Introduction
In France, invasive meningococcal disease (IMD) is a mandatory notifiable
disease [1] and strains isolated from patients are sent to the national
reference centre for meningococci (CNR, Centre National de Référence
des méningocoques). The last evaluation of IMD surveillance estimated
the exhaustivity of mandatory reporting at 80% [2,3]. The goal of the
surveillance is rapid detection of clusters or abnormal situations for
prompt response and monitoring of national trends. The IMD incidence
rate has been below 2 cases per 100 000 inhabitants for the past 10 years.
Ninety seven percent of IMD cases are sporadic and IMD is associated
with serogroup B in 59% of cases. Close contacts of IMD cases are offered
chemoprophylaxis, and if appropriate, vaccination, as documented in the
national guidance [4].
At the beginning of 2003 the national institute for public health surveillance
(InVS, Institut de Veille Sanitaire) was alerted by the high incidence
of serogroup B IMD cases in the north of the department of Seine-Maritime,
Haute Normandy region, population 1 237 263. A similar increase had been
observed in the same department in 1997, associated with high incidence
of the B serogroup serotype 14 and serosubtype P1.7,16 belonging to the
electrophoretic type 5 [5].
From 2003, health authorities set up an enhanced surveillance, collecting
data on demographic, clinical, epidemiological and biological characteristics
of each new cases and raised awareness of the disease among health practitioners
aware and the general public.
This report describes the outbreak in Seine-Maritime, between 1 January
2003 and 30 June 2005.
Methods
Since 2002 the case definition of IMD has been a patient with Gram negative
cocci in direct examination of cerebrospinal fluid (CSF) or N. meningitidis isolated
from a sterile site; a patient with purulent CSF with presence of meningococcal
antigens or positive polymerase chain reaction (PCR); or a patient with
purpura fulminans or purulent CSF and purpuric spots.
For this outbreak, B:14:P1.7,16 cases were identified by culture or PCR
from a sterile site. IMD cases included in the analysis were patients living,
studying or working in Seine-Maritime and with dates of hospital admission
between 1 January 2003 and 30 June 2005.
In the Seine-Maritime department we assumed that all cases were reported
because of the enhanced surveillance and the high medical awareness during
the outbreak. Specific care was taken to send samples to the CNR quickly.
To calculate incidence, each case was assigned to the department where
the patient was normally resident. An especially affected area was defined
by tracing a circle around the city of Dieppe including the homes of all
the cases, and a total of 84 500 inhabitants. The P values for comparisons
were estimated using the Fisher exact test or the chi-square test. Population
estimates in 2003 were issued from the national office for demographic
studies (INSEE) and from the 1999 census data for Dieppe area.
Results
The outbreak in Seine-Maritime
From 1 January 2003 to 30 June 2005, 31 of the 86 IMD cases notified
in the Seine-Maritime department were B:14:P1.7,16. The average annual
incidence of IMD was 2.7 cases per 100 000 inhabitants. During the same
period, the annual national incidence was 1.6 per 100 000 inhabitants
(P=0.000). Since the 1997 rise associated with N. meningitidis B:14:P1.7,16
the number of IMD reported has remained high [FIGURE 1].
Of the 86 IMD cases, 32 were notified in 2003, 28 in 2004 and 26 between
1 January and 30 June 2005 [FIGURE 2]. In February 2005 a large peak
of eight reported cases was observed. During the two first years the
cases occurred mainly in the Dieppe area with 10 cases (incidence 11.8/100
000) in 2003 and 13 (incidence 15.4/100 000) in 2004. The incidences
in the rest of the department were 1.9/100 000 (2003) and 1.3/100 000
(2004). In the first six months of 2005, 3 of the 26 cases were from
the Dieppe area, with a six month incidence of 3.6/100 000 in the Dieppe
area and 2.0/100 000 in the rest of the department. The situation was
localized to the department of Seine-Maritime and none of the 6 surrounding
departments presented an increase of IMD incidence rate during the study
period.
Of the 86 cases, 70 were laboratory confirmed: 61/70 (87%) were serogroup
B, 8/70 (11%) were serogroup C and one (1%) was serogroup W135 or Y.
Among the 61 serogroup B strains, 31 (50%) were B:14:P1.7,16, 15 (25%)
could not be typed nor subtyped and 15 (25%) belonged to a variety of
different types and subtypes.
The male:female ratio was 1.3 (48/38) compared with 1.0 in the whole
of France (P=0.260). All age groups were affected with the highest age
specific incidences observed among children less than 5 years and teenagers
15-19 years old [TABLE 1]. Teenagers accounted for 26% of the cases,
compared with 18% in France (P=0.068).
Of the 86 cases, 55 (64%) had septicaemia only or septicaemia associated
with meningitis and 31 (36%) had meningitis only. Purpura fulminans was
observed in 39 cases (45%), in a highest proportion than in France, 29%
(P=0.000). During the study period 14 patients died, giving a case fatality
rate (CFR) of 16%. The CFR decreased over time from 25% (8/32) in 2003
to 14% in 2004 (4/28) and 8% (2/26) in the 6 first months of 2005. Two
clusters occurred in the Dieppe area: one made up of two friends in the
same village (co-primary cases, 1 identified B:14:P1.7,16), the other
made up of two brothers (first case identified B:14:P1.7,16, the secondary
case occurred within 48 hours although chemoprophylaxis had been given).
A girl and her grandfather living in the city of Rouen also developed
the disease within 48 hours of one another (the cases were B serosubtype
P1.7,16).
B:14:P1.7,16 confirmed cases
A total of 31 B:14:P1.7,16 cases were confirmed by phenotyping methods
at the CNR, 14 in 2003, 10 in 2004 and 7 in the first six months of
2005. In 2003-2004, 16/24 cases (67%) occurred in residents of Dieppe
area. Residents of this area make up 6.8% of the population of the
Seine-Maritime department. From January to June 2005, among the 7 B:14:P1.7,16
cases, 2 occurred in Dieppe area [FIGURE 3].
The proportion of B:14:P1.7,16 cases varied by age group: 59% of all
cases in teenagers (aged 15-19 years) were B:14:P1.7,16, but no B:14:P1.7,16
cases occurred in children aged under 1 year [TABLE 2]. The male:female
ratio of B:14:P1.7,16 cases was 1.8 (20/11). In 2004-2005, the sex ratio
tended towards 1.
Among the 31 B:14:P1.7,16 cases, the CFR was 19% (6 deaths) (serogroup
B IMD CFR in France: 8%, P=0.031) and 42% (13) had purpura fulminans
(B IMD national proportion: 24%, P=0.026).
During the study period, the CNR identified a total of 1493 invasive N.
meningitidis samples in residents of France, of which 62 were invasive
isolates of N. meningitidis of the phenotype B:14:P1.7,16 from
a sterile site. Invasive isolates with phenotype B:14:P1.7,16 accounted
for 4.2% of all strains and 7% of serogroup B strains. Twenty eight isolates
(45%) of the phenotype B:14:P1.7,16 were from Seine-Maritime (differences
with presented data are due to one patient residing outside the department
and two cases classified B:14:P1.7,16 in our study because of the presence
of clinical and biological signs of meningococcal infection and a B:14:P1.7,16
strain isolated from the pharynx but not taken into account by the CNR).
Most of the other 34 invasive isolates were from neighbouring departments,
where their presence was not associated with increase in incidence. Isolates
from Seine-Maritime were further shown to belong to the clonal complex
ST-32/ET-5. Strains with phenotype B:14:P1.7,16 were first isolated in
France in 1989 in the Seine-Maritime department. They then appeared sporadically
in other departments and were identified from a cluster in the eastern
city of Metz in 2003 [6].
Control of the outbreak
Information meetings were organised by the local health authorities from
2004 for hospital physicians and other health professionals working
out of hospitals (general practitioners, paediatricians…). Awareness
of symptoms was promoted in the general public, with a document entitled ‘Les
infections invasives à méningocoque en Seine-Maritime
: “repérer pour agir”’ that was widely distributed
in December 2004, by items in print media articles and radio spots
from 2003, and a television programme on the topic in January 2005.
From January 2005, reports were produced on the InVS website, four
times a year to begin with, changing to monthly. Three meetings with
the local and national health authorities and the national experts
were organised by the national board of health (DGS, Direction Générale
de la Santé) and three telephone conferences were hold during
the period. Several meetings of the national vaccination advisory board
(CTV, Comité technique des vaccinations) were held in 2004 and
2005 to evaluate the risks and benefits of using an unlicensed outer
membrane vesicle (OMV) vaccine developed against N. meningitidis phenotype
B:15:P1.7,16 in Norway.
Discussion
In 2003, the incidence of IMD began to rise in Seine-Maritime because
of the incidence in Dieppe area. Teenagers were more affected by the
B:14:P1.7,16 strain than other age groups but 60% of the cases aged 5
to 9 years couldn’t be grouped, typed or subtyped and may be therefore
considered as possible B:14:P1.7,16. This might reflect different diagnosis
practices or feasibility of isolating the strain in samples from this
age group. In winter 2004-2005 and spring 2005, the outbreak seemed to
spread in the rest of the department.
The data presented suggest a local and persistent outbreak due to a particular
strain. This situation was observed in another French department from
1995 to 1999 [7]. In Seine-Maritime the outbreak was due to N. meningitidis phenotype
B:14:P1.7,16 belonging to the clonal complex ST-32/ET-5 and was associated
with severe infections. This phenotype is not common in France. In 2003
an outbreak of six cases of this phenotype emerged in Metz, which led
to a mass prophylaxis campaign for the 8000 people living in the affected
area [6]. B outbreaks have been described in the 30 past years in Europe
and America with common epidemiological characteristics: high attack
rate among teenagers [8], presence of the strain for several years before
the emergence of the epidemic [8] and high severity of the disease.
The high CFR and high incidence in teenagers gave the health authorities
cause for concern, and justified targeted responses. Evidence suggests
that awareness among healthcare professionals and the general population
have contributed to minimise the waiting period before treatment and
therefore to make the CFR decrease over the outbreak period [10,11].
Mass chemoprophylaxis for the population living in Dieppe and the surrounding
areas was considered to be an ineffective response because the strain
had already been shown to be present throughout the department, and any
untreated members of the population could easily re-introduce the strain
into the treated population, and contribute to the emergence of rifampicin
resistance [12] and the elimination of non-pathogenic Neisseria which
can help to boost immunity to meningococcal disease. The absence of a
universal vaccine against serogroup B had prompted the development of
protein-based, OMV vaccines that have proven to be efficacious against
specific strains in Norway and Cuba [13,14]. OMV vaccine especially developed
for New Zealand is currently being used in a mass vaccination campaign
targeting young people below 20 years of age [15]. These vaccines may
be effective against related strains. Vaccination with an OMV vaccine
prepared on the basis of a closely related strain was discussed by the
Ministry of Health in order to control the persistent outbreak in Seine-Maritime.
In 2005, the number of IMD cases in the department continued to rise
and the annual incidence was 3.4 per 100 000, with 42 cases. The B:14:P1.7,16 N.
meningitidis strain was isolated in Dieppe area as well as in the
rest of the department and remained associated with high proportion of
purpura fulminans and deaths.
On the advice of national vaccination advisory board, the Ministry of
health decided in 2006 to offer all those aged between 1 and 19 years
in Seine-Maritime vaccination with the Norwegian OMV vaccine developed
against the B:15:P1.7,16 strain. The vaccination campaign dedicated to
1 to 19 years old population residing in Seine-Maritime started in June
2006 in Dieppe area and will be offered progressively to the rest of
the population. Since June 2006, close contacts of identified B:14:P1.7,16
new cases occurring in France are also offered vaccination.
Acknowledgements
To all the physicians and biologists who participated in the national
surveillance of meningococcal diseases.
|