Norway (25) - confirm these results, although in different combinations (serious septicemia, severe septicemia with meningitis, septicemia with or without meningitis, meningitis). Results obtained in The Netherlands and Belgium (26) show a similar tendency. Death was also correlated with age, with higher death rates for 15-25 year olds (12.9 %) and over 50s (16.2 %). In England and Scotland (7), more than 10 % of cases of children of less than 5 years old and of adults of more than 30 years old were fatal; in Norway (25), the highest levels of mortality occur in patients between 5 and 12 years old and more than 50 years old. Our investigation into the relation between serogroups, serotypes, subtypes, and clinical evolution was based on a relatively small sample set considering the strong differentiation that exists between strains. No link was found between serogroup and clinical evolution, in agreement with a Norwegian study (25). However, other French (24) and Belgium studies (26) revealed the existence of a link. Spanjaard (5) has shown that in The Netherlands, from 1959 to 1983, the death rate (5.1%) varied as a function of serogroup: serogroup W135, 18 %; serogroup B, 5.1%; serogroup C, 4.8 %; and serogroup A, 2.3 %. A different correlation was found between after-effects and serogroup: serogroup A, 9.9 %; serogroup B, 7.3 %; serogroup W135, 7 %; and serogroup C, 6.5 %. In another French study (38 cases, 1984-1988) (27) the death rate associated with serogroup Y was 13.2 %. Serotypes 2a and 4 and subtype P1.1,2 - for all strains and including serogroup B - were related significantly to death. No significant differences were detected for serotypes and subtypes in serogroup C nor for the formulae in which serogroup C is most frequently encountered (e.g., C:2a:PI.I,2). In The Netherlands (20), the death rate associated with serotype 2b was 7.6 %, whereas it was 3.1% for strains B:non2b; the extent of neurological complications was the same for both serotypes. Serotypes 2b and 15 constitute the virulent subpopulations of serogroup B; this virulence was demonstrated in Belgium by De Mayer (21) who described a probable relation between serotype 2 and the disease. Spanjaard (20) found no RESUME
significant difference in mortality for serotype 2a in serogroup C. The results of serotyping and subtyping revealed that certain strains of the same serogroup were more virulent than others, with differences between the case and the carriers (28). The serotypes and subtypes associated with the most virulent strains were detected more often in the cases than in the carriers, notably for serotypes 2 and 2 associated. Certain strains are more frequently implicated in epidemics (e.g., A:4:P1.9 in the 1987 Mecca epidemic (16), and B:15:P1.7,16 in Gloucestershire) (22). Various serotypes and subtypes are encountered outside epidemics, but antigenic associations are increasingly common B: 15:P 1.7,16 (22, 29) and C:2a:PI.I,2 (30, 31). Analysis of prophylactic measures appears to reveal trends of increasing use of chemoprophylaxis and vaccination, both in the community and in the family. On 5 February 1990, the French Ministry of Health (Department of Health) (32) distributed a circular concerning measures to take in case of meningococcal infection, which included a section on prophylaxis. It recommends rifampicin (spiramycin in case of contra indication) for chemoprophylaxis (all serogroups), and vaccination (serogroups A and C). According to our study, rifampicin seems to have been well integrated in chemoprophylaxis policy. However, in a certain number of cases, prophylaxis was limited to the family without further investigation as to the patient's contact with the community. Vaccination was relatively rare in comparison with chemoprophylaxis, and was practiced later to have available the laboratory's response on the serogroup of the N. meningitidis strain (the vaccine acts only on strains of serogroup A or C). Omission of serogrouping, or errors, are often detrimental to the efficient vaccinal prophylaxis that is essential in all approaches. Enhanced prophylaxis relies on more comprehensive provision of relevant information (double declaration of cases, antibioprophylaxis, optimization of strain identification and serotyping). This would undoubtedly help limit secondary cases, which constituted 1.1% of cases in 1991 (1).
MENINGITES A MENINGOCOQUE ET MENINGOCOCCEMIES : EPIDEMIOLOGIE EN FRANCE ENTRE 1985 ET 1991
Les mrningites ~ mrningocoque et les mrningococc6mies, avec un taux d'incidence de 0,8 pour 100 000 et un taux de 16talit6 d'environ 10 %, reprrsentent un grave problrme de sant6 publique. L'Etude de 2 817 Gas drclarrs h la DGS de 1985 ?a 1991 par la drclaration obligatoire a montr6 qu'une plus forte 16talit6 est observre chez les jeunes enfants et les jeunes adultes (avec une prrdominance du groupe C chez ces derniers), lors de la prrsence d'une 591
m6ningococcdmie ou d'un purpura fulminans extensif et pour certains s6rogroupes (A et C). Pour ces cas, l'utilisation de la rifampicine depuis la circulaire de fdvrier 1990 semble bien entr6e dans les moeurs alors que l'utilisation de la vaccination contre les m6ningocoques A ou C doit ~tre am61ior6e: Par ailleurs,A'analyse des 1 569 souches de m6ningocoques adress6es au CNRM de 1989 ~ 1992 pour examens compldmentaires (s6rotypes, sous-types), a permis de montrer une plus forte incidence du s6rogroupe B avec des formules antigdniques tr6s h6t6rog~nes parmi lesquelles les souches B:15:P1.7,16 sont retrouv6es le plus fr6quemment. Ont aussi 6t6 not6es une progression du s6rogroupe C (42 % des isolements en 1992) avec pour principale formule antig6nique C:2a:P1.1,2 et du s6rogroupe Y (2 ~t 3 %). Parma ces souches, 556 ont 6t6 mises en relation avec l'6volution clinique des cas ce qui a permis de mettre en 6vidence une surmortalit6 associde au s6rotype 2a, au sous-type P1.1,2 et une plus faible mortalit6 associde au s6rotype 4. Une meilleure d6claration des cas (plus exhaustive, plus rapide) et les recherches sur d'autres marqueurs antigdniques devraient am61iorer la prdvention des cas secondaires et permettre un meilleur suivi des souches 6pid6miques et/ou virulentes. Mots-cl6s
: M6ningocoque
Epid6miologie
- M6ningites
- M6ningococc6mies
- Structure
antig6nique
- Facteurs
de gravit6
-
- Prophylaxie.
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4.
5.
6. 7.
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11. 12.
13.
14.
15.
16.
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1988). Relations avec l'6pid6mie de La Mecque d'Aofit 1987. M6d Mal Infect. 1989 ; 19 : 305-14. SPANJAARD L., BOL P., D E M A R I E S. et coll. - Age-distributions of meningococcal disease as predictor of epidemic. Lancet. 1982 ; 2 : 1039-40. RIOU J.Y., P O O L M A N J.T., A U R I O L J. et coll. - Sero-subtyping of group B, C, Y, and A meningococei isolated in France in 1988. Ann Biol Clin. 1990 ; 48 : 227-31. D E M A R I E S., P O O L M A N J.T., H O E I J M A K E R S J.HJ. et coll. Meningococcal digease in The Netherlands, 1959-1981 : the occurrence of serogroups and serotypes 2a and 2b of Neisseria meningitidis. J Infect. 1986 ; 12 : 133-43. S P A N J A A R D L., BOL P., DE M A R I E S. et coll. - Association of meningococcal serotypes with course of disease : serotypes 2a and 2b in the Netherlands, 1959-1981. J Infect Dis. 1987 ; 155 : 277-82. D E M A E Y E R S., SEBA J.M., R E G I N S T E R G. - E p i d e m i o l o g y of meningococcal meningitidis in Belgium. J Infect. 1981 ; 3 (suppl. 1) : 185-9. C A R T W R I G H T K.A.V., STUART J., N O A H N.D. - An outbreak of meningococcal disease in Gloucestershire. Lancet. 1986 ; 2 : 558-61. P O O L M A N J.T., LIND I., JONSDOTTIR K. et coll. - Meningococcal serotypes and serogroup B disease in north-west Europe. Lancet. 1986 ; 2 : 555-7. O L I V A R E S R., B O U Y E R J., H U B E R T B. - Risk factors of death in meningococcal disease, Path Biol. 1993 ; 41 : 164-8. HALSTENSEN A., PEDERSEN S.H.J., H A N E B E R G B. et c o i l - Case fatality of meningococcal disease in western Norway. S t a n d J Infect Dis. 1987 ; 19 : 35-42. D E W A L S P., H E R T O G H E L., D E M A E Y E R S. et coll. - Validity of the recording of meningococcal disease according to various sources of information. J Infect. 1984 ; 9 : 185-9. L E B A S T A R D D., RIOU J.Y., K O N C Z A T Y H. et coll. - Neisseria meningitidis : s6rogroupe Y. A p r o p o s de trente huit observations. Path Biol. 1989 ; 37 : 901-7. H O L T E N E., FROHOLM L.O., G A U S T A D P. - Virulence markers in patient and cartier swains of Neisseria meningitidis. Scan J hffect Dis. 1984 ; 16 : 267-70. A L L E R B E R G E R F., E I G E N T L E R A., DIERICH M.P. - Subtyping meningococci. Lancet. 1992 ; 339 : 125. RIOU J.Y., G U I B O U R D E N C H E M. - Meningococcies : fipid6miologie 1987-1992. Donn6es actuelles. M6d Mal Infect. 1992 ; 22 (HS) : 10-7. RIOU J.Y., P O O L M A N J.T., A U R t O L J. et coll. - Sero-subtyping of group B, C, Y, and A meningococci isolated in France in 1988. Ann Biol Clin. 1990 ; 48 : 227-31. G I R A R D J.F. - Les infections ~ m 6 n i n g o c o q u e . Circulaire D.G.S./P.G.E./1C, n°79 du 5 f6vrier 1990. Bull Epid Hebd. 1990 ; 7 : 25-7.
M6d Mal Infect. 1995 ; 25,584-93
Meningococcal meningitis and meningococcemia : epidemiological study, France (1985-1991)* N. BRASSIER**,
A. LEPOUTRE**, C. MOYSE**
M. GUIBOURDENCHE***,
e t J.Y. R I O U * * *
SUMMARY
In France, meningococcal meningitis and meningococcemia occur at an incidence of 0.8 per 100.000. As about 10 % of cases are fatal, these two diseases pose a serious threat to public health. Doctors are obliged to declare cases to the French Direction G6ndrale de la Sant6 (DGS). Cases (2817) declared at the DGS from 1985 to 1991 reveal that the death rate from meningitis and meningococcemia is elevated in young children and young adults (with a predominance of serogroup C in the latter) when meningitis is associated with meningococcemia or extensive purpura fulminans, and when certain serogroups are present (A and C). For such cases, the use of rifampicin appears to have become normal practice since distribution of a circular by the French Ministry of Health (Department of Health) in February 1990; however, it is necessary to improve vaccinal practice against meningococci A and C. In addition, analysis of the meningococcal strains (1569) addressed to the Centre National de R6f6rence des Meningocoques et Neisseria apparentdes (CNRM) from 1989 to 1992 for complementary examination (serotypes, subtypes) revealed a stronger incidence of serogroup B in extremely heterogeneous antigenic formulae of which the strains B:15:P1.7,16 are encountered most frequently. Also noted, were progressions of serogroup C (42 % of isolates in 1992; major antigenic formula, C:2a:P1.1,2) and serogroup Y (2-3 %). The clinical evolution of cases associated with 556 strains examined at both the DGS and the CNRM revealed elevated death rates associated with serotype 2a and subtype P1.1,2 and a low death rate associated with serotype 4. Improved channels for declaration of cases (more exhaustive, more rapid) and research on other antigenic markers ought to enhance prevention of secondary cases and allow better monitoring of epidemic and/or virulent strains.
Key-words : Meningococci - Meningitis - Meningococcemia - Antigenic formula - Risk factors - Epidemiology Prophylaxis.
Meningococcal meningitis and meningococcemia are subject to obligatory declaration in many countries. Of major studies undertaken, the most prominent are those that seek new disease risk factors, and new epidemiological markers among strains of Neisseria meningitidis. Since 1946, m e n i n g o c o c c a l meningitis and meningococcemia have posed a serious threat to public health in France. T h e i n c i d e n c e s o f these diseases varied between 1946 and 1980 (between 1 and 4 per 100 000); in 1980, the i n c i d e n c e b e g a n to * Re~u le 07.11.1994. Acceptation ddfinitive le 16.11.1994. ** Direction Gdndrale de la Sant6, Bureau des maladies transmissibles, Minist6re des Affaires Sociales, de la Sant6 et de la Ville, Bureau VS 2, 1 Place de Fontenoy - F-75350 Paris 07 SP. *** Centre National de Rdfdrence des M6ningocoques et Neisseria apparentdes, Institut Pasteur, 25 et 28 rue du Docteur Roux F-75724 Paris Cedex.
584
diminish to 0.76 per 100 000 in 1991, with a death rate of 10 % (1). However, a study conducted in 1990 by H u b e r t (2) used the " c a p t u r e - r e c a p t u r e " m o d e l to estimate the level o f u n d e r d e c l a r a t i o n in F r a n c e at around 20 to 30 %. The aim of our study was to review the epidemiological status of meningococcal meningitis and/or m e n i n g o c o c c e m i a in France, to identify risk factors based on the cases studied, to seek virulence factors for these germs (notably in the structure o f their envelopes), and to study the prophylaxis. Prophylaxis was modified following distribution o f a circular from the French Ministry of Health (Department of Health) dated 5 February 1990. This concerned the measures to take in case o f m e n i n g o c o c c a l infection, and the prevention of secondary cases. Prophylaxis
recommends, notably, the use of rifampicin (even spiramycin in case of contra-indications) for chemoprophylaxis (all serogroups), and of vaccination (serogroups A and C).
MATERIALS AND METHODS Data collection In France, meningococcal meningitis and meningococcemia must be strictly monitored (3). The Direction Grnrrale de la Sant6 (DGS) and the Centre National de Rrfrrence des Mrningocoques et Neisseria apparentres (CNRM), Institut Pasteur, Paris, are the two organizations responsible for centralizing declarations from all over France. Doctors at all the Direction Drpartementale des Affaires Sanitaires et Sociales (DDASS) provide the DGS with the declaration form concerning the details of each case, including prophylactic measures taken; the strains received from different French laboratories are analyzed at the CNRM.
Populations Descriptive analysis of cases and of strains of N. meningitidis concerned DGS data for the period 1985 to 1991 (2817 cases), and CNRM data for the period 1989 to 1992 (1569 strains). Cases common to the DGS and to the CNRM (556 cases) were examined to seek relations between (a) the severity of a case and its antigenic structures (serogroups, serotypes, and subtypes), and (b) the severity of a case and its characteristics (age, gender, type of infection, etc.). Prophylactic measures taken in cases of meningococcemiathat occurred between 1987 and 1991 (1859 cases) were reviewed. The following declaration criteria were selected: isolation of N. meningitidis in the cerebrospinal fluid (CSF) and/or in the blood, or the presence of soluble antigens of N. meningitidis in the CSF or urine.
RESULTS
Descriptive analysis of cases (DGS) Descriptive analysis was performed for the 2817 cases of meningococcal meningitis and/or meningococcemia declared at the DGS between 1985 and 1991; these corresponded to the selection criteria defined earlier. • Incidence and seasonal variations : the level of incidence decreased smoothly from 1.55 per 100 000 inhabitants in 1985 to stabilize at around 0.76 per 100 000 in 1991. But account must be taken of the level of underdeclaration in France, which has been estimated at 20-30 % (2). Also, as the level of incidence since 1945 has been marked by a succession of increases and decreases, the reduction to 1985 remains to be confirmed. Figure 1 shows that seasonal variations are characterized by variable-amplitude peaks in the first quarter of each year. • Distribution by age and gender : from 1985 to 1991, the gender ratio varied only slightly (1-1.4; mean, 1.2). This corresponds approximately to the gender ratio in the French population. The age of patients infected ranged from 12 days to 81 years; 46.5 % of patients were aged less than 5 years, and 86.5 % less than 25 years (19.3 % between 15 and 25 years). These results confirm that this type of infection affects predominantly young children and young adults. • Distribution by serogroup : according to DGS data, the distribution of serogroups identified on declaration forms over the period of study was as follows: serogroup B, 51.1% of declarations; serogroup C, 25.8 %; and serogroup A, 3.3 %. The other serogroups
Number of cases 9° t ...........................................................................................................
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii12111111111111111 i12 iiiiiiiiiiiiiiiiii12iiiiiiiiii
Data analysis All data were treated using Epi-Info software (CDC, Atlanta, USA) and the statistical analysis software BMDP-LR. Data held at the CNRM had been keyboarded on ORACLE; these were retranscribed for use with Epi-Info. Univariate analysis was performed to identify major death risk factors in terms of cases (age, gender, clinical form, purpura fulminans) and meningococci (serogroups, serotypes, subtypes). Logistic regression was used to study the relation between strain characteristics and death.
585
10 ................................................................................................................. o -I-FII II II I~I I~I ',~ H It III HI~II~'~II
85
86
87
I III I H III I I N~FI III I I1~I ',It III III II III III I~+~-I
~t
89
90
91
Fig. 1 : Monthly distribution of 2817 cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991)
identified (X, Y, 29E, W135) comprised 1.8 % of declarations. Nongroupable and nongrouped strains were observed in 18 % of cases - such a high figure can be explained by the fact that many declaration forms are completed before the result of serotyping is available.
80%
16%
70%
14%
60%
12%
\
50%
• Distribution by type of infection and evolution : meningococcemia (alone or in association with meningitis) was observed in 24.7 % of cases, and meningitis only; in 54 %, 21,3 % of cases were not defined. The death rate varied according to the clinical form of the infection: 19.6 % for meningococcemia (alone or in association with meningitis), and 6.8 % for meningitis only. Extensive purpura fulminans was indicated as being present or absent in 2655 cases (24 % incidence). The incidence of purpura fulminans decreased from 20 % in 1985 to 13.6 % in 1986; the incidence then rose again to 31.2 %. Levels began to decrease in 1991. After-effects - largely neurological and hearing difficulties - were noted in 3 to 5 % of cases. Over the 7-year period, the death rate was 9.7 % (range: 8.1-11.8 %). It varied as a function of type of infection, and, as was seen previously, of serogroup (table I) and of age (figure 2).
10%
40%
5%
30%
6%
20%
4%
10%
2%
• Geographic distribution : figure 3 shows the geographic distribution by region of the level of incidence (0.2-1.05 per 100.000) of meningococcal meningitis and meningococcemia in France. Mean levels are indicated, as great disparities are found in each region. In addition, cases were not always declared where contagion occurred.
Descriptive analysis of strains (CNRM) From 1989 to 1992, 1569 strains of N. meningitidis were isolated from blood or CSF at the CNRM. Various
0%
0% 100-011
101-05]
105-101
110-15]
I!!Illi A
115-201
B
~Tffff~ Y
~
120-251
I
Other
1;Z5-501
150-001
C
•
Death rate
Fig. 2 : Age distribution of 1569 cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991). The death rate corresponding to each age group is also indicated French (or foreign) microbiology laboratories serogrouped the strains prior to delivering them to the CNRM for typing. Serogroups A, B, and C were often identified correctly; for other serogroups (X, Y, Z, 29E, and W135), results were less good due to technical constraints. • Distribution by serogroup : analysis of strains by serogroup confirmed that serogroup B predominates in France, followed, respectively, by serogroups C, Y, and A. Trends in incidence from 1989 were as follows:
TABLE I : Clinical evolution, as a function of serogroup, of 2817 cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991) Serogroup
Death
Recovery
After-effects
Unknown
A B C Other* NG-NR**
(n= 92) (n=1439) (n= 728) (n= 50) (n= 508)
14.1% 8.1% 12.9 % 20.0 % 7.3 %
69.6 % 76.9 % 69.1% 66.0 % 66.4 %
1.1: % 4.3 % 6.0 % 6.0 % 3.5 %
15.2 10.7 12.0 8.0 22.8
Total
(n=2817)
9.7 %
73.4 %
4.6 %
12.3 %
* Strains with another serogroup (X, Y, Z, 29E, W135). ** Strains not grouped or for witch no information was supplied on the declaration forms.
586
% % % % %
Total 100.0 100.0 100.0 100.0 100.0
% % % % %
100.0 %
serogroup A, decreased from 3.5 to 0.6 %; serogroup C, increased from 27.1 to 41.9 %; serogroup B, decreased from 66.4 to 54.2 %; and serogroup Y, oscillated between 1.5 and-2.8 %. These results provide a more accurate estimate of the distribution of serogroups than was possible with the results from the DGS, and also complete analysis of the "nongrouped" strains - these belonged to serogroups X, Y, Z, and W135. • Distribution by serotype : of the 1569 strains studied
at the CNRM from 1989 to 1992, 1490 were typed. The serotypes most frequently encountered were 2a (29.4 %), 15 (12.8 %), and undetermined serotypes (33.5 %). Serotypes 4 (8.9 %) and 2b (6.8 %) were the next most common. Serotype 2a was increasingly (6.8 %) isolated from 1989, whereas serotype 16 was not studied after 1991. The incidences of other serogroups remained relatively stable, with the exception of that of serotype 4, which fell sharply between 1989 and 1990 (from 20 to 5 %). O.Z - 8 . 5 1 0.57_
-
0.63
0.64
-
e.67
0.68
-
0.81
8.82
-
1.05
Table II confirms the associations that exist between serogroup B and serotype 15, serogroup C and serotype 2a, and serogroup A and serotype 4. Forty-two percent of serogroup B strains and 63 % of serogroup Y strains were nontypable. With serogroup B, serotypes 2b, 2a, 4, and 14 were encountered at approximately the same frequencies; serotypes 1 and 16 were encountered at lower frequencies. Serogroup C was mostly associated with serotype 2a, but associations with serotypes 2b and 4 were also encountered.
[ ~
i
Fig. 3 : Geographic distribution, in terms of level of incidence (per 100 000), of cases of meningococcal meningitis and/or meningococcemia declared in France (1985-1991)
TABLE II : Distribution, as a function of serogroup and serotype, of 1490 strains of received at the C N R M from 1989 to 1992
Serotype
1
14 15 16 2a 2b 4 NT** Total
A (n = 31)
B (n --- 915)
C (n = 504)
0.0 %
3.0 %
0.2 %
0.0 0.0 0.0 0.0 0.0 93.5 6.5
% % % % % % %
8.3 % 20.3 % 1.5 % 9.8 % 7.4 % 8.6 % 41.1%
100.0 %
100.0 %
1.0 0.6 0.0 68.9 6.7 3.6 19.0
X (n = 3) 0.0 0.0 0.0 0.0 0.0 0.0 66.7 33.3
% % % % % % %
100.0 %
% % % % % % % %
100.0 %
* nongroupable strains. ** nonserotypable strains.
587
Y (n = 30) 0.0 13.3 6.7 3.3 3.3 0.0 10.0 63.4
% % % % % % % %
100.0 %
N. meningitidis
Z (n = 6) 0.0 %
0.0 0.0 0.0 0.0 0.0 16.6 83.4
% % % % % % %
100.0 %
Other* (n = 1) 0.0 %
0.0 0.0 0.0 0.0 0.0 100.0 0.0
% % % % % % %
100.0 %
* Distribution by subtype : the principal subtype of N. meningitidis was P1.1,2 (19.4 % of strains), followed
133 strains of serotype 4 in combination with Pl.15 (20 %), P1.9 (19 %), and nonsubtypable strains (21%);
by subtypes P1.2 .(6.7 %), P1.7,16 (6.7 %), Pl.15 (5.4 %), P1.15,16 (4.4 %), and P1.6 (4.1%); 28.1% of strains of N. meningitidis were nonsubtypable. But these figures are averages over all strains. In reality, subtypes and serotypes were found associated to different degrees. The major combinations were as follows:
499 nonserotypable strains in combination with P l . l , 2 (9 %), Pl.15 (8 %), and nonsubtypable strains (38 %).
- 438 strains of serotype 2a in combination with P l . l , 2 (45 %), P1.2 (17 %), and nonsubtypable strains (23 %); - 190 strains of serotype 15 in combination with P l . l , 2 (15 %) and P1.7,16 (41%); - 102 strains of serotype 2b in combination with P1.1,2 (28 %), PI.10 (24 %), and nonsubtypable strains (26 %);
T A B L E III : Overall distribution of the antigenic f o r m u l a e of 1490 strains of N. meningitidis (serogroup B or C) received at the C N R M f r o m 1989 to 1992
Antigenic formula
B B B B B B B B B
: NT : NST : 15 : P1.7,16 : NT : P1.15,16 : NT : Pl.15 : NT : P l . l , 2 : 2a : P l . l , 2 : 15 : NST : NT : PI.14 : Other
Total
Number of strains
131 78 39 39 35 35 27 27 504
Strains of serogroupB
Typed strains
(%)
(%)
14.3 % 8.5 % 4.3 % 4.3 % 3.8 % 3.8 % 3.0 % 3.0 % 55.0 %
8.8 % 5.2 % 2.6 % 2.6 % 2.3 % 2.3 % 1.8 % 1.8 % 33.8 %
915
160 91 52 45 15 15 126
61.4 %
Total
504
31.7 % 18.1% 10.3 % 8.9 % 3.0 % 3.0 % 25.0 %
serotype/subtype associations, there are serogroup/ serotype/subtype associations. For example, 31.7 % of serogroup C strains had antigenic formula C:2a:P1.1,2, and 8.5 % of serogroup B strains antigenic formula B:15:P1.7,16 (table III). Of serogroup A strains (32), 74.2 % had antigenic formula A:4:P1.9, and 12.9 %, formula A:4:NST. A n a l y s i s o f risk f a c t o r s
In this study, different death risk factors - known or suspected - were considered: age, gender, clinical form, purpura fulminans, serogroup, serotype, and subtype. The results indicated that age, clinical form, and the presence of purpura fulminans were correlated with death. For virulence factors, although no significant difference was found between serogroups, serotype 2a and subtype P l . l , 2 correlated significantly with a high death rate. In contrast, serotype 4 appeared to be linked with a lower death rate. The results of the univariate analysis are shown in table IV. Analysis of the 556 cases common to both the DGS and the CNRM did not appear to reveal a link between serogroups B or C and a high death rate; this contrasts with the results of the analysis of the 2817 cases declared at the DGS from 1985 to 1991. Analysis of the larger sample set revealed that serogroups C (p < 0.001) and B (p < 0.01) were linked with a higher than average death rate. All serogroups were tested separately, and only serotype 2a and the association 2a + 2b were found to be correlated with a higher than average mortality. In contrast, serotype 4 appeared to be related to a lower mortality rate over all strains, but not when serogroups B and C were studied separately.
.. of serogroup C (%) C : 2a : Pl.l,2 C : 2a : NST C : 2a : P1.2 C : NT : NST C : 2a : P1.7,16 C : 2b : Pl.l,2 C : Other
• Distribution by antigenic formula : in addition to
10.7 % 6.1% 3.5 % 3.0 % 1.0 % 1.0 % 8.5 %
Analysis of the prophylaxis
Information relating to prophylaxis provided by the 1859 declaration forms concerning the period 1987-1991 was used to review the prescription of antibiotics and vaccination for community and/or family prophylaxis. The results - which vary according to serogroup (table V) show that family chemoprophylaxis was practiced in 75 % of cases, and community prophylaxis in 24.8 %. Trends were' more marked for family prophylaxis (practice
33.8 %
588
TABLE IV : Risk factors associated with death based on 556 cases of meningococcal meningitis and/or meningococcemia registered in France at the DGS and the CNRM from 1989 to 1991 Risk factors
Number of cases
Age [0-5[ [5-15[ [15-25[ [25-90[
Death
100%
90%
Significance
80%
...........................................................
70~
..........................................................
60%
...........................................................
50%
...........................................................
...........................................................
40%
233 128 124 71
23 (9.9 %) 8 (6.3 %) 20 (16.1%) 8 (11.3 %)
NS
30%
...........................................................
20%
..........................................................
10q~
0% 87 TI
Age [15-25[ Yes No
124 432
20 (16.1%) 34 (7.9 %)
p < 0.01
Sexe Male Female
289 240
32 (11.1%) 27 (11.3 %)
NS
Clinical factors Septicemia (_+m6ningitis) M6ningitis alone
130 230
26 (20.0 %) 19 (8.3 %)
p < 0.01
Purpura Yes No
133 310
49 (36.8 %) 8 (2.6 %)
p < 0.001
T2
T3
T4
88 TI
T2
T3
T4
89
I"2
TI
T3
T4
90 TI
"1"2
"1'3
T4
91 TI
T2
T3
1"4
T : Trimestre Rifampicine A
Spiramycine
Other
Fig. 4 : Trends in prophylactic measures applied in cases of meningococcal meningitis and/or meningococcemia declared in France (1987-1991) being spiramycin (42.7 % of prescriptions) and rifampicin (15.8 % of prescriptions). Other antibiotics used included betalactamines, macrolides or tetracyclines. The trend in antibioprophylaxis is clearly to reduce use of spiramycin and to increase use of rifampicin.
increased from 54 to 87 %) than for community prophylaxis (practice increased from 30 to 32 %) (figure 4). Between 1987 and 1991, numerous antibiotics were prescribed, the two major ones
When meningococcal strains A or C were present, vaccinations were restricted to the family in 20.8 % of cases (14.6 % in 1987; 27.5 % in 1991), and practiced in the community in 18.1% of cases (11.5 % in 1987; 22.9 % in 1991).
TABLE V : Distribution by serogroup of chemoprophylaxis practiced in the family or community based on 1859 cases of meningococcal meningitis and/or meningococcemia declared in France (1987-1991) S erogroup
A C B Other* NG-NR**
Chemoprophylaxie
(n= 75) (n=512) (n=976) (n= 38) (n=258)
Vaccination
Family
Community
Family
Community
73.3 % 71.1% 77.8 % 64.7 % 73.7 %
28.0 % 31.6 % 21.5 % 33.3 % 22.1%
24.0 % 20.3 % 0.6 % 11.1% 3.6 %
13.3 % 18.8 % 0.4 % 11.1% 3.6 %
* Strains with another serogroup (X, Y, Z, 29E, W135). ~* Strains not grouped or for which no information was supplied on the declaration forms.
589
DISCUSSION Our results confirm that the reduction in incidence of meningococcemia, which began in the early 1980s, is a long-term trend. The incidence in France is relatively low compared with other European countries (4). Death rates have remained constant in France since 1985; however, this information depends largely on the quality of the declaration. Spanjaard (5) has shown that in The Netherlands, from 1953 to 1983, the death rate was 5.1%. In Canada, on average, 10 % of cases between 1980 and 1986 were fatal (6) - a reduction from the pre-1970's level of 28 %. In England, the death rate was 10 % in 1989 (7), and in Belgium, between 1975 and 1979, 6 . 1 % in 309 patients less than 15 years old (8). The seasonal variations observed in this study confirm that there is a sharp increase in incidence during winter/spring (December-May). A study of 248 cases declared in France between 1980 and 1984 revealed that 64.6 % bad been declared between December and May (9). Identical seasonal variations have been observed for other countries (e.g., the United States, 1975-1980) (10). The higher incidence in young adults and young children has also been observed in other countries, notably Italy (11), Dakar (12), Russia (13), and Belgium (8). In France at present, serogroup B is the most frequently isolated serogroup (54.2 % of strains); however, the level is decreasing in parallel with an increase in isolation of serogroup C. Serogroup Y is encountered fairly often, whereas serogroups W135 and A are rare. Serogroup A is predominant in epidemics (e.g., Morocco, 1990 (14), and Mecca, 1987). Riou et al (15, 16) were able to demonstrate - largely through interviews with patients - that 20 cases of serogroup A N. meningitidis infection in France were linked with strains of the 1987 Mecca epidemic. The following hypothesis is one of several that have been proposed to explain the distribution of serogroups as a function of age. When young children are not fully immunized, they are liable to be struck by serogroup B meningococci (the most frequently encountered serogroup in the population); once immunized against serogroup B, they then go down with infections due to the serogroup C strains that are associated with a higher than average mortality in young adults.
majority (72.2 % of strains, 1985-1987). In Dakar, until 1977, serogroup A predominated (74.5 % of cases), but since 1978, its incidence has diminished to the benefit of serogroup C, which, in 1980, represented 68.4 % o f cases (12). In Africa, serogroup A is the major serogroup, especially in the endemic zones of subtropical Africa (serogroup B is very rare). Analysis of the distribution of serogroups by age revealed a greater frequency of serogroup C in patients between 10 and 25 years old, and of serogroup B, in patients less than 10 years old and older than 25 years. This distribution is similar to those reported by Band et al (10) for the USA between 1975 and 1980. The relationship between the distribution of serogroups and age class has also been revealed for The Netherlands (17). The two major serotypes found in France are 2a (29.6 %) and 15 (12.7 %). Serotype 2a has been isolated increasingly since 1989 in parallel with an increase in serogroup C strains. The serogroup C/serotype 2a association is very common, often in combination with subtype Pl.l,2. Besides France (18), it is also very common in countries such as The Netherlands (19, 20), Belgium (21), and England and Scotland (7). The diversity of the serotypes and subtypes associated with serogroup B is much greater than that for C, but the association B:15 is the most common, often in combination with subtype P1.7,16; B: 15 meningococci were responsible for an epidemic in Gloucester, UK, which occurred between 1981 and 1986 (22) (major subtype, PI.16). In Holland (5), the associations B:2b (44 %), B:15, C:2a (21%), and W135:2a (60 %) are most commonly encountered; B:2a (4 %), C:2b (21%), and W135:2b (3 %) are rarer. In Canada (6), the most common antigenic formulae are B:15:P1.7,16 (18 %), B:nt:Pl.15 (13 %), and B:2b:PI.10 (13 %). The emergence of strains B:4:P1.4 (4 %) is relatively recent. The N. meningitidis strains B:2a:P1.2 and B:2b:P1.2 (23) have often been associated with infection peaks - in The Netherlands (1966), Iceland (1976-1977), and England and Scotland (1973-1975). Strains B:15:PI.16 have been associated with infection peaks in northern Norway (1974-1975) and in the Faroe Islands (19801981).
Within the factors of risk and of virulence, the extensive purpura fulminans, which are particularly serious are The distribution of serogroups in most other European associated with death. A relative risk of 5.6 in our study countries and in the USA, is identical to that in France. • confirms previous results (24). Septicemia - either in However, in Italy, serogroup C is present in large association with meningitis or alone - provides bad 590
prognosis. Studies conducted elsewhere - in France (24) and in western Norway (25) - confirm these results, although in different combinations (serious septicemia, severe septicemia with meningitis, septicemia with or without meningitis, meningitis). Results obtained in The Netherlands and Belgium (26) show a similar tendency. Death was also correlated with age, with higher death rates for 15-25 year olds (12.9 %) and over 50s (16.2 %). In England and Scotland (7), more than 10 % of cases of children of less than 5 years old and of adults of more than 30 years old were fatal; in Norway (25), the highest levels of mortality occur in patients between 5 and 12 years old and more than 50 years old. Our investigation into the relation between serogroups, serotypes, subtypes, and clinical evolution was based on a relatively small sample set considering the strong differentiation that exists between strains. No link was found between serogroup and clinical evolution, in agreement with a Norwegian study (25). However, other French (24) and Belgium studies (26) revealed the existence of a link. Spanjaard (5) has shown that in The Netherlands, from 1959 to 1983, the death rate (5.1%) varied as a function of serogroup: serogroup W135, 18 %; serogroup B, 5.1%; serogroup C, 4.8 %; and serogroup A, 2.3 %. A different correlation was found between after-effects and serogroup: serogroup A, 9.9 %; serogroup B, 7.3 %; serogroup W135, 7 %; and serogroup C, 6.5 %. In another French study (38 cases, 1984-1988) (27) the death rate associated with serogroup Y was 13.2 %. Serotypes 2a and 4 and subtype P1.1,2 - for all strains and including serogroup B - were related significantly to death. No significant differences were detected for serotypes and subtypes in serogroup C nor for the formulae in which serogroup C is most frequently encountered (e.g., C:2a:PI.I,2). In The Netherlands (20), the death rate associated with serotype 2b was 7.6 %, whereas it was 3.1% for strains B:non2b; the extent of neurological complications was the same for both serotypes. Serotypes 2b and 15 constitute the virulent subpopulations of serogroup B; this virulence was demonstrated in Belgium by De Mayer (21) who described a probable relation between serotype 2 and the disease. Spanjaard (20) found no RESUME
significant difference in mortality for serotype 2a in serogroup C. The results of serotyping and subtyping revealed that certain strains of the same serogroup were more virulent than others, with differences between the case and the carriers (28). The serotypes and subtypes associated with the most virulent strains were detected more often in the cases than in the carriers, notably for serotypes 2 and 2 associated. Certain strains are more frequently implicated in epidemics (e.g., A:4:P1.9 in the 1987 Mecca epidemic (16), and B:15:P1.7,16 in Gloucestershire) (22). Various serotypes and subtypes are encountered outside epidemics, but antigenic associations are increasingly common B: 15:P 1.7,16 (22, 29) and C:2a:PI.I,2 (30, 31). Analysis of prophylactic measures appears to reveal trends of increasing use of chemoprophylaxis and vaccination, both in the community and in the family. On 5 February 1990, the French Ministry of Health (Department of Health) (32) distributed a circular concerning measures to take in case of meningococcal infection, which included a section on prophylaxis. It recommends rifampicin (spiramycin in case of contra indication) for chemoprophylaxis (all serogroups), and vaccination (serogroups A and C). According to our study, rifampicin seems to have been well integrated in chemoprophylaxis policy. However, in a certain number of cases, prophylaxis was limited to the family without further investigation as to the patient's contact with the community. Vaccination was relatively rare in comparison with chemoprophylaxis, and was practiced later to have available the laboratory's response on the serogroup of the N. meningitidis strain (the vaccine acts only on strains of serogroup A or C). Omission of serogrouping, or errors, are often detrimental to the efficient vaccinal prophylaxis that is essential in all approaches. Enhanced prophylaxis relies on more comprehensive provision of relevant information (double declaration of cases, antibioprophylaxis, optimization of strain identification and serotyping). This would undoubtedly help limit secondary cases, which constituted 1.1% of cases in 1991 (1).
MENINGITES A MENINGOCOQUE ET MENINGOCOCCEMIES : EPIDEMIOLOGIE EN FRANCE ENTRE 1985 ET 1991
Les mrningites ~ mrningocoque et les mrningococc6mies, avec un taux d'incidence de 0,8 pour 100 000 et un taux de 16talit6 d'environ 10 %, reprrsentent un grave problrme de sant6 publique. L'Etude de 2 817 Gas drclarrs h la DGS de 1985 ?a 1991 par la drclaration obligatoire a montr6 qu'une plus forte 16talit6 est observre chez les jeunes enfants et les jeunes adultes (avec une prrdominance du groupe C chez ces derniers), lors de la prrsence d'une 591
m6ningococcdmie ou d'un purpura fulminans extensif et pour certains s6rogroupes (A et C). Pour ces cas, l'utilisation de la rifampicine depuis la circulaire de fdvrier 1990 semble bien entr6e dans les moeurs alors que l'utilisation de la vaccination contre les m6ningocoques A ou C doit ~tre am61ior6e: Par ailleurs,A'analyse des 1 569 souches de m6ningocoques adress6es au CNRM de 1989 ~ 1992 pour examens compldmentaires (s6rotypes, sous-types), a permis de montrer une plus forte incidence du s6rogroupe B avec des formules antigdniques tr6s h6t6rog~nes parmi lesquelles les souches B:15:P1.7,16 sont retrouv6es le plus fr6quemment. Ont aussi 6t6 not6es une progression du s6rogroupe C (42 % des isolements en 1992) avec pour principale formule antig6nique C:2a:P1.1,2 et du s6rogroupe Y (2 ~t 3 %). Parma ces souches, 556 ont 6t6 mises en relation avec l'6volution clinique des cas ce qui a permis de mettre en 6vidence une surmortalit6 associde au s6rotype 2a, au sous-type P1.1,2 et une plus faible mortalit6 associde au s6rotype 4. Une meilleure d6claration des cas (plus exhaustive, plus rapide) et les recherches sur d'autres marqueurs antigdniques devraient am61iorer la prdvention des cas secondaires et permettre un meilleur suivi des souches 6pid6miques et/ou virulentes. Mots-cl6s
: M6ningocoque
Epid6miologie
- M6ningites
- M6ningococc6mies
- Structure
antig6nique
- Facteurs
de gravit6
-
- Prophylaxie.
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