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JOURNAL OF CLINICAL MICROBIOLOGY, Dec. 2011, p. 4094–4100 Vol. 49, No. 12
0095-1137/11/$12.00 doi:10.1128/JCM.00070-11
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Epidemiology of Invasive Streptococcus pyogenes Infections
in France in 2007
䌤
A. Lepoutre,
1
* A. Doloy,
2,3,4
P. Bidet,
5,6
A. Leblond,
1
A. Perrocheau,
1
E. Bingen,
5,6
P. Trieu-Cuot,
7
A. Bouvet,
2,3
C. Poyart,
2,3,4,7
D. Le´vy-Bruhl,
1
and the Microbiologists of the Epibac Network†
French Institute for Public Health Surveillance, Saint Maurice, France
1
; Assistance Publique Hoˆpitaux de Paris, Service de
Bacte´riologie, Centre National de Re´fe´rence des Streptocoques, Hoˆpital Cochin, Paris, France
2
; Universite´ Paris Descartes,
Paris, France
3
; INSERM, U567, Paris, France
4
; Assistance Publique Hoˆpitaux de Paris, Service de Bacte´riologie,
Hoˆpital Robert Debre´, Paris, France
5
; Universite´ Paris Diderot, Paris, France
6
; and Institut Pasteur,
Unite´ de Biologie des Bacte´ries Pathoge`nes a` Gram Positif,
URA CNRS 2172, Paris, France
7
Received 13 January 2011/Returned for modification 16 March 2011/Accepted 27 September 2011
Invasive group A streptococcal (GAS) infections cause significant morbidity and mortality. A national survey
was initiated to assess the burden of invasive GAS infections in France, describe their clinical characteristics,
and assess the molecular characteristics of GAS strains responsible for these infections. The survey was
conducted in 194 hospitals, accounting for 51% of acute care hospital admissions in France. Clinical data,
predisposing factors, and demographic data were obtained, and all GAS isolates were emm sequence typed. We
identified 664 cases of invasive GAS infections, with an annual incidence of 3.1 per 100,000 population. The
case-fatality ratio was 14% and rose to 43% in the case of streptococcal toxic shock syndrome. Bacteremia
without identified focus (22%) and skin/soft tissue infections (30%) were the most frequent clinical presenta-
tions. Necrotizing fasciitis was frequent in adults (18%) and uncommon in children (3%). The 3 predominant
emm types were emm1, emm89, and emm28, accounting for 33%, 16%, and 10% of GAS isolates, respectively. The
emm1 type was associated with fatal outcomes and was more frequent in children than in adults. Six clusters
of cases were identified, with each cluster involving 2 invasive cases due to GAS strains which shared identical
GAS emm sequence types. Four clusters of cases involved eight postpartum infections, one family cluster
involved a mother and child, and one cluster involved two patients in a nursing home. Invasive GAS infection
is one of the most severe bacterial diseases in France, particularly in persons aged >50 years or when
associated with toxic shock syndrome.
Streptococcus pyogenes (group A streptococcus [GAS])
causes a wide variety of diseases ranging from mild pharyngitis
and impetigo to severe invasive infections, including strepto-
coccal toxic shock syndrome (TSS) and necrotizing fasciitis.
The lethality of severe GAS infections remains high, ranging
from 14% to 19% in high-income countries (8, 11, 12, 16, 22,
29). In addition, outbreaks of invasive GAS infections have
been described in the community, in nursing homes, and in
hospitals (7, 13, 17, 24, 26). Although rarely reported, second-
ary transmission occurs among household contacts (9, 18, 25).
In France, invasive GAS infection surveillance relies on the
Epibac national hospital-based laboratory network and on the
characterization of GAS strains sent to the French National
Reference Center for Streptococci. Since 1987, the Epibac
network has been collecting data from participating hospital
laboratories on bacteremic infections and meningitis due to 6
bacterial species, including GAS. These infections are defined
as the isolation of the bacterium from blood (bacteremia) or
cerebrospinal fluid (CSF; meningitis). The participating hospitals
account for more than 75% of French acute care admissions, as
described at http://www.invs.sante.fr/surveillance/epibac/default
.htm.
The French National Reference Center for Streptococci has
been collecting GAS strains isolated from invasive and nonin-
vasive GAS infections since 1995 (28).
According to Epibac data, between 2000 and 2006, the inci-
dence of GAS bacteremia and meningitis increased by 32% in
France, from 1.5 to 2.0 cases per 100,000 population (French
Institute for Public Health Surveillance, unpublished data).
National guidelines for the prevention of secondary cases of
invasive GAS infection in the community and hospitals were
issued in 2005 and 2006, respectively (5, 6). Antibiotic prophy-
laxis is recommended for all household contacts of a patient
with invasive GAS infection when one of them presents with a
predisposing factor to invasive GAS infection.
In order to better characterize the epidemiology of invasive
GAS infections, we conducted a national prospective survey of
invasive GAS infections in metropolitan France. The main
goals were to (i) estimate the burden of invasive GAS infec-
tions with or without a positive blood culture, (ii) characterize
the clinical presentations, (iii) assess predisposing factors and
outcomes, (iv) describe the molecular characteristics and an-
tibiotic susceptibility of GAS strains isolated from invasive
infections, and (v) assess the level of implementation of the
recommendations on antibiotic prophylaxis among household
contacts (6).
* Corresponding author. Mailing address: Institut de Veille Sani-
taire, 12 rue du Val d’Osne, 94415 Saint-Maurice Cedex, France.
Phone: 331 41 79 68 91. Fax: 331 41 79 68 72. E-mail: a.lepoutre@invs
.sante.fr.
† A list of the microbiologists of the Epibac network is available at
http://www.invs.sante.fr/.
䌤
Published ahead of print on 5 October 2011.
4094
MATERIALS AND METHODS
Design. We conducted a cross-sectional survey over a 1-year period from
November 2006 to November 2007. Among the 332 hospital laboratories eligible
for Epibac surveillance, 194 laboratories located throughout the 22 French ad-
ministrative regions participated on a voluntary basis. The participating hospitals
accounted for 51% of French acute care inpatient admissions in 2007.
Case definition. GAS invasive infection was defined as the isolation of the
bacterium from a usually sterile site (e.g., blood, cerebrospinal fluid, joint, bone,
or synovial fluid) or from samples obtained from deep-body-site aspirates, in-
traoperative specimens, or a nonsterile site in association with one of the fol-
lowing clinical conditions: necrotizing fasciitis, clinically ascertained pneumonia,
endometritis, salpingitis, or TSS not attributable to any other cause and defined
according to the U.S. Working Group on Severe Streptococcal Infections defi-
nitions (31).
Invasive GAS infections identified during the hospital stay or within the 7 days
following the hospital discharge were presumed to be nosocomial if they oc-
curred at least 48 h after the time of admission or if the patient underwent a
surgical operation during the 7 days preceding the onset of GAS infection.
Postpartum infections were presumed to be nosocomial if they occurred during
the hospital stay or within 7 days after discharge.
A confirmed GAS infection in a case contact was defined as isolation of GAS
from the site of infection or, in case of acute pharyngitis, as a positive rapid
antigen detection test for GAS.
Data collection. Cases were identified by the local microbiologist, who com-
pleted a standardized questionnaire for each case meeting the case definition
with the support of the local infectious diseases specialist and of the attending
physician. Data collected included age, sex, clinical presentations, predisposing
factors, and outcomes at the time of discharge from hospital. Information re-
garding the occurrence of a GAS infection among close contacts 30 days before
or after the onset of disease of the identified case was also collected. Close
contacts were defined as individuals living in the same household or institution
as the case or having close and/or repeated contact during the 7 days preceding
the onset of the index case (5). In hospitals, close contacts were patients hospi-
talized in the same ward (6). Additional information regarding possible clusters
of nosocomial invasive GAS infection was retrieved from mandatory notifica-
tions of nosocomial invasive GAS infection and from available investigation
reports. The survey’s questionnaires were sent to the French Institute for Public
Health Surveillance staff, who reviewed the inclusion criteria and the complete-
ness of the data. The microbiologists were reminded to report cases by regular
phone calls and mailings.
Microbiological methods. GAS isolates were confirmed to be S. pyogenes by
beta-hemolysis on sheep blood agar, presence of Lancefield group A antigen, and
production of pyrrolydonyl arylamidase (20). Susceptibility to penicillin, amoxi-
cillin, vancomycin, erythromycin, tetracycline, and clindamycin was determined
according to the French Society for Microbiology guidelines described at http:
//www.sfm.asso.fr. All available isolates were also screened for streptococcal
pyrogenic exotoxin speA,speB, and speC genes and ssa genes by multiplex PCR
assay. When identical isolates on these markers were obtained from any given
patient, only the first invasive isolate was further characterized by molecular
typing. The emm gene sequencing was performed as described by Beall et al. (1)
with the modifications described at www.cdc.gov/ncidod/biotech/strep.htm.
Data analysis. The incidence of invasive GAS infections in France was esti-
mated by applying a correcting factor yielded by the survey to the incidence of
GAS bacteremic infections and meningitis in 2007 ascertained by Epibac sur-
veillance (IncEPI). IncEPI is calculated by dividing the number of reported cases
by the population covered by Epibac surveillance, corrected for the rates of
underreporting of cases, which is evaluated by 3 sources of capture-recapture
analysis (2, 3, 10, 14, 23). The population coverage was assessed to be 78% in
2007, and a 20% underreporting rate was assumed.
Invasive GAS incidence was therefore computed as IncEPI/(1 ⫺k), where kis
the correcting factor corresponding to the proportion of invasive GAS infections
in the survey where GAS has not been isolated from blood or cerebrospinal fluid,
and IncEPI is the incidence estimated through Epibac. Age-specific incidence
rates for invasive GAS infections were estimated by applying to the specific age
groups considered the same methodology described above for the all-age inva-
sive GAS infection incidence rate.
A cluster of invasive GAS infections was defined as the occurrence of ⱖ2
invasive GAS infection cases in close contacts within 30 days for community-
acquired invasive GAS infections and within 6 months for institutionalized in-
vasive GAS infection cases. Clusters were confirmed if the related invasive GAS
infection cases were due to GAS strains of identical emm sequence types.
Associations between outcomes, clinical presentations, predisposing factors,
and strain characteristics were tested using Fisher’s exact test for binomial data.
Associations between each specific clinical presentation or predisposing factor
with death were tested irrespective of the presence of other clinical presentations
or predisposing factors. Death predictors were evaluated using logistic regression
modeling. Statistical analysis was performed using Stata (version 9.2) software
(Stata Corporation, College Station, TX).
RESULTS
Number of cases, demographic characteristics, and inci-
dence. We identified 664 invasive GAS infections meeting the
case definition. GAS strains were isolated from blood cultures
alone (n⫽345, 52%), blood cultures and other sterile sites
(n⫽47, 7%), blood cultures and nonsterile sites (n⫽75,
11%), sterile sites other than blood (n⫽127, 19%), and
nonsterile sites (n⫽70, 11%); cases where strains were iso-
lated from nonsterile sites were included on the basis of the
presence of at least one of the following clinical manifesta-
tions: toxic shock syndrome (n⫽21), necrotizing fasciitis (n⫽
22), endometritis (n⫽23), salpingitis (n⫽2), or pneumonia
(n⫽2).
The median age of the patients was 55 years (range, 28 days
to 103 years). The male-to-female ratio was 0.9.
The estimates of invasive GAS infection incidence in 2007 by
age group are presented in Fig. 1. On the basis of Epibac
surveillance, the incidence of GAS bacteremic infections and
meningitis was 2.2 cases per 100,000 population in 2007. More-
over, GAS invasive infections where GAS was not isolated
from blood or cerebrospinal fluid accounted for 29% (n⫽193)
of the total invasive GAS infections reported in the survey.
Therefore, the overall incidence of invasive GAS infections in
France was estimated to be 3.1 (95% confidence interval [CI],
2.9 to 3.2) cases per 100,000 population in 2007. The highest
incidence occurred in children ⬍5 years of age (5.7 per
100,000) and in adults ⱖ70 years of age (8.4 per 100,000).
Incidence rates were similar for men and women except in
those aged 50 to 69 years, where the incidence was higher in
men than in women (3.5 versus 2.2 per 100,000; P⬍0.001).
Clinical presentations. Among the 664 invasive GAS infec-
tions included, various clinical presentations were reported
(Table 1). Nonnecrotic skin or soft tissue infections were the
most frequent, accounting for 30% of the cases; blood cultures
were positive in 82% of these cases. Necrotizing fasciitis was
reported in 16% of cases, pleuropulmonary infection in 11%,
septic arthritis in 9%, and postpartum sepsis in 5%. Other
FIG. 1. Age-specific rates and case-fatality ratios of invasive group
A streptococcal infections in France in 2007.
VOL. 49, 2011 GROUP A STREPTOCOCCAL INVASIVE INFECTION 4095
clinical presentations, such as intra-abdominal infections, os-
teomyelitis, and gynecological infections, were reported in less
than 5% of cases. No identified focus of invasive GAS infection
was reported in 22% of cases, although the portal of entry was
clinically suspected in 71% (n⫽105) to be the skin in 60%, the
respiratory tract in 30%, or other sites in 10%.
Septic arthritis, osteomyelitis, and pleural infection were
observed more frequently in children (age, ⬍15 years; n⫽109)
than in adults (age, ⱖ15 years; n⫽554), being reported in
20%, 15%, and 12% of children, respectively, and in 7%, 1%,
and 2% of adults, respectively (P⬍0.001 each). Necrotizing
fasciitis was mostly observed in adults and uncommon in chil-
dren (18% versus 3%; P⬍0.001). Postpartum cases accounted
for 32% (32/100) of cases in women of childbearing age (15 to
49 years).
A TSS was associated in 20% of cases (Table 2). It was 3-
and 1.9-fold more frequent in the presence of necrotizing fas-
ciitis and pulmonary infection, respectively (P⬍0.001 and P⬍
0.01), than in other clinical presentations. TSS was reported in
children (15%) and in adults (21%), but it was more frequent
in persons aged 50 to 69 years than in other age groups (31%
versus 17%; P⬍0.001) (Table 2).
Predisposing factors. Predisposing factors were ascertained
for 657 (99%) cases; 507 (77%) presented at least one predis-
posing factor for invasive GAS infection (Table 3). A cutane-
ous pathology (e.g., burns, varicella, skin disease, and wounds)
was reported in 247 (38%) cases and in 114 (52%) of those
aged ⱖ70 years. A chronic medical condition such as diabetes,
malignancy, or liver or cardiac chronic disease was reported in
234 (36%) cases. Among children (age, ⬍15 years), 55 (51%)
presented a predisposing factor; varicella was reported in 20
(19%), primarily in those under 5 years of age (19/20), and some
other lesion or disease of the skin was reported in 19 (18%). Only
6 (6%) children presented with a chronic medical condition.
Ninety-six cases (15%) were considered nosocomial; among
them, 32 (5%) were postpartum infection cases.
emm sequence typing and antimicrobial susceptibility.
Among the 664 cases, at least one GAS strain for 623 cases
(94%) was sent to the National Reference Center for Strep-
tococci, which analyzed only one representative strain per case.
A total of 48 different emm types were identified, and 3 types,
emm1(n⫽203, 33%), emm89 (n⫽100, 16%), and emm28
(n⫽65, 10%), accounted for 59% of isolates, followed by
emm4(n⫽34, 5%) and emm12 (n⫽33, 5%) (Fig. 2). No
association between the distribution of emm types and geo-
graphical location was observed. emm1, emm3, and emm12
types were more frequently identified in children than in adults
(45% versus 30% [P⬍0.05], 7% versus 2% [P⬍0.05], and
12% versus 4% [P⬍0.01], respectively), while the emm89 type
was less frequently identified in children than in adults (9%
versus 18% [P⬍0.05]).
The speA,speB,speC, and ssa genes were detected in 37%,
100%, 49%, and 12% of strains, respectively. The speA gene
was carried by 97% of emm1 strains (196/203) and 100% of
emm3 strains (18/18), whereas it was carried by only 4% (16/
399) of strains of other emm types.
The emm1 type was associated with a higher frequency of
TSS (P⬍0.001) and fatal outcomes (P⬍0.001) than other
emm types in univariate analysis. The presence of the speA
gene was also associated with a higher frequency of TSS (P⬍
0.001) and fatal outcomes (P⬍0.001).
All GAS strains were susceptible to penicillin, amoxicillin,
and vancomycin; 8% were resistant to erythromycin, 13% to
tetracycline, and 6% to clindamycin. Among GAS isolates
from children (n⫽105), 4%, 3%, and 1% were resistant to
erythromycin, tetracycline, and clindamycin, respectively. A
TABLE 1. Clinical presentations, incidence of positive blood
cultures, and outcomes among 664 invasive group
A streptococcal infection cases
Clinical presentation
No. (%) of cases No. of cases
with fatal
outcome/
total no.
(%)
c
Total
a
With positive
blood
culture
b
Presenting
with a
TSS
b
Bacteremia without
identified focus
147 (22) 147 (100) 24 (16) 32/144 (22)
f
Skin or soft tissue
infection
196 (30) 160 (82) 29 (15) 17/193 (9)
g
Necrotizing fasciitis 104 (16) 49 (47) 45 (43) 22/102 (22)
f
Pleuropulmonary
infection
d
71 (11) 44 (62) 24 (34) 15/68 (22)
Postpartum
infection
32 (5) 12 (38) 0 (0) 0/32 (0)
g
Intra-abdominal
infection
24 (4) 11 (46) 5 (21) 3/23 (13)
Septic arthritis 59 (9) 22 (37) 7 (12) 2/54 (4)
g
Osteomyelitis 22 (3) 13 (59) 0 (0) 0/22 (0)
Other clinical
presentation
e
48 (7) 30 (63) 10 (21) 5/45 (11)
a
The total number does not add up to 664, as certain patients presented with
more than one clinical presentation; percentages are given with respect to the
664 cases.
b
Percentages are of cases presenting with the clinical presentation.
c
Outcomes were available for a total of 646 cases. The total number of cases
does not add up to 646, as certain patients presented with more than one clinical
presentation.
d
Cases presenting a pleuropulmonary infection (n⫽71) included 48 cases
presenting with pneumonia, 12 cases presenting with a primary pleural infection,
and 11 cases presenting with pneumonia and pleural infection.
e
Other clinical presentations included 48 patients presenting 51 clinical pre-
sentations: meningitis (n⫽7), salpingitis/endometritis (n⫽14), endocarditis
(n⫽7), other upper respiratory tract infection (n⫽10), brain abscess (n⫽3),
renal abscess/pyelonephritis (n⫽4), vascular catheter infection (n⫽2), urinary
catheter infection (n⫽2), hip prosthesis infection (n⫽1), and bacteremia from
digestive tract infection (n⫽1).
f
P⬍0.05 for a positive association between the presence of the specific
clinical presentation and death (Fisher exact test for binary data).
g
P⬍0.05 for a negative association between the presence of the specific
clinical presentation and death (Fisher exact test for binary data).
TABLE 2. Ages and outcomes among 664 invasive group A
streptococcal infection cases
Age group
(yr)
No. (%) of cases No. of cases with
fatal outcome/
total no. (%)
a
Total Presenting with
a TSS
0–14 109 (17) 16 (15) 4/105 (4)
15–49 188 (28) 27 (14) 12/184 (7)
50–69 142 (21) 44 (31) 35/138 (25)
b
ⱖ70 224 (34) 44 (20) 40/218 (18)
b
All ages
c
664 (100) 131 (20) 91/646 (14)
a
Outcomes were available for 646 cases.
b
P⬍0.05 for the test of a difference in the frequency of death compared with
that for the 0- to 14-year-old age group, used as the reference group (Fisher exact
test for binary data).
c
Includes one patient without age information.
4096 LEPOUTRE ET AL. J. CLIN.MICROBIOL.
higher prevalence of resistance was observed among GAS isolates
from adults (n⫽518), with 9%, 15%, and 7% being resistant to
erythromycin, tetracycline, and clindamycin, respectively.
Outcomes. Overall, 31% (n⫽209) of cases required inten-
sive care unit admission and 28% (n⫽183) underwent sur-
gery. The outcome at the time of discharge from hospital was
available for 646 cases (Table 2). The overall in-hospital le-
thality was 14% (95% CI, 11% to 17%), reaching 43% (56/129)
in patients who presented with TSS. More than two-thirds of
the deaths (62/91, 68%) occurred within the 4 days following
the onset of infection.
Among 104 necrotizing fasciitis cases, 64% required inten-
sive care unit admission and 69% underwent surgery, 22%
(22/102) died, and 31% (32/102) had a permanent complica-
tion at the time of discharge from hospital, such as an ampu-
tation (11%) or skin or soft tissue or muscular defects (14%)
due to necrosis. Overall, only 46% (47/102) of the patients who
presented with a case of necrotizing fasciitis recovered without
sequelae.
Bacteremia without an identified focus, necrotizing fasciitis,
pneumonia, and TSS were all associated with a higher risk of
death in univariate analysis (P⬍0.01, P⬍0.05, P⬍0.05, and
P⬍0.001, respectively).
Death was associated with the presence of a predisposing
factor (16% versus 9%, P⬍0.05). Among predisposing fac-
tors, chemotherapy, diabetes, malignancy, and hepatic disease
were all associated with death in univariate analysis (P⬍0.01,
P⬍0.01, P⬍0.05, and P⬍0.01, respectively).
According to the results of multivariate logistic regression
analysis, age ⱖ50 years, hepatic disease, TSS, bacteremia with-
out an identified focus, and emm1 type were all independently
associated with an increased risk of a fatal outcome (Table 4).
Antibiotic prophylaxis and cluster of GAS infections in close
contacts. Information on the prescription of an antibiotic pro-
phylaxis to household contacts was available for 451 (68%)
cases. Among them, 50 (11%) reported having one or more of
their household contacts who presented with a predisposing
factor for invasive GAS infection; 266 (59%) cases did not
report such a factor among their contacts, and 135 (30%) lived
alone. In following French recommendations, an antibiotic
prophylaxis was to be prescribed to each member of these 50
households (i.e., 103 household contacts); the recommenda-
tions were actually fully respected for all the household con-
tacts in only 7 households (including 11 household contacts)
and partially realized in 1 household (1 antibiotic was pre-
scribed to 1 child with varicella, while the 5 other household
contacts did not receive any). No prophylaxis at all was con-
ducted in 42 households (including 86 household contacts).
Despite a poor compliance with the recommendations, no sub-
TABLE 3. Predisposing factors and outcomes among invasive GAS
infection cases
Predisposing factor
a
No. (%) of cases No. of cases with
fatal outcome/
total no. (%)
d
Total
b
Presenting with
a TSS
c
Immunosuppression 49 (7) 9 (18) 9/47 (19)
Steroid use 30 (5) 8 (27) 6/28 (21)
Chemotherapy 18 (3) 6 (33) 7/16 (44)
g
Injection drug use 9 (1) 1 (11) 1/9 (11)
Skin disease or wound
e
247 (38) 48 (19) 33/242 (14)
Varicella 20 (3) 3 (15) 1/20 (5)
Skin wound 193 (29) 41 (21) 27/188 (14)
Skin disease 46 (7) 8 (17) 6/46 (13)
Burn 3 (0) 0 (0) 0/3 (0)
Chronic medical
condition
f
234 (36) 56 (24) 56/226 (25)
g
Diabetes 88 (13) 22 (25) 21/86 (24)
g
Malignancy 42 (6) 12 (29) 11/39 (28)
g
Hepatic disease 28 (4) 6 (21) 10/28 (36)
g
Renal impairment 25 (4) 6 (24) 7/25 (28)
Heart disease 44 (7) 10 (23) 10/43 (23)
Other chronic medical
condition
31 (5) 8 (26) 6/29 (21)
Alcoholism 34 (5) 14 (41) 7/33 (21)
Surgery ⬍8 days earlier 18 (3) 4 (22) 2/16 (13)
Childbirth ⬍4 wk earlier 32 (5) 0 (0) 0/32 (0)
h
No predisposing factor
reported
150 (23) 28 (19) 13/149 (9)
h
a
Information on the presence of a predisposing factor was available for 657 patients.
b
Patients may have more than one predisposing factor; percentages are cal-
culated using the 657 cases as the denominator.
c
Percentages are calculated using the number of cases presenting the specific
predisposing factor as the denominator.
d
Outcomes were available for 646 cases. The total number of cases does not
add up to 646, as certain patients presented more than one predisposing factor.
e
The total of the subcategories does not add up to 247, as certain patients
presented more than one type of skin disease or wound.
f
The total of the subcategories does not add up to 234, as certain patients
presented more than one chronic medical condition.
g
P⬍0.05 for a positive association between the presence of the specific
predisposing factor and death (Fisher exact test for binary data).
h
P⬍0.05 for a negative association between the presence of the specific
predisposing factor and death (Fisher exact test for binary data).
FIG. 2. Distribution of emm types among 623 GAS strains responsible for invasive infections in children and adults.
VOL. 49, 2011 GROUP A STREPTOCOCCAL INVASIVE INFECTION 4097
sequent case of invasive GAS infection was reported in the 103
household contacts of these 50 households.
Information concerning the occurrence of a GAS infection
in close contacts of the case was available for 518 (78%) cases.
A noninvasive GAS infection was confirmed in a close contact
of 11 (2%) cases; the contact case was a member of the house-
hold (8 cases), shared the same hospital room (1 case), or was
a resident of the same nursing home (2 cases).
Subsequent invasive GAS infection cases were identified in
the 30 days following the onset of a case among the close
contacts of 7 (1%) cases; for 5 of these cases, GAS strains were
of identical emm type, and for 2 they were of different emm
types. In addition to these 5 clusters, a cluster of 3 cases of
GAS infection (2 invasive cases and 1 noninvasive case) which
shared identical emm89 GAS strains was identified with a delay
of 77 days in 3 residents of the same nursing home.
Overall, 6 clusters involving 12 invasive GAS infections cases
were confirmed on the basis of epidemiological links and iso-
lation of GAS strains of identical emm types (Table 5). One
family cluster due to an emm1 strain (cluster 1) occurred in a
34-year-old mother and her 3-year-old daughter, both of whom
were previously healthy; the mother died and the young girl
recovered. One cluster of two invasive infections and one non-
invasive infection due to an emm89 strain (cluster 2) occurred
in three chronically disabled residents of a nursing home. Four
postpartum clusters involved two women each who shared the
same emm4, emm11, emm28, or emm89 strain. Investigation
reports were available for 3 clusters; the suspected route of
contamination was direct transmission in the members of the
family in cluster 1, indirect transmission from one resident to
another during skin wound care in cluster 2, and intrahospital
patient-to-patient contamination during the postdelivery pe-
riod in cluster 5 (Table 5).
DISCUSSION
This nationwide prospective survey enables the determina-
tion of the incidence of invasive GAS infections in France. It
indicates that cases not captured by routine surveillance of
bacteremia and meningitis account for a substantial part (29%)
of invasive GAS infections. Given this result, the estimated
rate in 2007 was 3.1 cases per 100,000 population, a rate com-
parable to the 2.2 to 3.8 recently reported from surveys in
Europe, the United States, and Canada (11, 22, 27).
The highest risks of invasive GAS infections were identified
in young children and elderly patients, as previously reported
(11, 27). This study also highlights the high severity of invasive
GAS infections, with a case-fatality ratio of 14%, which is also
in agreement with the ratios reported in the United States
(14%) (22), Sweden (14.5%) (8), and Denmark (16%) (16).
This survey allowed a comprehensive assessment of the ep-
idemiology of invasive GAS infections in France, since predis-
TABLE 4. Results of multivariate logistic regression analysis of
factors associated with death in invasive GAS infection
a
Variable Odds ratio
(95% CI) Pvalue
Age ⬍50 yr Reference
Age ⱖ50 yr 2.9 (1.5–5.6) ⬍0.01
Toxic shock syndrome 9.9 (5.6–17.5) ⬍0.001
Bacteremia without
identified focus
2.5 (1.4–4.7) ⬍0.01
Chemotherapy 3.9 (0.9–16.2) 0.06
Diabetes 1.8 (0.9–3.6) 0.10
Liver disease 3.7 (1.3–10.5) 0.02
emm1 type 2.2 (1.2–3.8) ⬍0.01
a
Data are for 600 cases. Clinical presentations, predisposing factors, emm
types, and patient characteristics were entered in the model if associated with an
increased or a decreased frequency of death on univariate analysis (P⬍0.20)
and retained in the model if associated with death (P⬍0.10). Finally, factors
were considered to be independently associated with death if associated with a P
value of 0.05 or less (Wald test). Patients with missing data (n⫽64) were
excluded from the analysis. Two-way interactions were evaluated.
TABLE 5. Confirmed clusters
a
of invasive GAS infections
Cluster
no. Setting
No. of cases (clinical presentation) Duration
(days)
emm type(s)
(no. of
strains/total
no. of strains)
Suspected mode of transmission
b
Invasive Noninvasive
1 Household 2 (1 pneumonia with empyema,
1 pneumonia and TSS)
1 (pharyngitis) 7 emm1 (3/3) Intrafamilial
2 Nursing home 2 (2 bacteremic skin infections) 1 (lower genital tract
infection)
77 emm89 (3/3) Indirect transmission from patient to
patient during the care of skin
wounds of the 3 patients by hand-
borne transmission or by
transmission from a carrier among
health care staff (not screened)
3 Postnatal ward A 3 (1 wound infection from
cesarean delivery and
endometritis, 2 endometritis)
20 emm11 (2/3),
emm1 (1/3)
Unknown
4 Postnatal ward B 2 (1 bacteremic endometritis, 1
endometritis)
3emm89 (2/2) Unknown
5 Postnatal ward C 2 (1 bacteremic endometritis, 1
endometritis)
2emm4 (2/2) Patient to patient in the postdelivery
period, where the 2nd case shared
the same room as the index case
6 Postnatal ward D 2 (1 bacteremic endometritis, 1
endometritis)
3emm28 (2/2) Unknown
a
A confirmed cluster was defined as the occurrence in 30 days (in the community) or 6 months (in institutional settings) of ⱖ2 invasive GAS cases due to GAS strains
sharing identical emm sequence types.
b
The mode of transmission was suspected on the basis of the results of investigations of the infection control staff.
4098 LEPOUTRE ET AL. J. CLIN.MICROBIOL.
posing factors, outcomes, and GAS isolates were obtained
from more than 90% of the cases.
Regarding the representativeness of the survey, although the
survey was conducted on a voluntary basis, the participating
hospitals accounted for 51% of French acute care admissions
in 2007 and were distributed in all French regions. Regarding
case characteristics, the age and sex distribution of bacteremic
invasive GAS cases included did not differ from those of bac-
teremic cases identified in Epibac surveillance in 2007, suggest-
ing no significant bias in the recruitment of cases. Regarding
the estimation of invasive GAS infection incidence, as Epibac
results are regularly validated through 3 sources of capture-
recapture analysis, we consider that in our survey our estima-
tion of global invasive GAS infection incidence based on the
Epibac rates for bacteremia or meningitis, corrected by the
proportion of invasive GAS infections where the GAS has not
been isolated from blood or CSF, provides the best incidence
estimate.
Inclusion of cases with GAS isolates obtained from a non-
sterile site (i.e., 23 cases of endometritis, 2 cases of salpingitis,
and 2 cases of pneumonia), accounting for 4% of the total
cases, may hamper comparison of the results with those of
surveys which include only cases with GAS isolates from nor-
mally sterile sites (8, 16, 22). However, the design of our survey
led to a more comprehensive ascertainment of the burden of
invasive GAS infections in our country.
The results emphasize the severity of invasive GAS infec-
tions in adults over 50 years of age, who accounted for the
majority (82%) of fatal invasive GAS infections. This may in
part be explained by the high frequency of TSS and preexisting
chronic medical conditions in this age group. On the contrary,
children and women with postpartum endometritis were less
likely to present severe clinical manifestations, such as necro-
tizing fasciitis, TSS, or a fatal outcome. The highest risk of fatal
outcome was associated with pneumonia, necrotizing fasciitis,
and bacteremia without an identified focus.
emm1 was the main emm type associated with a higher risk
of a fatal outcome, after adjusting for other predisposing fac-
tors, as previously reported in Europe and the United States
(15, 22). Most of the emm1 strains carried the speA gene, which
was also associated with severe infections and outcomes. How-
ever, as the presence of the speA gene was highly correlated
with emm1 type, the role of the speA gene in the occurrence of
TSS or a fatal outcome could not be distinguished from that of
emm1 type. Moreover, emm1 strains were more frequent in
patients without chronic medical conditions (36% versus 27%,
P⬍0.02) and in children. These results confirm the high
virulence potential of emm1 strains circulating in France and
other countries. The second most frequent emm types included
emm89 and emm28, which were also frequent in the United
States, Denmark, and Sweden (8, 16, 22). On the contrary, the
emm3 type, which was identified to be preponderant and highly
virulent in the United States and other European countries
(15, 21, 22), accounted for only 3% of the strains isolated from
invasive infections in our survey.
Skin diseases or cutaneous lesions were the most common
predisposing factor, especially in elderly and younger patients.
Skin conditions were reported in more than half of the elderly
(52%), and varicella was reported in one-fifth of children un-
der the age of 15 years. This observation highlights the impor-
tance of skin breaches as portals of entry for GAS infection, as
also noticed in previous reports (12, 29, 30).
Six clusters of 12 GAS invasive infections with identical emm
types were identified; 4 of them involved 8 postpartum cases
accounting for 25% (8/32) of postpartum cases. This suggests
that a substantial proportion of postpartum GAS infections is
preventable. In addition, 10% (64/632) of nonpostpartum in-
vasive GAS infections were suspected to have been acquired in
hospital. The significant number of postpartum cases reported
in the survey could partially be related to the mandatory re-
porting of nosocomial infections since 2001 and the incentive
to investigate postpartum and postsurgery GAS infections, as
recommended in guidelines issued in 2006 (5). Sequencing of
the emm gene was very important in the investigation of clus-
ters of cases to confirm the links between epidemiologically
related cases.
The prescription of antibiotic prophylaxis in household
members of GAS-infected patients when one of them presents
with a predisposing factor has been recommended since 2005
(5, 6). This survey suggests that these recommendations were
inconsistently applied and strengthens the need to reinforce
their implementation in community settings.
In France, as in other developed countries, invasive GAS
infections are among the most severe bacterial infections.
Overall, we estimated that 1,900 cases of these infections oc-
curred in France in 2007. Assuming that the cases included in
the survey were representative of invasive GAS infections in
France, we estimated that 270 patients died from such infec-
tions in 2007.
Current strategies to prevent GAS invasive diseases still rely
on early detection of GAS infections, rapid and effective med-
ical care, and reinforcement of outbreak investigation and con-
trol, particularly in health care settings. However, identifica-
tion of factors associated with mortality can guide disease
prevention efforts. It was estimated that a 26-valent vaccine
candidate, which has reached phase II trials in adults, could
potentially prevent 40% to 50% of cases and 50% to 60% of
deaths due to invasive GAS infections among children and the
elderly (4, 19). In this context, the follow-up of GAS strains
involved in severe GAS infections is important to adapt cur-
rent vaccine development strategies.
ACKNOWLEDGMENTS
We thank the members of the survey’s scientific committee, Cathe-
rine Chirouze, Julien Loubinoux, Alain Lortat Jacob, Jean Pierre Be-
dos, Fre´de´ric Laurent, Marc Lecuit, and Claude Bernet, for their
assistance in the preparation of the survey’s protocol and question-
naire and their advice for the implementation of the survey; Jean
Claude Desenclos for his helpful reading and comments on the man-
uscript; all the clinicians and microbiologists from the participating
hospitals who collected the data; and Gisle`ne Collobert and Ge´rald
Touak for excellent technical assistance.
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