l’entérocolite ulcéro-nécrosante...results (1) description of cases and risk factors •106...
TRANSCRIPT
J. NEU, NEJM 2011
L’entérocolite ulcéro-nécrosante : point de vue de l’épidémiologiste
J. NEU, NEJM 2011
American Journal of Clinical Nutrition, 2017 * soutien de Nestlé pour le recueil des selles
EPIFLORE* (ANR) CLOSNEC (ANR)
Included preterm infants with gestational age between 24 and 31weeks hospitalized in NICU
n= 3658
Preterm infants alive at day 7 with known information on Necrotizing enterocolitis
N=3151
Without information about Necrotizing enterocolitis
N=59
Infants with Necrotizing enterocolitis
> stade II of Bell
N=106
With spontaneous intestinal perforation
N=54
Deceased before day 7 N=167 dont 3 NEC et 2 perforations
32 without information
Preterm infants alive at day 7
n= 3491
Infants without Necrotizing enterocolitis
> stade II of Bell
N= 3045
Preterm infants alive at day 7 with known information on Necrotizing enterocolitis
N=3378
Hospitalized in small units with less 10 infants enrolled in the EPIPAGE II cohort N=227
Results (1) Description of cases and risk factors
• 106 necrotizing enterocolitis – 62 Bell stage II
– 44 Bell stage III whose 20 treated by surgical intervention.
– Rate of NEC > Bell stage II according to gestational age: • 24-26 weeks : 4.7 % ( 3.3 – 6.7) p<0.001
• 27-29 weeks : 4.0 % ( 3.0 – 5.2)
• 30-31 weeks : 4.0 % ( 1.5 – 3.1)
Nom
brede
CAS
0
5
10
15
20
25
30
W2 W3 W4 W5 W6 W7 W8 W9 W10W11W12>W12
Ageaumomentdel’ECUN(semaines)Post natal age at time of NEC (weeks)
Nombrede
CAS
Agepostmenstruelaumomentdel’ECUN(semaines)
0
2
4
6
8
10
12
14
16
18
27 28 29 30 31 32 33 34 35 36 37 39
Nu
mb
er o
f ca
ses
of
of
NEC
Post menstrual age at time of NEC (weeks)
IMMATURITE
GENETIC
ISCHEMIE / ANOXIE
Risk Factors for NEC, at birth
N ORa 95% Confidence
interval p
GA: 30-31 weeks 1295 1
GA: 27-29 weeks 1224 2.0 1.2 3.2 0.002
GA: 24-26 weeks 632 2.4 1.401 4.181 0.006
Birth weight Z-score 3151 0.8 0.621 0.909 0.003
Female 1499 0.7 0.494 1.091 0.126
APGAR score >6 at 5 min 2446 1
APGAR score not known at 5 min 168 0.6 0.2 1.8 0.430
APGAR score <7 at 5 min 537 1.7 1.1 2.6 0.028
Multiple pregnancy 1017 1.2 0.8 1.8 0.320
Risk Factors for NEC, during the first week n ORa 95% Confidence interval p
RDS 1.7 1.0 2.8 0.042
Hemodynamic treatment during first week • No Hemodynamic Treatment 2698 1
• volume expansion 64 5.7 2.4 13.5 0.001
• Volume expansion and corticosteroids 55 4,312 1.6 12.0 0.005
• Volume expansion and catecholamines 118 11.1 6.1 20.1 0.001
• Catecholamines 129 1.2 0.4 3.4 0.779
• Corticosteroids 13 2.9 0.3 24.7 0.337
• Corticosteroids and catecholamines 53 5.9 2.3 15.0 0.001
Sedation/analgesia during the first week • No sedation/analgesia treatment 2097 1
• Morphin 199 0.4 0.2 0.9 0,024
• Fentanyl 146 1.0 0.4 2.4 0,956
• Surfentanyl 562 0.5 0.3 0.9 0,022
• Ketamine 35 1.5 0.3 6.8 0,640
• Midazolam 89 0.5 0.1 2.2 0,383
• Other treatments* 23 6.4 1.9 21.6 0,003
Instestinal transit during first week
• Good transit 1923 1 • Not known 197 0,22 0,03 1,633 0,139
• Bad transit 1031 2,137 1,382 3,302 0,001
Risk Factors for NEC, during the first week n ORa 95% Confidence interval p
RDS 1.7 1.0 2.8 0.042
Hemodynamic treatment during first week • No Hemodynamic Treatment 2698 1
• volume expansion 64 5.7 2.4 13.5 0.001
• Volume expansion and corticosteroids 55 4,312 1.6 12.0 0.005
• Volume expansion and catecholamines 118 11.1 6.1 20.1 0.001
• Catecholamines 129 1.2 0.4 3.4 0.779
• Corticosteroids 13 2.9 0.3 24.7 0.337
• Corticosteroids and catecholamines 53 5.9 2.3 15.0 0.001
Sedation/analgesia during the first week • No sedation/analgesia treatment 2097 1
• Morphin 199 0.4 0.2 0.9 0,024
• Fentanyl 146 1.0 0.4 2.4 0,956
• Surfentanyl 562 0.5 0.3 0.9 0,022
• Ketamine 35 1.5 0.3 6.8 0,640
• Midazolam 89 0.5 0.1 2.2 0,383
• Other treatments* 23 6.4 1.9 21.6 0,003
Instestinal transit during first week
• Good transit 1923 1 • Not known 197 0,22 0,03 1,633 0,139
• Bad transit 1031 2,137 1,382 3,302 0,001
CONCEPT du deuxiéme cerveau
MICROBIOTE
IMMATURITE
GENETIC
PRATIQUES DES UNITES
ISCHEMIE / ANOXIE
Risk Factors for NEC, during the first week n ORa 95% Confidence interval p
RDS 1.7 1.0 2.8 0.042
Hemodynamic treatment during first week • No Hemodynamic Treatment 2698 1
• volume expansion 64 5.7 2.4 13.5 0.001
• Volume expansion and corticosteroids 55 4,312 1.6 12.0 0.005
• Volume expansion and catecholamines 118 11.1 6.1 20.1 0.001
• Catecholamines 129 1.2 0.4 3.4 0.779
• Corticosteroids 13 2.9 0.3 24.7 0.337
• Corticosteroids and catecholamines 53 5.9 2.3 15.0 0.001
Sedation/analgesia during the first week • No sedation/analgesia treatment 2097 1
• Morphin 199 0.4 0.2 0.9 0,024
• Fentanyl 146 1.0 0.4 2.4 0,956
• Surfentanyl 562 0.5 0.3 0.9 0,022
• Ketamine 35 1.5 0.3 6.8 0,640
• Midazolam 89 0.5 0.1 2.2 0,383
• Other treatments* 23 6.4 1.9 21.6 0,003
Instestinal transit during first week
• Good transit 1923 1 • Not known 197 0,22 0,03 1,633 0,139
• Bad transit 1031 2,137 1,382 3,302 0,001
*Others analgesia/ treatment
• 7 infants received analgesia by sevofluran (Inhalational anaesthetic ) during the first week (day of birth =2, day 1=2,day2=4). All theses infants were hospitalized in one NICU
• 4/7 developped NEC, 1 during Week2, 1 during Week3, 1 during week4, 1 during Week5.
• Adjusted OR= 24.3 (4.1-145)
*Others analgesia/ treatment
• 65 infants in live at day7 were hospitalized in this unit using sevofluran :
– 24-26weeks : n=2 NEC / 8 infants 1NEC/ 2 sevofluran
– 27-29weeks : n=8 NEC / 34 infants 3NEC/ 5 sevofluran
– 30-31weeks : n=4 NEC /23 infants No sevofluran
10 NEC/48 ( 17.2%) infants without sevofluran versus 4 NEC/7 (57.1% ) infants receving Sevofluran before Day7
P=0.034 Fisher exact test
MICROBIOTE
IMATURITE
GENETICc
ISCHEMIE / ANOXIE
PRATIQUES DES UNITES
n= number of infants, N= number of neonatal intensive care units (NICUs)
24-26 weeks` 27-29 weeks 30-31 weeks
n= number of infants, N= number of neonatal intensive care units (NICUs)
24-26 weeks` 27-29 weeks 30-31 weeks
MICROBIOTE
IMMATURITE
ISCHEMIE / ANOXIE
PRATIQUES DES UNITES
Phyla composition between NEC and healthy preterm infants
0
25
50
75
100
App1 App2 App3 NEC
Bacteroidetes
Actinobacteria
Proteobacteria
Firmicutes
Healthy
NEC NEC
Firmicutes
Proteobacteria
Actinobacteria
Bacteroidetes *
META ANALYSE
Differential bacterial species (delta % are presented (% in NEC - % in healthy controls)
-6 -4 -2 0 2 4 6
Clostridium butyricum; YE48; AY442812
marine bacterium CS-2; EF040537
Clostridium neonatale; LCDC no.99-A-005; AF275949
bacterium NLAE-zl-C493; JQ608194
Morganella morganii; SSCT63; AB210972
Gram-negative bacterium cL10-2b-4; AY239469
Gram-negative bacterium cTPY-13; AY239461
Staphylococcus haemolyticus JCSC1435; AP006716
Enterococcus sp. AK61; AY098492
Proteus sp. VBC3; JX089650
Escherichia coli; AK108; AY098487
Bifidobacterium breve; JCM 1273; AF491832
Peptoniphilus gorbachii (T); WAL 10418; DQ911241
Streptococcus agalactiae; GY102; HQ658086
Citrobacter sp. DW38; AJ534867
Desulfotomaculum guttoideum (T); DSM 4024; Y11568
Klebsiella sp. YHB; AY517552
Salmonella sp. AHL 6; AY379978
Haemophilus parainfluenzae (T); CCUG 12836; AY362908
Klebsiella sp. D-D; DQ278420
Enterococcus faecalis; Y18293
Staphylococcus sp. CMJ1-7; KC119123
Delta % NEC vs Healthy
Genus
Species
CLOSNEC : analyse des phenotypes des Clostridium Neonatale et Butyricum
Sophia Schönherr-Hellec, Julio Aires dans le laboratoire de MJ Butel
MICROBIOTE
IMMATURITE
GENETIC
PRATIQUES DES UNITES
ISCHEMIE / ANOXIE
?
EPIFLORE
• Analyses microbiotes faites 458 -> 6 clusters?
• Relation
NICU
PRATIQUES • Allaitement • Peau à peau • Ventilation
M I C R O B I O T E
Hôte • AG • Z score Poids • Transit
MICROBIOTE
IMMATURITE
GENETIC
ISCHEMIE / ANOXIE
PRATIQUES DES UNITES
Defects in genes that inhibit intestinal innate immune signaling can contribute to NEC. Adequately powered studies are needed to study the impact of SIGIRR variants and variant–clinical variable interactions in the causation of NEC.
PEDIATRICS 2014
MICROBIOTE
GENETIC
PRATIQUES DES UNITES
BIOMARKER
IMMATURITE
ISCHEMIE / ANOXIE
NEU, NEONATALOGY 2013
PROTEINOME
NEU, NEONATALOGY 2013
MICROBIOTE
GENETIC
PRATIQUES DES UNITES
BIOMARKER
IMMATURITE
ISCHEMIE / ANOXIE
MERCI DE VOTRE ATTENTION
?
?
• les Firmicutes (on y trouve notamment les genres : Ruminococcus, Clostridium, Lactobacillus (dont plusieurs souches utilisées comme probiotiques), et des Eubacterium, Faecalibacterium et Roseburia (productrices de butyrate) ;
• les Bacteroidetes (dans ce groupe, les Bacteroides, Prevotella et Xylanibacter dégradent une grande variété de molécules complexes de glycanes) ;
• les Actinobacteria (ce groupe inclut les genres Collinsella et Bifidobacterium (dont certaines souches de probiotiques connus) ;
• les Proteobacteria (dont communément des Escherichia (de la famille des Enterobacteriaceae et des bactéries du groupe Desulfovibrio (bactéries réductrices de soufre) ;
ISCHEMIE / ANOXIE
Altered microvasculature responses Inflamation
VEGF
Altered metabolome Altered metabolome
NEONATALOGY 2013
PROTEINOME
NEC Cases
Control matched on first propensity score (not including nutritional and antibiotic strategy) Control matched on second propensity score and hospitalizes in the same NICU Control matched on third propensity ( including nutritional and antibiotic strategy)
P<0.001
P<0.001
Neonatal characteristics Cases n=15 Controls=53 p Gestational age (weeks) 27.3 1.8 28.2 1.7 0.08
Post natal age (days) 27.9 17.8 24.8 15.0 0.50
Birth weight Z-score 0.16 1.1 -0.44 1.0 0.045
Bad intestinal transit during first 7 days 11 73.3 25 47.2 0.07
APGAR score <7 at 5 minutes 3 20.0 10 18.9 0.83
NICU profiles concerning enteral feeding
slower 2 13.3 8 15.0 0.85
intermediate 11 73.4 35 66.7
faster 2 13.3 10 19.3
NCIU breastfeeding policy
lesss favorable 3 20.0 11 20.8 0.74
intermediate 12 80.0 40 75.5
more favorable 0 0 2 3.8
Family composition between NEC and healthy preterm infants
Healthy
NEC
0
25
50
75
100
App1 App2 App3 NEC
Erysipelotrichaceae
Bacteroidaceae
Corynebacteriaceae
Lactobacillaceae
Peptostreptococcaceae
Bifidobacteriaceae
Clostridiales_Incertae Sedis XI
Porphyromonadaceae
Streptococcaceae
Lachnospiraceae
Pasteurellaceae
Clostridiaceae 1
Enterococcaceae
Staphylococcaceae
Enterobacteriaceae
Healthy Staphylococcus Enterococcus Klebsiella Clostridium sensu stricto Escherichia/ Shigella unclassified_Enterobacteriaceae Citrobacter Haemophilus Enterobacter Clostridium XlVa Streptococcus Peptoniphilus Bifidobacterium Morganella unclassified_Pasteurellaceae Clostridium XI Lactobacillus Barnesiella
Repartition of dominant genera in the overall cohort
IN NEC, increased proportions of Clostridium sensu stricto, Escherichia/Shigella and Morganella (p=0,054) genera but non significant.
Healthy NEC
Prevalence of selected genera
0
25
50
75
100
Stap
hyloco
ccus
Entero
cocc
us
Entero
bacte
riace
ae
Clostr
idium
sens
u str
icto
Bacte
roides
Bifid
obac
teriu
m
Lacto
bacil
lus
Cases Control matched on first propensity score (not including nutritional and antibiotic strategy) Control matched on first propensity score and hospitalizes in the same NICU Control matched on second propensity ( including nutritional and antibiotic strategy)
% P=0.06
Significantly differentially represented bacterial species
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
Esch
erich
ia coli C
FT07
3; A
E014
075
bacte
rium N
LAE-zl-
P257
; JQ60
6938
Stap
hyloco
ccus aureu
s; SU
-BIO
2; JN83
1369
swine
feca
l bac
teriu
m RF3
D-Cel1
; FJ7
5382
5
Bacte
roides sp
. Smar
lab 33
0299
6; A
Y643
081
Esch
erich
ia coli; AF0
7603
7
Stap
hyloco
ccus aureu
s 08B
A0217
6; C
P003
808
Proteu
s mira
bilis; M
1; H
Q25
9934
Esch
erich
ia coli; mothe
r C4;
10C
4; A
M15
7436
Esch
erich
ia co
li; W
D01; E
F620
925
Esch
erich
ia coli; mothe
r C3;
9C3;
AM15
7425
Stap
hyloco
ccus aureu
s; GSA
-44;
JN31
5148
alph
a pr
oteo
bacterium
PI_GH1.
1.B2
; AY1
6203
8
Stap
hyloco
ccus aureu
s; DM
H 7; H
M55
9237
Stap
hyloco
ccus epide
rmidis;
19N
3; H
Q28
4959
Sphin
gobium
yan
oiku
yae; W
1BR1
5; JF4
5993
2
Shigella dysen
teria
e; X
8068
0
Entero
bacter sp
. E4M
-P; G
Q47
8269
Stap
hyloco
ccus sp
. CUL-
LABL
G2X
2; H
Q84
1047
Stap
hyloco
ccus sp
. U13
69-1
0112
2-SW
168;
JQ08
2147
bacterium
OC18
(201
1); H
Q17
8988
App1 App2 App3 NEC
P<0,05 for all App1 +2 +3 versus NEC
App1 App2 App3 NEC
010
20
30
40
50
60
OTU denovo6512
Extrapolation of OTU J Neu (Mai et al, Plos One 2011) representation in our data
Sequencing V1-V3 for data J Neu while V3-V4 for us. 1- Blast OTU_Neu Klebsiella pneumoniae strain B16 (98% coverage 95%) 2- Get full 16S of K.pneumoniae 3- Blast all K. pneumoniae strain B16 full 16S against our OTU representatives 4- e-val 0.0 / 98.8% similarity with denovo6512
The OTU found significantly associated to NEC cases in Mai et al’s paper is not associated to our NEC cases