Otite media acuta con

perforazione timpanica

Paola MarchisioUOSD Pediatria ad Alta Intensità di Cura

Università degli Studi di Milano

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milano

Di chi parliamo?

Infezione prime vie respiratorie

Congestione mucosa vie respiratorie

Disfuzionetuba Eustachio

Accumulo secrezioni nell’orecchio medio

Risalitapatogeni dal nasofaringe

Perforazione spontanea della MT

NORMALITA’

OMAOME

PERFORAZIONE

Complicanza più frequente

10%>90%

GUARIGIONE PERFORAZIONE CRONICA

Incidenza

2,1 2,24,8

6,8

17,2

0

5

10

15

20

Italy UK Spain Germany Sweden

%

LIESE JG et al

Spontaneous tympanic membrane perforation Europe = 7%

OTITE MEDIA ACUTA vera o falsa o immaginata?

ACUTE OTITIS MEDIA

rapid onset of signs and symptoms of acute infection within

the middle ear, with evidence of effusion

IF each and every AOM diagnosisis not accurate

AOM count is wrong

ACUTE OTITIS MEDIA

rapid onset of signs and symptoms of acute infection within

the middle ear, with evidence of effusion

Valutare la potenziale associazione tra i polimorfismi a singolo nucleotide (SNPs) in geni selezionati e l‘otite media acuta ricorrente

Analizzare se le varianti genetiche possano predisporre, o meno, allo sviluppo di casi ricorrenti e complicati, come quelli con perforazione della membrana timpanica (PMT)

Analisi genetica

Per ogni bambino sono stati prelevati 3 ml di sangue intero

Sono stati selezionati 33 geni e 47 loro SNPs (polimorfismi a singolo nucleotide) da ricercare nei campioni ottenuti

Alcuni geni studiati

Gene dbSNP Descrizione HGVS Conseguenze funzionali Posizione (bp) Cr Locus genetico

IFNʏ rs12369470 NC_000012.12:g.68151116T>C Variante downstream 68151116 12 Intergenico

IL10 rs1800896 NG_012088.1:g.3943A>G Variante upstream 2KB 206773552 1 Intergenico

IL1α rs6746923 NC_000002.12:g.112795849A>G Variante upstream 112795849 2 Intergenico

IL1β rs1143627 NG_008851.1:g.4970C>T Variante upstream 2KB 112836810 2 Intergenico

IL8 rs2227306 NG_029889.1:g.5833C>T Variante intronica 73741338 4 Introne

TLR4 rs2737191 NC_000009.12:g.117700437A>G Variante upstream 117700437 9 Intergenico

Sono geni coinvolti nella regolazione del sistema immunitario, nella patogenesi dell'infiammazione e nella regolazione del metabolismo cellulare

Risultati

C/C C/T T/T

14,3%

61,9%

23,8%

16,4%

44,0%39,7%

SNP IL-10 rs1800896

Bambini con solo OMAR

Frequenze genotipiche

OR: 2,33 (95% IC: 1,17-4,77)

A/A A/G G/G

15,5%

41,7% 42,9%

20,7%

54,3%

25,0%

SNP IL-1α rs6746923

Bambini con OMAR e PMT

p=0,02 *

**OR: 0,44 (95% IC: 0,17-1,08)

* OR: 0,45 (95% IC: 0,22-0,89)

p=0,06 **

p=0,01

Conclusioni

Per quanto concerne l’OMAR con perforazione della MT

• Il SNP IL-10 rs1800896CT sembra ridurre il rischio di perforazione della MT

• Il SNP di IL-1α rs6746923AG sembra aumentare il rischio di OMA complicata

• Il SNP di IL-1α rs6746923A potrebbe avere un ruolo nel favorire la perforazione della MT

8,1 8,8

6,7

9,5

0

5

10

15

20

Total uncomplicated AOM only otorrhea mixed

%Spontaneous tympanic membraneperforation and immune deficiency

personal data - 2017

Eziologia

Patogeni in OMA - USA“The Infernal Trio” o “Quartetto”

StreptococcoPneumoniae 32%

StreptococcoPyogenes 5%

Haemophilus Influenzae 22%

Moraxella Catarrhalis 16%

No growth

Haemophilus influenzae

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

others

Moraxella catarrhalis

Isolates in 475 Italin children with acute otitis media [6 m - 12 a]Marchisio P et al. 8th International Symposium on Recent Advances in Otitis Media.

Fort Lauderdale; June 3–7, 2003

timpanocentesi[n: 145]

otorrea[n: 330]

28.3 %

22.8 %

14.5 %

2.7 %

2.7 %

3.4 %

25.6 %

13.6 %

32.7 %

20.9 %

3.3 %

1.2 %

5.1 %

23.0 %

Infection 2013; 41: 629

• prospective, single-center study, Italy

• enrollment for 12 months: May 1, 2015 to April 30,2016

• 177 previously healthy children (6 m – 7 yrs, mean age 3.5)

• 91% vaccinated with conjugate pneumococcal vaccine

• diagnosis of AOM with spontaneous otorrhea:

(a) middle ear effusion + signs of acute inflammation of the

tympanic membrane + acute symptoms and (b) otorrhea

(within 12 hours of spontaneous rupture of TM)

• excluded: tubes, midfacial abnormalities, chronic middle ear conditions, includingchronic perforation, immunodeficiency, antibiotics in the previous 2 weeks, topicaltreatment

• purulent fluid removed and MEE collected close to the perforation using an extra-thin flexible wire swab (Copan eNAT transport and preservation medium, Brescia, Italy).

• bacterial genomic DNA was extracted by clinical specimens by semi-automatic DNA extraction system. The presence of Streptococcus pneumoniae (S.pn) (and itsserotypes) , Haemophilus influenzae (Hi), Moraxella catarrhalis (M.cat), group A beta hemolyticus Streptocccus (GABHS) and Staphylococcus aureus was evaluatedby means of real-time PCR using specific oligos-probe sets. S.pn. cases were serotyped using primers and probes designed on the basis of the GenBankdatabase sequences (www.ncbi.nlm.nih.gov)

0,0% 10,0% 20,0% 30,0% 40,0% 50,0% 60,0%

S. aureus

S. pyogenes

S. pneumoniae

M. Catarrhalis

H. influenzae

11,3%

26,0%

27,1%

35,0%

50,8%

Culture – Italian data 2001 to 2011 Marchisio P et al., Infection, 2013

0,0% 10,0% 20,0% 30,0% 40,0% 50,0% 60,0%

10,7%

17,4%

19,4%

1,1%

51,0%

PCR – Italian data 2015 to 2016 Marchisio P et al., CMI, epub 2017

COMPARISON BETWEEN TIME AND DETECTION METHODS

In half of the cases 2 or more pathogens were identified.Non typeable H.Influenzae was the most frequent pathogen

(70%) in co-infections (M.catarrhalis GAS S.pneumoniae)

27,1

36,9

20,0 23,8

0

20

40

60

80

100

%

all

children

< 24

months

24-59

months

> 60

months

Streptococcus pneumoniae positive cases: age distribution

S. pneumoniae is still one of the main pathogens despite full immunization with

PCV13

0

20

40

60

80

100

all children < 24 m 24-59 m > 60 m

28 3329 30

77

6771 70

%

PCV13 ST non PCV 13 ST Streptococcuspneumoniae

positive cases: PCV13 versus non-

PCV13 serotypes

0

2

4

6

8

10

% p

os

itiv

e c

as

es

4

6B 9V 14

18

C

19

F

23

F 1 3 5

6A

7F

19

A

6C

/D 811

A/D

12

A/B

/F15

A/F

16

F

21

22

A/F

23

A

23

B24

A/B

/F33

F/3

7

35

B

35

F

38

no

nty

p

PCV7 PCV13 non PCV13

A significant

replacement

phenomenon has

developed,

reducing the

potential effect of

PCV13 on AOM

incidence

Terapia

OTITE MEDIA ACUTA - TERAPIA

Non antibiotico ?

Antibiotico subito?

Attesa vigile?

DIAGNOSI CERTA

LATERALITA’ bilaterale monolaterale

SEVERITA’ SINTOMI

grave lieve grave lieve

Età < 6 m. AB AB AB AB

Età 6 – 24 m. AB AB AB AV

Età > 24 m. AB AV AV AV

2010 – LG italiana –

OMA non complicata *

* NO OTORREA, NO RICORRENZA RECENTE, NO COMPLICANZE

AB = antibiotico immediato AV= possibile attesa vigile

2013 – AAP updated guidelines

OTITE MEDIA ACUTA - TERAPIA

Quale molecola?

• Non typeable H.influenzae , which is the most frequently pathogen

associated with biofilm formation, is predominant in spontaneous

otorrhea

• Group A Strep is confirmed to be a main cause of otorrhea, especially

in older children

• M. catharralis seems to be a relevant pathogen

• Co-infections are common , especially in children with recurrent AOM

and especially for NTHi

• The therapeutic approach should be different from that which is

usually reported for uncomplicated AOM, taking into account the

possible formation of biolfim and the presence of betalactamase

producers

Prevenzione

Occurrence of AOM (≥1 episodes) during the 6-months study

period: all children

54,4

82,2

0

20

40

60

80

100

%

influenza vaccine controls

p = 0.004

EFFICACY 33,8%

Marchisio P et al, PIDJ 2009

41,7

79,669,1

85,4

0

20

40

60

80

100

%

non complicated AOM complicated AOM

influenza vaccine controls

p = 0.002

p = NS

EFFICACY 47,6% EFFICACY 19,0%

Marchisio P et al, PIDJ 2009

• The study involved a total of 116 children aged 1 to 5 years witha history of rAOM

• Children were randomized to receive 1.000 IU/day by mouth for4 months or placebo

• The study was conducted double-blind

• Two extra months of follow-up were planned, for a total of 6months

• All the children had to return to the center for a control visit(anamnesis, complete physical examination, pneumaticotoscopy, tympanometry) every month

• A blood sample was obtained from each enrolled child atenrolment and within 2 days after the end of supplementation inorder to determine the serum vitamin D concentration

0.0

00.2

50.5

00.7

51.0

0

0 30 60 90 120 150 180

Time (days after randomisation)

ControlsTreated with vitamin D

complicatedwith othorrea AOM episodes

0.0

00.2

50.5

00.7

51.0

0

0 30 60 90 120 150 180Time (days after randomisation)

Controls

Treated with vitamin D

0.0

00.2

50.5

00.7

51.0

0

0 30 60 90 120 150 180Time (days after randomisation)

Controls

Treated with vitamin D

uncomplicatedAOM episodes

Efficacy of vitamin D3 1000 U/day (Nov through March) in children 1 – 5 yrs old with a history of rAOM

ALL episodes

Marchisio P et al. PIDJ 2013

Reduction

32% (p=0.03)

Is CAM effective in the treatment or

prevention of perforated

acute otitis media?

NO

a) Homepathy NO

b) Echinacea NO

c) Osteopathy NO

d) Propolis YES (29%) in uncomplicated AOM

e) Xylitol YES (9%) (in uncomplicated AOM)

16 studies of long-term antibiotic use (review

published in 2006, updated in 2010)

prevention of 1.5 episodes of AOM per year,

reducing in half the number of AOM episodes

during the period of treatment

PROFILASSI ANTIBIOTICA

Futuro

• periodical monitoring of pneumococcal ST circulation

after introduction of PCV with a defined number of ST is

needed in order to evaluate replacement phenomenon

and the need for new vaccines with greater protective

activity

• evaluation of new systemic treatments (broader

antibiotics to cover H.influenzae)

• assessment of nasopharyngeal microbiota

• easier (and early) identification of children prone to

perforation

Grazie per

l’attenzione! Never look for the

extraordinary, but, on the

contrary, concentrate on the

more prevalent and common

diseases, and try to cure them

These are the diseases you

will most frequently encounter

in your practice”

Emile Ménière

Deuxième Congrés

Otologique Internationale

Milan 1880