T h e NE W ENGL A ND JOUR NA L o f MEDICINE

CLINICAL PRACTICE

Streptococcal Pharyngitis
Michael R. Wessels, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal
guidelines, when they exist. The article ends with the authors clinical recommendations.

A 10-yearold
girl
presents
with a sore
throat and
fever that
has lasted
for 1 day.
She appears
flushed and
From the Division of Infectiousmoderately
Diseases, Childrens Hospital Boston
and Harvard Medical School, Boston. ill. Physical
Address reprint requests to Dr.examination
Wessels at the Division of Infectious
reveals
a
Diseases, Childrens Hospital Boston,
300 Longwood Ave., Boston, MAtemperature
02115,
or
atof
39C,
michael.wessels@childrens
tender
.harvard.edu.
bilateral
N Engl J Med 2011;364:648-55.
anterior
Copyright 2011 Massachusetts Medical
cervical
Society.
lymph
nodes that
are 1 to 2
An audio cm in the
version of this
greatest
article is
dimension,
available at
NEJM.org and
erythema
and whitishyellow
exudate
over
enlarged
tonsils and
the
posterior
pharynx. A
rapid
antigendetection
test from a
throat-swab
specimen is
positive for
group
A
streptococc

us. How should the patient be

evaluated and treated?

THE
CLIN
ICAL
PRO
BLE
M
Sore throat is an extremely
common presenting symptom.
Acute pharyngitis accounts for
1.3% of outpatient visits to
health care providers in the
United States, and it ac counted
for an estimated 15 million
1
patient visits in 2006. Group A
streptococcus (Streptococcus
pyogenes) is responsible for 5
to 15% of cases of pharyngitis
in adults and 20 to 30% of
2
cases
in
children.
Streptococcal
pharyngitis
occurs most commonly among
children between 5 and 15
years of age. In temperate
climates, the incidence is
highest in winter and early
spring. The economic burden of
streptococcal
pharyn
gitis
among children in the United
States has been estimated at
$224 million to $539 million
per year, with a substantial
fraction of the associated costs
attribut able to parents lost
3
time from work.
Streptococcal
pharyngeal
infection not only causes acute
illness but also can trig ger the
postinfectious syndromes of
poststreptococcal
glomerulonephritis and acute
rheumatic fever. Rheumatic fever
is currently uncommon in most
developed countries, but it
remains the leading cause of
acquired heart disease among
children in many resource-poor
areas such as sub-Saharan Africa,

India, and parts of Australasia.

STR

ATEGIES
AND
EVALUATION
EVIDENC

Download
scarlet of
fever, which isparticularly
man
if
The onset
edfrom
ifested in
as a finely papular
these symptoms
symptoms
nejm.org
rash that arise
spares
or
patientserythematous
with
on
the face, may be accentuated
progress several
streptococcal
October
in skinis folds, and days
may into the
14,2015.
pharyngitis
For
desquamate
during
illness. Among
often abrupt.
In
personal
convalescence.
Cough,
children
addition to throat
useonly.
coryza,
and
con
younger
than
3
pain, symptoms
Noother
not typical symptoms
yearsof of age,
may areinclude
uses
pharyngitis,
exudative
without
fever, streptococcal
chills,
permission
pharyngitis due
malaise,and, if present, they suggest
.
an alternative
cause such
to as
streptococcal
a
headache,
and
Copyri
viral infection.
Throatinfection
pain
is
particularly
in
ght
be severe, and it israre.
oftenIn this age
youngermay
children
2011
worsepain,
on one side. However,
group,
Massac
abdominal
husetts
unilateral pain streptococcal
or an
nausea,severeand
Medica
inability to swallow should
vomiting. 648
l
N ENGL
J MED
raise concern
about
a local
Society
casionally,364;7 NEJM.ORG
suppurative
complication
FEBRUARY 17, 2011
.All
streptococcal
such as periton
rights
pharyngitis
is
TheNewEnglandJournalof
reserve
retropharyngeal
abscess,
accompanied by
Medicine
d.

CLINICAL PRACTICE

even
witho
inf ut
ectspecif
io ic
n treat
m ment.
ay 6,7
be Th
m e
an
ife diagn
ste osis
d of
as strept
co
ry ococc
za, al
ex phary
co ngitis
ria
t on
ed clinic
na al
resgroun
,
an ds is
d notori
ge ously
ne unreli
ral
izeable.8,
d 9
ad
en Sym
op
at p
hy toms
5
. and
In signs
m are
ostvariab
pe
rs le,
on and
s, the
fe severi
ve
r ty of
resillness
ol ranges
ve from
s
wi mild
thi throat
n disco
3 mfort
to
5 alone
da to
ys, classi
an c
d
thr exuda
oa tive
t phary
pa
in ngitis
reswith
ol high
ve fever
s
wi and
thi prostr
n ation.
1 The
we
ek diagn
, osis is

further
compli
cated by
the fact
that
infection
due to
many
other
agents
may be
indisting
uishable
clinicall
y from
streptoco
ccal
pharyngi
tis
(Table
1).
Clini
cal
scoring
systems
have
been
develope
d
to
predict
the
likelihoo
d
of
streptoco
ccal
infection
among
children
and
adults
presentin
g with
sore
throat.
These
systems
are
based on
assessme
nt
for
suggesti
ve
clinical
findings:
fever,
tonsillar
swell ing
or
exudate,
tender
and
enlarged
anterior

ce less in
r patien
victs
al with
ly no
m sugge
ph stive
no clinic
de al
s, crite
an ria to
d appro
theximat
ab ely 30
se to
nc 50%
e in
of those
co with
ug all of
h. them8,
Th 10-12
e
pr (Table
ob 2).
abiClinic
lit al
y predic
of tion
po rules
sitibased
ve on
res these
ult criteri
s a have
of been
a valida
thr ted in
oatboth
culadults
tur and
e childr
or en to
a help
ra identif
pi y
d patien
antts in
igewhom
n- evalua
dettion
ect with a
io throat
n cultur
tes e or
t rapid
ra antige
ng nes detect
fro ion
m test is
3 warra
% nted.1
or

For

exam
ple, in
the
absence
of
particula
r
risk
factors,
such as
known
exposure
to
a
person
with
streptoco
ccal
pharyngi
tis or a
history
of acute
rheumati
c fever
or
rheumati
c heart
disease,
a throat
culture
or rapid
antigendetection
test
would
not be
indicated
in
a
patient
meeting
only one
or none
of
the
criteria
listed
above.
Anot
her
consider
ation in
deciding
whether
to
perform
a throat
culture
or rapid
antigendetection
test
is
the fact
that
certain

pe during
rsowinter
ns month
ares in
as appro
y ximat
m ely
pt 10%
o of
m school
ati -age
c childr
caren
rie and
rs less
of freque
S. ntly in
py perso
og ns in
en other
es age
. group
Th s.
e Carria
or ge can
ga persist
nis for
m weeks
ca or
n month
be s and
culis
tur associ
ed ated
fro with a
m very
thelow
ph risk of
ar suppu
yn rative
x or
in nonsu
theppurat
ab ive
se sequel
nc ae or
e of
of trans
sy missio
m n to
p others
to .
ms There
or fore,
sig in the
ns absen
of ce of
inf sugge
ect stive
io clinic
n al

findings,
a
positive
culture
or rapid
anti gendetection
test
is
likely to
reflect
incidenta
l
carriage
of
S.
pyogene
s.

13,14

Yersinianpestis

T Mycoplasma pneumoniae
s
a
pneumoniae
b Chlamydophila
i
l Chlamydophila
psittaci
s
e
1
o
.
I LAB
f
n ORAT
f
ORY
s
e
c TEST t
ti S
r
oB
e
u
e
p
s
t
Cc
aa
o
uu
c
s
s
o
e
c
se
o
c
ft
a
A
l
ch
ue
t
p
ep
h
P
r
a
h
ae
r
rs
y
y
e
n
n
g
gn
it t
i
i a
t
s
t
i
.

o
Organism
n
Viruses

s
h
Rhinovirus
i
o
Coronavirus
s
u
Adenovirusl
n
d
Influenza
virus
o
Parainfluenza
virus
n
b
Coxsackievirus
s
e
Herpes
simplex virus
p
EpsteinBarr
e
b virus
c
a
Cytomegalovirus
i
s
Human immunodeficiency
virus
f
e
Bacteria
i
d
Group
c A streptococci
Group
C and
,
o group G streptococci
Mixed anaerobes
n
t
h
Fusobacterium
t necrophorum
e
h
Arcanobacterium
haemolyticum
e
d
Neisseria
gonorrhoeae
i
Treponemarpallidum
e
Francisella tularensis
s
Corynebacterium
diphtheriae
a
u
Yersinia
enterocolitica
g
l

t
s t
h
o r
f o
a
a t
s
p
e
c
i
f
i
c

c
u
l
t
u
r
e

o
t r
e
s a
t
r
t a
o p
i
d d
e
t a
e n
c t
t i
g
t e
h n
e d
p e
r t
e e
s c
e t
n i
c o
e n
o t
f e
s
t t
h
e o
f
o
r a
g
a t
n h
i r
s o
m a
: t
a s

w
a
b
s
p
e
c
i
m
e
n
.
S
w
a
b
b
i
n
g
t
h
e
p
o
s
t
e
r
i
o
r
p
h
a
r
y
n
x
a
n
d
t
o
n
s
i
l
s
a
n
d
n
o

t y
t o
h f
e
b
t o
o t
n h
g
u t
e h
, e
l
i
p
s
,

c
u
l
t
u
r
o e
r
a
b n
u d
c
c r
a a
l p
i
m d
u
- a
n
c t
o i
s g
a e
n
i n d
c e
r t
e e
a c
s t
e i
s o
n
t
h t
e e
s
s t
e .
n 1
s 5
i
t
i M
v e
i a
t s

u
r
e
m
e
n
t
o
f
s
e
r
u
m
a
n
t
i
b
o
d
i
e
s
t
o
s
t
r
e
p
t
o
l
y
s
i
n
O
o
r
D
N
a
s
e
B
,
a
l
t
h
o

u o
g n
h
t
u o
s
e p
f r
u o
l v
i
f d
o e
r
s
r u
e p
t p
r o
o r
s t
p
e f
c o
t r
i
v t
e h
e
d
i d
a i
g a
n g
o n
s o
i s
s i
s
o
f o
f
s
t a
r c
e u
p t
t e
o
c r
o h
c e
c u
a m
l a
t
i i
n c
f
e f
c e
t v
i e

r
o
r
p
o
s
t
s
t
r
e
p
t
o
c
o
c
c
a
l
g
l
o
m
e
r
u
l
o
n
e
p
h
r
i
t
i
s
,
i
s
n
o
t
h
e
l
p
f
u
l
i
n

t h

N ENGL J MED 364;7 NEJM.ORG FEBRUARY 17, 2011

.or 15. uses s

TheNew
g
For withou Medi
England
on pers t
cal
Journalof
O
onalpermis Socie
Medicine
ct
use sion. ty.
Downloadedfrom
ob onl Copyri All
n
er y. ght rights
e
14 No 2011 reser
j
,
otheMassa ved.
m
20 r chusett

T h e NE W ENGL A ND JOUR NA L o f MEDICINE

available for 1
or 2 days, rapid
antigendetection tests
have
been
developed
to
detect
S.
pyogenes
di
rectly
from
throat swabs,
generally
within
min

of
rapid
antigendetection tests
Table 2.
Clinical
is
95%
or
Scoring
greater,
and
System and
thus a positive
Likelihood
result can be
considered to
of
be
definitive
Positive
and to obviate
Throat
Culture
the need for
for Group
culture. A rapid
A
16
utes.
These antigenStreptoco
detection test is
ccal
tests are based
less sensitive
Pharyngit
on
acid
than cul ture, so
is.*
extraction
of
most guidelines
cell-wall
Criteria
recommend
carbohydrate
Fever (temperature
>38C)
obtaining
a
antigen
and
Absence of cough
throat culture if
detection of the
the
rapid
Swollen, tender anterior
antigen cervical
with thenodes
antigenTonsillar swellinguse
or exudate
of
a
detection test is
specific
Age
negative.
An
3 to <15 yr antibody.
alternative
15 to <45 yr
approach has
45 yr
been the rapid
* The information iden tification
is adapted from of S. pyogenes
10
McIsaac et al.
specific DNA
sequences by
1
A
score of 0 or a means
of
negative score hybridization
is associated
with a risk of 1 with a DNA
probe or by
to 2.5%, 1
point is
means of a realassociated with
time
a risk of 5 to
polymerase10%, 2 points
is associated
chain-reac tion
with a risk of
assay. A wide
11 to 17%,
of
3
points
isrange
associated withsensitivity
a risk of 28 to(generally, 70
35%, and
4 or more pointsto 90%) has
is
associatedbeen
reported
with a risk of 51for
currently
to 53%.
avail able rapid
antigenmanagement ofdetection tests,
and the mea
pharyngitis,
since titers dosured
not begin tosensitivity has
increase until 7been shown to
to 14 days afterdepend on the
clinical
the onset of
likelihood
of
infection,
streptococcal
reaching a peak
infection in the
in 3 to 4 weeks.
test
Because the
17,18
results of throatpopulation.
cultures are notThe specificity

question
isthat
included
such
whether it isnine
worthwhile tostudies
pursue
di(involving 6702
agnostic testingpatients)
that
and to offershowed
administra
tion
antibiotic
various
treatment
forof
regimens
of
suspected
or
intramuscular
confirmed
peni cillin was
cases. Although
associated with
post
an
80%
streptococcal reduction in the
glomerulonephriincidence
of
tis does notacute rheumatic
appear to befever,
as
prevented
bycompared with
antibiotic
no
antibiotic
treatment
oftreatment
strepto coccal(relative risk,
0.20;
95%
pharyngitis,
several
otherconfidence
potential beneinterval [CI],
22

fits have been0.11 to 0.36).

suggested
to Antibiotic
justify
therapy
also
reduces the risk
treatment.
of sup purative
Studies
complications
largely
of streptococcal
involving
A
military recruitsinfection.
in the 1950sCochrane
of
have shown thatreview
randomized,
antibiotic
placebo-con
treatment
trials
reduces the risktrolled
of subsequentshowed
that
development ofantibiotic
acute rheumatictherapy
sig
7,19-21
nificantly
fever.
In
the
general, thesereduced
risks
of
acute
trials involved
otitis media (in
study-drug
11
studies;
assignment
relative
risk,
based
on
0.30;
95%
CI,
military record
0.15
to
0.58)
number (rather
than
trueand
randomization) peritonsillar
and were notabscess (in 8
studies;
rela
consistently
tive
risk,
0.15;
placebocontrolled, nor95% CI, 0.05 to
were they fully0.47).23
blinded. Despite Without
these
treatment,
limitations,
astreptococcal
meta-analysis pharyngitis is
RATION TIC
TREAT
ALE
MENT
FOR
ANTIBIO Since

associated with
persistence of
positive throat
cultures for up
to 6 weeks in
50%
of
24
patients.
In
contrast,
treatment with
an
active
antibiotic
results
in
negative throat
cultures within
24 hours in
more than 80%
25,26
of patients.
It is recom
mended
that
children receive
treatment
for
strep tococcal
pharyngitis for
24 hours before
they return to
school because
shorter
intervals are as
sociated with a
higher rate of
positive
27
cultures.
Antibiotic
therapy
also
reduces
the
duration
of
streptococcal
symptoms. In
controlled
trials, the rates
of fever and
sore throat were
significantly
lower at 24
hours
among
patients treated
with antibiotics
than
among
patients
who
received
pla
6,7,25,26

cebo.
Antibiotics may
be less effective
in ameliorating
symptoms
if
treatment
is
delayed.

APPROACHES
TO DIAGNOSIS
AND
TREATMENT

streptoc selfoccal limited

pharyng illness
itis is a in the

vast
majority
of cases,
a

the ng
t
of prevent
reasonab In
1950s
reason streptoc acute
le
and
1960s,
the most
compelli

for
occal
rheumati
antibioti pharyngi c fever.
c
tis was
treatmen to

October14,2015.
permission.
All
Forpersonaluse
Copyright2011rights
RG
TheNewEnglandJournalofMedicine
only.Noother
Massachusetts reserve
650 FEBRU
Downloadedfromnejm.orgon
N ENGL ARY
useswithout
MedicalSociety. d.
364;7
NEJM.O

J MED

17,

2011

CLINICAL PRACTICE

ing
whethe
Alt r the
ho traditio
ug n
al
h approa
hig ch to
h the
rat diagno
es sis and
per treatm
sistent of
in strepto
sevcoccal
era pharyn
l gitis is
are still
as approp
of riate in
the such
wo setting
rld 28
s.
,
the In
inc this
ide context
nc ,
e several
of decisio
ac n
ute analyse
rhe s have
um compar
ati ed the
c costfev effectiv
er eness
in of
de various
vel strate
op
gies for
ed
diagno
co
unt sis and
rie treatme
s nt.
hasThese
de strategi
cli es
ne include
d antibiot
dra ic
ma treatme
tic nt
all based
y, on the
rai results
sin of
a
g throat
qu culture,
est
no
ion
s treatme
reg nt,
ard treatme
nt

all
patient
s with
sympto
ms,
treatme
nt
based
on the
results
of
a
rapid
antigen
detecti
on test
alone,
treatme
nt
based
on the
results
of
a
rapid
antigen
detecti
on test
plus
culture
in
patient
s with
a nega
tive
rapid
antigen
detecti
on test,
and
treatme
nt
based
on an
algorit
hm of
signs
and
sympto
ms
alone
or in
combin
ation
with
the
selectiv
e use
of
culture,
of rapid

ant alone,
ige culture
n- alone,
det or
ect rapid
ion antigen
test, ordetecti
bot on test
h. plus
On culture
e )
ana conclu
lys ded
is that a
of rapid
fou antigen
r str detecti
ate on test
gie plus
s culture
for was
the most
ma costna effectiv
ge e when
me the
nt costs
of of
ph managi
ary ng
ngi compli
tis cations
in of
chi strepto
ldr coccal
en infectio
(tre n and
at treatme
me nt were
nt include
of d.29 In
all
this
pat
analysi
ien
s,
a
ts
relative
wit
ly low
h
sensitiv
sy
ity
mp
value
to
(55%)
ms
was
,
assigne
rap
d to the
id
rapid
ant
antigen
ige
ndetecti
det
on test,
ect
and the
ion
margin
test

al
benefit
of
culture
decreas
ed with
increas
ing
sensitiv
ity of
the
rapid
antigen
-detec
tion
test.
Anothe
r study
involvi
ng
childre
n,
which
include
d these
four
strategi
es plus
a treat
none
strateg
y and
used a
sensitiv
ity of
80%
for the
rapid
antigen
detecti
on test,
showed
that the
rapid
antigen
detecti
on test
alone
was the
most
costeffectiv
e
approa
30

ch. A
similar
study
involvi
ng
adults

co strateg
ncl y
of
ud treating
ed only
tha patient
t s with
em a
piri positiv
cal e
tre culture
at was the
me least
nt expensi
of ve.
all Howev
sy er,
a
mp rapid
to antigen
ma tic detecti
pat on test
ien plus
ts culture
wa would
s be the
the most
lea costst effectiv
cos e
t- strateg
eff y if the
ect preva
ive lence
str of
ate strepto
gy coccal
an pharyn
d gitis
tha were
t greater
the than
oth 20%.31
er
A
fou
consist
r
ent
str
finding
ate
is that
gie
empiri
s
cal
ha
antibiot
d
ic
si
treatme
mil
nt on
ar
the
cos
basis
tof
eff
sympto
ect
ms
ive
alone
nes
results
s.
in
Th
overus
e

e
of
antibiot
ics,
increas
ed
costs,
and an
increas
ed rate
of side
effects
from
antibiot
ics, as
compar
ed with
other
strategi
es.

TR ed after
EA treatme
TM nt for
EN
T uncom
RE plicate
GI d
M strepto
EN coccal
S

phary

Re n gitis.
co A
m positiv
me e
nd culture
ed after
tre approp
at riate
me treatme
nt nt is of
reg uncerta
im in
ensclinical
are signific
ance if
su
sympto
m
ms and
m
signs
a of
riz pharyn
ed gitis
in have
Ta resolve
ble d.
3. Althou
gh

FO such a
LL result
O
W- could
UP imply
AF failure
TE of
R treatme
TR
nt, it
EA
TM also
EN may
T mean

Re that the
pea patient
t is
a
cul strepto
tur coccal
e iscarrier
not who
ge had an
ner intercu
all rrent
y episode
rec of
om phar
me yngitis
nd caused

by
another
organis
m.
A
rapid
antigen
detecti
on test,
culture,
or both
should
be
perfor
med if
sympto
matic
pharyn
gitis
recurs
after
treatme
nt; if
the
result
is
positiv
e,
re
treatme
nt
is
indicat
ed. If
incomp
lete
adhere
nce to
the
initial
regime
n is a
concer
n,
intram
uscular
benzat
hine
penicill
in may
be
preferr
ed for
retreat
ment.
Recurr
ence
may
also
result
from
reinfe
c tion

fro ab
m specim
a ens
ho from
use househ
hol old
d contact
co s and
nta treatme
ct nt of
wh all
o carriers
is aif
car reinfect
rier ion is
. suspect
Alt ed.
ho Clinda
ug mycin
h and
car cepha
ria lospori
ge ns
is appear
not to be
an more
ind effectiv
ica e than
tio peni
n cillin
for in
tre eradica
at ting
me carriag
nt e, and
in either
mo of
st these
cir agents
cu is
ms preferr
tan ed in
ces this
, situatio
ma n.39,40
ny
S.
ex
pyogen
per
es can
ts
persist
re
for
c
days
om
on
me
toothbr
nd
ushes,
cul
but a
tur
role in
es
reinfect
of
ion has
thr
not
oat
been
proved.
sw
There

is no
convin
cing
eviden
ce that
househ
old
pets are
a
source
of
recurre
nt
strepto
coccal
infectio
n.

A
R
E
A
S
O
F
U
N
C
E
R
T
A
I
N
T
Y
Several
articles
have
suggest
ed that
bacterio
logic
cure
rates
associat
ed with
penicill
in
treatme
nt
of
streptoc
occal
pharyn
gitis
have
decreas
ed
in
recent
decades
and that
cephalo

spo teriolog
rin ic fail
s ure rate
are associat
mo ed with
re penicill
effi in
ca treatme
cio nt
be
us. tween
41,4 the
2 period
Afrom
me 1953 to
ta- 1979
ana and the
lysi period
s offrom
51 1980 to
stu 1993
die (10.5%
s and
sho 12%,
we respecti
d
43
vely).
no
sig A later
nifi metacan analysis
t of 35
diff compar
ere ative
nce trials
in from
the 1970
bac through
1999,

involvi
ng 7125
chil
dren,
showed
a small,
but
signific
ant
differen
ce
in
the
bacteria
l cure
rate
favorin
g
cephalo
sporins
over
penicill
41

in.
Howev
er, as in
the
earlier
study,
there
was no
signific
ant
change
in the
cure
rate

N ENGL J MED 364;7 NEJM.ORG FEBRUARY 17, 2011

or
Fo other Medic
TheNew
g
r uses al
England
on pe without Societ
Journalof
Oc rsopermiss y.All
Medicine
to
nal ion. rights
Downloadedfrom
be us Copyri reserv
n
r
e ght ed.
ej
14, on 2011
m
20 ly. Massac
.
15. Nohusetts

652
Table 3. Recommended
Treatment Regimens for
Group A Streptococcal
Pharyngitis.*

D
r

5 days
Comments
o

.
reservedrightsAll.SocietyMedicalMassachusetts2011CopyrightwithoutusesotherNo.onlyusepersonalFor.201514,Octoberonorg.nejmfromDownloadedMedicineofJournalEngla
ndNewThe

P
e

Or

N
a
C
l
a
l
rr patient P
for 10 idays;
weight 27o kg: 500 mg
h
n
w
two or three
d
s
a
p for 10 days
times m
a day
e
y
ct
c
B
r
i
e
single dose;
u patient
weightn27
m kg: 1.2
million units
,
intramuscularly
as a
7 in
single dose
e
m x
A
g p
m
/ e
k n
for 10 gdays
si or 50 mg/kg
orally /once
v a day to
maximum
d e,
of 1 g oonce
v a day for 10
days
s a
e st
cl
o in
r ic
a al
l e
A
l x
l
y p
w
e
i
t ri
t
h e
h
r n
p
e c
e
e e
n
i
t
c
iBes
i
m t
l
e
l
s e
i
n
v
a i
a
d
d
l
e
a
l
n
y
e
c
r
e
g
t
y
o
C
e

f
o
m
r

a
x
p
for 10 idays
r
m
e
C
u
v
e
m
e

n
10 days
o
A
z

t
i
300 mg/dose for 10 days
o
n

l
l
y
o
n
c
e
a
d
a
y
f
o
r
1
0
d
a
y
s
;
a
l
t
h
o
u
g
h
n
o
t

l
i
n

oxih
cill o
in
or d
va o
rio
us n
pe o
nict
illi
n
h
re
a
gi
m v
en e
s

o
n
c
e
d
a
i
l
y

h
a
s
e
f
f
i
c
a
c
y
i
n
c
h
i
l
d
r
e
n

a
F n
D d
A
- a
a d
p u
p l
r t
o s
v
e s
d i
, m
i
s l
t a
a r
n
d t
a o
r
d t
- h
f a
o t
r
m o
u f
l
a t
t w
i i
o c
n e
a d
m a
o i
x l
i y
c
i a
l m

Ce
p
h
a
l
o
s
p
o
r
i
n
s
c
o
n
s
i
d
e
r
e
d
a
c
c
e
p
t
a
b
l
e
a
l
t
e
r
n
a
t
i
v
e
f
o
r

h
i
s
t
o
r
y
o
f
i
m
m
e
d
i
a
t
e
h
y
p
e
r
s
e
n
s
i
t
i
v
i
t
y
t
o
p
e
n
i
c
i
l
l
i
n
;

f
i
r
s
t
g
e
n
w e
r
p
a
t
i
e
n
t
s

a
t

FD

A
<
8

Or

o
t

T h e NE W ENGL A ND JOUR NA L o f MEDICINE

permission.

1
1

CLINICAL PRACTICE

in the
proport
ass ion of
oci S.
ate pyogen
d es
wit carriers
h in the
pe study
nic populat
illi
44,
ions.
n
45
fro
m Penicill
the in
is
19 less
70s effectiv
to e than
the cephal
19 osporin
90s s
or
. Aclinda
pro mycin
pos in
ed eradica
ex ting
pla asympt
nat omatic
ion carriag
for e of S.
the pyogen
var es.
yin Accord
g ingly,
rat inclusi
es on of a
of larger
bac proport
teri ion of
olo carriers
gic in
a
cur trial
e would
ass result
oci in
a
ate lower
d bacteri
wit ologic
h cure
pe rate. In
nic one
il random
lin ized
tre trial
at compar
me ing
nt cefadro
is xil
the with
var penicill
iati in
in
on chil

dren
with a
positiv
e throat
culture
or
rapid
anti
gendetecti
on test,
overall
rates of
bacteri
ologic
cure
were
94%
and
86%,
respect
ively
(P<0.0
40

1).
Howev
er,
among
patient
s
classifi
ed
clinical
ly (be
fore
analysi
s of the
bacteri
ologic
results)
as
likely
to have
strepto
coccal
pharyn
gitis
(i.e.,
those
with
tender
cervica
l
lympha
denopa
thy,
tonsilla
r
exudat
e,
or
tonsilla
r
petechi

ae were
an classifi
d ed
no clinical
co ly as
ug probabl
h, e
nas carriers
al ,
the
co rate of
n bacteri
ges ologic
tio cure
n, was
or 95% in
dia the
rrh cefadro
ea) xil
, group
the and
re only
wa 73% in
s the
no penicill
sig in
nifi group.
can Sev
t eral
di explan
f ations
fer have
enc been
e propos
in ed for
cur the
e occasio
rat nal
es failure
bet of
we penicill
en in
the treatme
tw nt, but
o data
tre are
at lacking
me to
nt provide
reg support
im for
ens them.
. InPotenti
co al
ntr mecha
ast, nisms
am include
on local
g degrad
ation
pat
of
ien
penicil
ts
lin by
wh
betao

lactam
ases
produc
ed by
other
throat
flora
and the
inhibit
ory
effect
of
penicill
in on
com
peting
flora.
Howev
er, data
in
support
of
either
mecha
nism
are not
conclus
40

ive.
There
is no
evi
dence
that S.
pyogen
es has
becom
e more
resistan
t
to
penicill
in.

GUIDE
LINES
Recom
mendat
ions for
the
evaluat
ion and
treat
ment of
strepto
coccal
pharyn
gitis
have
been
pub
lished
or
endors
ed by

the Society
A of
me Americ
ric a
an (IDSA)
Co 48; and
lle the
ge Americ
of an
Ph Heart
ysi Associ
cia ation
ns Americ
(A an
CP Acade
), my of
the Pediatr
A ics
me (AHA)
ric 49
All
an .
Ac these
ade guideli
my nes
of con
Fa sider it
m reasona
ily ble not
Ph to
ysi perfor
a
cia m
ns throat
(A culture
AF or
P), rapid
an antigen
d the detecti
Ce on test
nte in
rs persons
for who
Dis have
eas none of
e the
Co clinical
ntr feature
ol s
an suggest
d ive of
Pre strepto
ve coccal
nti infectio
on n
(C (fever,
DC tender
46, cervica
)
l
ad
47
; enopat
the hy,
Inf tonsilla
ect r
or
iou pharyn
s geal
Dis swellin
eas g
or
es exu

al
dat criteria
e, describ
an ed
d above.
absThe
en first
ce strateg
of y is to
co treat
ug patient
h). s with
Th a
e positiv
gui e rapid
del antige
ine ns detecti
of on test.
the The
A second
CP strateg
, y is to
the treat
A pa
AF tients
P, who
an meet
d all four
the clinica
C l
D criteria
C withou
en t
dorfurther
se testing
thr and
ee those
alt who
er meet
nat two or
ive three
str clinica
ate l
gie criteria
s and
for have a
ad positiv
ult e rapid
s antige
wit nh detecti
tw on test.
o The
or third
mo strateg
re y is to
of test no
the one
cli and to
nic treat

patient
s who
meet
three
or four
clin
ical
criteria
. The
IDSA
and
AHA
do not
endors
e the
second
and
third
strateg
ies of
the
ACP,
the
AAFP,
and the
CDC
becaus
e these
approa
ches
re sult
in
higher
rates
of
prescri
bing
unnece
ssary
antibio
tics.
All
guideli
nes
recom
mend
penicill
in
orally
or
intram
uscular
ly as
the
preferr
ed
therapy
for
strep
tococca
l

ph the use
ary of
ngi eryth
tis. romyci
Th n
in
e patient
mo s who
re are
rec allergic
ent to
ly penicill
pu in. The
bli AHA
she recom
d mends
A a firstHAgenerat
gui ion
del cepha
ine lospori
s n
in
als patient
o s with
en penicill
dor in
se allergy
on who do
ce- not
dai have
ly immedi
am ate
oxi hypers
cil ensitivi
lin ty
to
as betafirs lactam
t- antibiot
lin ics,
e with
the clinda
rap mycin,
y. azithro
Th my cin,
e or
AC clarithr
P, omycin
the as an
A alternat
AF ive
P, treatme
the nt
CD option.
C, Guideli
an nes in
d some
the Europe
ID an
SA countri
rec es are
om largely
me consist
nd ent

with
these
approa
ches,
wherea
s other
Europe
an
guideli
nes
conside
r strep
tococca
l
pharyn
gitis to
be
a
selflimited
illness
that
does
not
require
a
specifi
c
diagno
sis or
anti
biotic
treatme
nt
except
in
highrisk
patient
s (i.e.,
those
with a
history
of
acute
rheuma
tic
fever
or
rheuma
tic
heart
disease
)
or
severel
y
ill
patient
28

s.
In
contras
t,
guideli
nes

fro ong
in the
m recom
vignett
Ind mende e,
a
ia, d
specifi
wh therapi c
ere es for diagno
the strepto sis
in coccal should
cid phary
be
enc n
determ
e gitis.50 ined
of
by
acu
COperfor
te
NCL
ming a
rhe
USI
throat
um
ONS
culture
ati
ANor
a
c
D rapid
fev
REantige
er
COnre
M detecti
ma
on test
ME
ins
NDwith a
hig
throat
ATI
h,
culture
ON
list
if the
S
intr
rapid
am In
usc patient antige
nula
s with detecti
r
sympt on test
be
oms
is
nza
and
negati
thi
signs
ve, at
ne
sugges least in
pe
tive of childre
nic
strepto n.
illi
coccal Penicil
n
G pharyn lin is
the
firs gitis,
t such as preferr
ed
am the

patient

treat

N ENGL J MED 364;7 NEJM.ORG FEBRUARY 17, 2011

or
Fo other Medic
TheNew
g
r uses al
England
on pe without Societ
Journalof
Oc rsopermiss y.All
Medicine
to
nal ion. rights
Downloadedfrom
be us Copyri reserv
n
r
e ght ed.
ej
14, on 2011
m
20 ly. Massac
.
15. Nohusetts

T h e NE W ENGL A ND JOUR NA L o f MEDICINE

streptococcal
infection.
I
ment, and awould
rec
first-generation ommend
cephalosporin isibuprofen
or
an
acceptableacetaminophen
alternative
for
symp
unless there is atomatic relief
history
ofand
would
immediate
prescribe oral
hypersensitivity penicillin V
to a beta-lactam
anti biotic. In
the patient in
the
case
vignette,
the
pos itive rapid
antigendetection
test
establishes
a
diagnosis
of

for 10 days.
Since the rapid
antigendetection test
is positive, a
throat culture
is not needed
for diag nosis,
nor is one
necessary after
treatment, if
symp
toms
resolve.
No
potential
conflict of interest
relevant to this
article was reported.
Disclosure forms
provided by the
author are available
with the full text of
this
article
at
NEJM.org.

REFERENCES

Pedi atrics

1. Hing E,2008;121:

Hall
MJ,229-34.
Xu
J.
Carap
National
etis
JR,
Hospi tal
Steer AC,
Ambulatory
Mulhollan
Medical
d
EK,
Care
Weber M.
Survey:
The global
2006
burden of
outpatient
group A
department
streptococ
summary.
cal
Hyatts
diseases.
ville, MD:
Lancet
National
Infect Dis
Health
2005;5:68
Statistics
5-94.
Re ports,
Wanna
2008.
maker LW.
Ebell
Perplexity
MH, Smith
and
pre
MA, Barry
cision in
HC, Ives K,
the
Carey M.
diagnosis
The
of
rational
streptococ
clinical
cal
examina
pharyngiti
tion: does
s. Am J
this patient
Dis Child
have strep
1972;124:
throat?
352-8.
JAMA
Brink
2000;284:2
912-8.
WR,
Rammelka
Pfoh E,
mp CH Jr,
Wessels
Den
ny
MR,
FW,
Goldmann
Wannama
D, Lee GM.
ker
LW.
Burden and
Effect of
economic
penicil lin
cost
of
and
group
A
aureomyci
streptococc
n on the
al
natural
pharyngitis.

4.

5.

2.

6.

3.

course ofM physi

streptococ ak cians
cal
in proba
tonsillitis g bility
and
19estima
pharyngiti 81tes for
s. Am J;1 patien
Med
:2 ts with
1951;10:3 39sore
00-8.
- throat
46s:
Denny
. implic
FW,
ations
Wannama for
ker
LW, deci
Hahn EO. sion
Comparati P makin
ve effectsos g.
es
of
JAMA
penicillin, R 1985;
M
au
254:9
reomycin , 25-9.
C
and
terramycin eb
ul McIsa
on
streptoco R ac WJ,
c
calD, Kellne
tonsillitis C r JD,
ol Aufric
and
pharyngiti li ht P,
ns Vanja
s.
Pediatrics M ka A,
1953;11:7- , Low
FaDE.
13.
g Empir
Centor er
ical
RM,
S valida
Witherspo S. tion of
on
JM,T guidel
Dalton HP,he ines
Brody CE,ac for the
Link
K.cu manag
The
ra ement
diagnosis cy of
of
strepof phary
throat inex ngitis
adults inpe in
the
ri childr
emergency en en and
room.
ce adults.
Med Decisd JAMA

7.

9
.

10.

8.

2004
;291:
1587
-95.
[Erra
tum,
JAM
A
2005
;
294:
2700
.]

11.
Bree
se
BB.
A
simpl
e
score
card
for
the
tentat
ive
diagn
osis
of
strept
ococ
cal
phar
yngit
is.
Am J
Dis
Child
1977
;131:
5147.

12.
Kom
aroff
AL,
Pass
TM,
Aron

son
MD,
et al.
The
predic
tion of
strepto
coccal
phary
ngitis
in
adults.
J Gen
Intern
Med
1986;
1:1-7.

13.
Kapla
n EL.
The
group
A
strepto
coccal
upper
respira
tory
tract
carrier
state:
an
enigm
a.
J
Pediat
r
1980;
97:33
7-45.

14.

Kabat

W,

T
Rippe
J,
anz
RR,Seshadri R,
Shulman Shulman
ST.
ST.
Streptococc Performanc
al
e of a rapid
pharyngitis: antigenthe carrierdetection
state,
test
and
definition, throat
and
culture in
managemencommunity
t. Pediatrpediatric
Ann
offices:
1998;27: implication
281-5.
s
for

15.

manageme
F
of
ox
JW,nt
Marcon MJ,pharyn
Bonsu BK.gitis.
Diag nosisPediatrics
2009;123:4
of
streptococca 37-44.
l pharyngitis[Erratum,
by detec tionPediatrics
2009;124:8
of
Streptococc 46.]

19.

us pyogenes
in posteri or
Chamovitz
pharyngeal
R,
versus oral
Catanzaro
cavity
FJ, Stetson
specimens. J
CA,
Clin
Rammelka
Microbiol
mp CH Jr.
2006;44:259
Prevention
3-4.

of
rheumatic
G
erber MA,fever by
Shulman treatment
ST. Rapidof
diag nosisprevious
streptococ
of
pharyngitis cal
caused byinfections.
group
AI.
streptococciEvaluation
.
Clinof
Microbiol benzathine
Rev 2004;penicillin
17:571-80. G. N Engl
J
Med
E
1954;251:
dmonson 466-71.
MB,
Farwell
Denny
KR.
Relation FW,
Wannama
ship
LW,
between theker
Brink WR,
clinical
likelihood Rammelka
of group Amp CH Jr,
streptococc Custer
EA.
Pre
al
pharyngitis vention of
and
therheumatic
sensitivity fever;
of a rapidtreatment
of
the
antigendetection preceding
test in astreptococ
pediatric cic
practice. infection.
Pediatrics J Am Med
Assoc
2005;
115:280-5. 1950;143:
151-3.

16.

17.

20.

18.

T
anz
RR,
Gerber MA,Wannama

21.

ker
LW,ca trolled
Rammelka l doubl
mp CH Jr,pheDenny
ar blind
FW, et al.ynevalua
Prophylaxi gi tion of
s of acutetis clinica
rheumatic : l
fever bypl respon
treatment
se to
ac
of the pre penici
eb
ceding
llin
ostreptococ therap
co
cal
y.
infection n JAMA
with vari 1985;
ous
253:1
amounts
271-4.
of depot
penicillin.
Am J Med Rando
1951;10:6 lph
MF,
73-95.
Gerbe
r MA,
DeMe
Robertson
o KK,
KA,
Wrigh
Volmink
L.
JA, Mayosi t
Effect
BM.
Antibiotics of
for
the antibi
otic
primary
therap
prevention
of
acute y on
the
rheumatic
fever:
a clinica
l
metacourse
analysis.
of
BMC
Cardiovasc strept
ococc
Disord
al
2005;5:11.
phary
ngitis.
Del Mar J
CB,
Pediat
Glasziou
r
PP, Spinks 1985;
AB.
106:8
Antibiotic 70-5.
s for sore
throat.
Snell
Cochrane
Da tabase man
Syst Rev LW,
Stang
2006;4:C
D000023. HJ,
Stang
JM,
Catanzaro Johns
FJ, Stetson on
CA,
DR,
Morris AJ, Kapla
et al. The n EL.
role of the Durati
streptococ on of
cus in the posi
pathogene tive
sis
of throat
rheumatic cultur
fever. Am es for
J
Med group
1954;17:7 A
49-56.
strept
o
cocci
Krober
MS, Bass after
initiati
JW,
on of
Michels
antibi
GN.
otic
Streptococ
therap

26.

22.

23.

27.

24.

25.

y.
Pedia
trics
1993
;91:1
16670.

28.
Matt
hys J,
De
Meye
re M,
van
Driel
ML,
De
Sutte
r A.
Diffe
rence
s
amon
g
intern
a
tional
phary
ngitis
guide
lines:
not
just
ac
adem
ic.
Ann
Fam
Med
2007;
5:436
-43.

29.
Lieu
TA,
Fleis
her
GR,
Schw
artz
JS.
Costeffec
tiven
ess
of
rapid
latex
agglu
ti
natio
n
testin
g and
throa
t
cultu
re for
stre
p
tococ
cal
phar
yngit
is.
Pedia
trics
1990
;85:
246-

56.

30.
Ehrlich
JE,
Demo
poulos
BP,
Daniel
KR Jr,
Ricarte
MC,
Glied
S.
Costeffecti
ve ness
of
treatm
ent
option
s for
preven
tion of
rheum
atic
heart
disease
from
group
A
strepto
coccal
pharyn
gitis in
a
pediatr
ic
popula
tion.
Prev
Med
2002;3
5:2507.

31.
Neune
r JM,
Hamel
MB,
Phillip
s RS,
Bona
K,
Arons
on
MD.
Diagn
osis
and
manag
ement
of
adults
with
phary
ngitis:
a costeffecti
veness
analys
is.
Ann
Intern
Med
2003;
139:11
3-22.

32.
Clegg
HW,

Ryan AG,ennon DR,

Dallas SD,Farrell E,
et
al.Martin
Treatment DR,
of
Stewart
streptococc JM. Onceal
daily
pharyngitis amoxicilli
with once-n versus
daily
twicecompared daily
with twice-penicillin
daily
V in group
amoxicillin:A
betaa
haemolyti
noninferiori c
ty
trial.streptococ
Pediatr
cal
Infect Dis Jpharyngiti
2006;25:76 s.
Arch
1-7.
Dis Child
2008;93:4
L

33.

74-8.

dr CD00
en 4872.
.
Altamimi C
S, Khaliloc Liu X,
A,
hr Shen
Khalaiwi an X,
KA,
e Chang
Milner R,D H, et
Pusic MV,at al.
Al
ab High
Othman as macro
MA. Shorte lide
versus
S resista
standard ys nce in
duration t Strept
antibiotic R ococc
therapy forev us
acute
20pyo
streptococ 09genes
cal
;1 strains
pharyngiti : isolate
s in chil d from

34.

35.

child
ren
with
phar
yngit
is in
Chin
a.
Pedia
tr
Pulm
onol
2009
;44:4
3641.

36.
Tama
yo J,
Prez
-

RG
Downloadedfromnejm.orgon
FEBRU
October14,2015.
ARY
654 17,
Forpersonaluse
N ENGL 2011
only.Noother
J MED
useswithout
364;7
TheNewEnglandJournalofMedicine
NEJM.O

Traller
o E,
Gme
zGarc
s JL,
Als
JI.
Resist
ance
to
macr
o
lides,
clinda
mycin
and
telithr
omyci
n in

ety.All
rights
reserve
d.

CLINICAL PRACTICE
irator
y
Stre disea
ptoc se
occ seaso
us ns.
pyo Clin
gen Infect
es Dis
isol 2004;
ated 39:17
in 94Spai801.

of
grou
p A
stre
ptoc
occi
. J
Pedi
atr
199
1;11
9:12
3-8.

38. 40
. G

n
duri Kim
ng S,
200 Yong
4. JLee
Anti N.
mic Antib
rob iotic
Che resis
mot tance
her and
200 genot
5;56ypic
:780chara
-2. cteris
tics
of
Tgroup
anz A
RR, strept
Shu ococc
lma i
n assoc
ST, iated
Sho with
rtrid acute
ge phary
VD, ngitis
et in
al. Kore
Co a.
mm Micr
unit ob
y- Drug
baseResis
d t
surv 2004;
eilla 10:30
nce 0-5.
in
the
UnitTanz
ed RR,
Stat Ponc
es her
of JR,
mac Cory
roli don
de- KE,
resi Kaba
stan t K,
Yoge
t
pedi v R,
atricShul
pharman
yng ST.
eal Clind
gro amy
up cin
A treat
stre ment
ptoc of
oc chron
ci ic
duri phary
ng 3ngeal
resp car
riage

37
.

39.

erbe
r
MA
,
Tan
z
RR,
Kab
at
W,
et
al.
Pote
ntial
mec
hani
sms
for
failu
re to
erad
i
cate
grou
p A
stre
ptoc
occi
fro
m
the
pha
r
ynx.
Pedi
atric
s
199
9;10
4:91
1-7.

41
. C
asey
JR,
Pich
iche
ro
ME.
Met
aanal
y sis
of
ceph
alos
pori
n
vers
us
peni
cilli

n
treat
ment
of
group
A
strept
ococc
al
tonsi
l

treat
lophment
aryn for
gitis strept
in o
chil cocca
drenl
phary
.
Pedingitis
a
atric:
s revie
200 w.
4; Clin
113: Ther
866 1994;
-82. 16:60
4-20.

42
44.
. PBisno

ichi AL.
cher Are
o cepha
ME, lospo
Cas rins
ey super
JR, i or
Ma to
yes penic
T, etillin
al. for
Penitreat
cilli ment
n of
fail acute
ure strept
in ococc
stre al
ptoc phary
occ ngitis
al ?
ton Clin
sillo Infect
pharDis
yngi 2004;
tis: 38:15
caus35-7.
es
and
rem Shul
edie man
s. ST,
Pe Gerb
diat er
r MA.
Infe So
ct what
Dis s
J wron
200 g
0;19with
:917penic
-23. illin
for
strep
Bthroat
?
lum
Pedia
er
trics
JL,
2004;
Gol
113:1
dfar
816b J.
9.
Met
aanal Coop
ysis er RJ,
in Hoff
the man
eval JR,
uati Bartl
on ett
of JG, et

45.

43
.

46.

al.
Prin
cipl
es
of
appr
opri
ate
anti
bioti
c
use
for
acut
e
phar
yngi
tis
in
adul
ts:
bac
k
grou
nd.
Ann
Inte
rn
Med
200
1;13
4:50
917.

47
. S
now
V,
Mot
turPils
on
C,
Coo
per
RJ,
Hof
fma
n
JR.
Prin
cipl
es
of
appr
opri
ate
an
tibio
tic
use
for
acut
e
phar
yngi
tis
in
adul
ts.
Ann
Inte
rn
Med
200
1;13
4:50
6-8.

48
. B

is
n
o
A
L
,
G
er
b
er
M
A
,
G
w
al
tn
e
y
J
M
J
r,

et al.

Kap Preve
lan ntion
EL, of
Sch rheu
wart matic
z fever
RH. and
Pracdiagn
tice osis
guidand
e treat
line ment
s of
for acute
the Strept
diag o
nosi cocca
s l
and phary
man ngitis:
age a
men scient
t ofific
gro state
up ment
A from
stre the
ptoc Amer
occ ican
al Heart
pharAssoc
yngi iation
tis. Rheu
Clin matic
Infe Fever,
ct Endo
Dis cardit
200 is,
2;35and
:113 Ka
-25. wasak
i

49 Disea
. GseCom

erbe mittee
r
of the
MA, Coun
Balt cil on
imor Cardi
e ovasc
RS, ular
Eato Disea
n se in
CB, the

You
ng,
the
Inter
disci
plin
ary
Cou
ncil
on
Fun
c
tion
al
Gen
omi
cs
and
Tran
slati
onal
Biol
o gy,
and
the
Inter
disci
plin
ary
Cou
ncil
on
Qual
ity
of
Care
and
Outc
ome
s
Rese
arch
:
endo
rsed
by
the
Ame
rica
n
Aca
dem
y of
Pe
diatr
ics.

n
a
o b r
i
w e t
s
g i
s
a i c
u
v n l
e
a n e
i i
o
l n p
f
a g u
b
b
t
l wl
h
e i i
e
t s
a h h
J
t
e
o
t d
u
N h
r
E e i
n
J
n
JOURNAL
a
M f
NEJM
l
. i J
E
o r a
v
i
r s n
e
s
g t u
r
,
a

Circul
ation
2009;
119:1
54151.

50.
Saxe
na A,
Kum
ar
RK,
Gera
RP,
Rad
hakri
shnan
S,
Mish
ra S,
Ahm
ed Z.
Con
sensu
s
guide
lines
on
pedia
tric
acute
rheu
matic
fever
and
rheu
matic
heart
dis
ease.
India
n
Pedia
tr
2008;
45:56
5-73.
Copyri
ght
2011
Massa
chuset
ts
Medic
al
Societ
y.

r s
y
o
1 f
8
1 c
2 o
. n
t
Te
h n
e t
s
e
n i
t s
i
r e
e a
s
a y
r
c a
h n
i d
v
e a
v
i a
s i
l
f a
u b
l l
l e
y
t
s o
e
a a
r l
c l
h .
a
b I
l n
e d
, i
v
a i
n d
d u
a
b l
r
o s
wu
s b
i s
n c
g r
i
o b
f e
r
t s
i
t a
l r
e e
s
e
a n
n t
d i
t
t l
a e
b d
l
e t

o
f
r
e
e
2
4
h
o
u
r
a
c
c
e
s
s
t
o
5
0
a
r
c
h
i
v
e
a
r
t
i
c
l
e
s
p
e
r
y
e
a
r
.
A
c
c
e
s
s
t
o
c
o
n
t
e
n
t
i
n
t
h
e
a

r
c
h
i
v
e
i
s

y
i
n
s
t
i
t
u
t
i
o
n
a
l

a
v
a
i
l
a
b s
l u
e b
s
o c
n r
i
a p
t
p i
e o
r n
- s
a .
r
t
i
c
l
e
b
a
s
i
s
a
n
d
i
s
a
l
s
o
b
e
i
n
g
p
r
o
v
i
d
e
d
t
h
r
o
u
g
h
m
a
n

N ENGL J MED 364;7 NEJM.ORG FEBRUARY 17, 2011

o r luse Mass
TheNew
r F only. achus
England
g 1 o No
etts
Journalof
o 4 rother Medi
Medicine
n , p uses cal
Downloadedfrom
O e without Socie
n
c 2 r permissi ty.
e
t 0 s on.
All
j
o 1 o Copyrig rights
m
b 5 n ht reserv
.
e . a 2011 ed.