Transcript current concepts in otitis media - Connecticut Pediatric Otolaryngology

Current Advances in Otitis Media
Bench to Bedside and Back
Joseph E. Kerschner, MD, FACS, FAAP
[email protected]
Dean and Executive Vice President
Medical College of Wisconsin
Professor, Pediatric Otolaryngology
Children’s Hospital of Wisconsin and Medical College
of Wisconsin
Topics
Guidelines
Antimicrobials
Hearing loss and speech development
Vaccines
Eustachian Tube
Biofilms
Translational research
Pathogen resistance
Host-pathogen interactions
Knowledge Base Check
We are all at different levels
Expert
Very comfortable with all aspects of OM management
Need to learn more
Show of Hands
I have read the AAP (AAO-HNS) guidelines on acute
otitis media (AOM)
There exist more than one set of guidelines
I am not interested in the publication of guidelines
because they do not help with the management of
individual patients
Guideline Quiz
The AAO (AAP) guidelines contain 6 recommendations?
True = Raise Your Hand
2 of these 7 recommendations relate to the use of
antibiotics for AOM? True = Raise Your Hand
The strongest recommendation from the guidelines
relates to how practitioners should use antibiotics to treat
AOM? True = Raise Your Hand
http://pediatrics.aappublications.org/
cgi/reprint/113/5/1451
World-wide = 15 AOM
guidelines
• Australia
• Canada
• South Africa
• USA - 2004
• Europe
AOM Guidelines
Diagnosis
Treatment of pain
Antimicrobial use
Observation option
First-line, second-line therapy
Failure to respond to therapy
Risk factor reduction
Alternative therapy
Diagnosis
Huge problem in otitis media
Impacts treatment – When and If
Has seriously flawed research into this disease
NEJM papers in ABX section
Will be the cornerstone of new concepts in
treatment
Clinical history is a poor predictor
“80% of Dx can be made by history”
Not true for OM
Huge overlap with viral URI
Need diagnostic skills
Diagnosis: US vs. Dutch
Acute onset of signs
and symptoms
Presence of middle ear
effusion (MEE)
Signs or symptoms of
middle ear inflammation
Erythema of the TM
Otalgia clearly referable
to the ear
Pneumatic otoscopy
Tympanometry
Symptoms: otalgia,
otorrhea, fever, or
irritablity and
Signs: red, opaque or
bulging tympanic
membrane or
Difference in redness
right and left tympanic
membrane or
Acute otorrhea
AOM verses OME
Major challenge
OME is more common than AOM and does not
need Rx
May accompany viral URI
May be a residual of a resolved AOM
Signs and symptoms
Acute onset
Distinct erythema
Otalgia
Interfering with normal activity and/or sleep
Asymptomatic purulent otitis
Pain
“The management of AOM should
include an assessment of pain”
If present it should be treated
Only STRONG recommendation from
panel
Present with most AOM
In past – was seen as a peripheral
concern
Treatment of Pain in AOM
Analgesics
Acetaminophen
Ibuprofen
Myringotomy
Topical Agents (Benzocaine)
Little additional benefit
Homeopathic treatments
No controlled studies
Narcotics
Effective
Increased risk profile
Antibiotics – Why do We
Treat?
“George saved his
brother’s life that
day. But he caught a
bad cold which
infected his left ear.
Cost him his hearing
in that ear.”
Antibiotic Usage
Amoxicillin
Still best drug (?)
Efficacy
Safety
Cost
Compliance
Efficacy
90mg/kg/day
Most effective against intermediate and highly
resistant S. pneumoniae (SP)
Vaccines & Antibiotic Usage
Pneumococcal Vaccine – changing story
PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F,
23F) – Introduction
Decrease in SP prevalence
Increase NTHI
Subsequently
Increase in serotypes not covered
Increasing resistance in these
With over 90 serotypes we can expect this to
will be played into the future
PCV13 serotypes (1, 3, 4, 5, 6A, 6B,
7F, 9V, 14, 18C, 19A, 19F, and 23F)
Consider broader spectrum for more
severe illness, recent antibiotic usage,
higher NTHI percentage, daycare
Casey, JR Ped Inf Dis J, 2010
High-dose amoxicillin-clavulanate has
become drug of choice in these settings
Cost
Safety profile
Penicillin (PCN) Allergy
Not type I hypersensitivity to PCN
(urticaria/anaphylaxis)
Cefdinir – drug of choice
Cefuroxime – compliance concerns
Ceftriaxone – compliance concerns
Type I hypersensitivity to PCN
Quinolones
Clindamycin
Macrolides
2nd-Line Therapy
Of 16 FDA approved ABX for OM in children - only 5 have
demonstrated much efficacy against resistant S. pneumo
High dose Amoxicillin - most effective
Cefdinir (Omnicef)
Cefuroxime (Ceftin) (compliance)
IM ceftriaxone (Rocephin) (invasive)
Clindamycin
Quinolones – not approved
Amoxicillin failure
High dose amoxicillin/clavulanate
Amoxicillin/clavulanate failure
3-day parenteral ceftriaxone
Cefdinir
Cefuroxime
PCN allergy – very poor choices for Type I hypersensitivity
Quinolones
Clindamycin
3rd-Line Therapy
Tympanocentesis
We will see these patients ASAP
Significant past history of AOM – consider
tube placement
Dutch Model
Low use of antibiotics
High rate of tympanostomy tube placement
Observation Option
Treatment of OM is the most common reason
for an antibiotic to be prescribed for children
in the US
Began in 1989 in Netherlands
Selective antibiotic therapy
Withhold antibiotic treatment for 48 to 72 hours to
allow for spontaneous resolution of OM
Rationale
Reduce antibiotic “pressure”
Reduce development of resistant organisms
Observation Option
Age
<6 months
6-23 months
>24 months
Severity
Non-severe Disease
T<102°F (39 °C) orally
Mild or no otalgia
Non-toxic appearing
Certainty of Diagnosis
Follow-up and Communication
Observation Option
Age
<6 mos.
Certain AOM
Uncertain AOM
Antibiotics
Antibiotics
Antibiotics if severe
Observe if non-severe
6-23 mos. Antibiotics
24 mos.
Antibiotics if severe
Observe if non-severe
Observe
Rosenfeld R, IJPORL, 2001
This algorithm still will treat most episodes of real
bacterial OM – will help limit treatment of less severe
and episodes that are not “real” OM
Diagnosis is key
Evidence For
Observation Option
Most episodes of OM will resolve without antibiotic
treatment
~80% (Rosenfeld, J Pediatr, 1994)
Between 7-20 children must be treated for each child who
receives a “benefit”
Selective therapy is not equivalent to placebo trials regarding
risks of complications from OM
Allows treatment in cases not spontaneously resolving
Allows treatment before complications arise
Pre-antibiotic era
Significant complications and death
Placebo studies - 17% incidence of mastoiditis (Rudberg, 1954)
AHRQ – Review and agreed that there was not an increase
in suppurative complications
Evidence For
Observation Option
Selective therapy reduces costs, morbidity
associated with antibiotic use and antimicrobial
resistance
Penicillin-resistant Streptococcus pneumoniae in the
Netherlands only 1.1% - (Hermans, J Infect Dis, 1997)
Prescriptions – these are in study populations – real
world?
49% reduction in antibiotic use with no increased adverse
events – (Spiro DM, et al. JAMA. 2006)
Trial of initial versus deferred antibiotics: only 24% of latter
group filled prescription – (Little, et al BMJ 2001)
Observation Option
Evidence ??
Hoberman A, et al NEJM 2011
Excellent study
Examined young children < 2 years
Demonstrated that antibiotics helped regardless of severity
First study to demonstrate this – question – likely will impact
new guidelines with respect to severity
Overall modest impact of antibiotics
Used stringent criteria for diagnosis
This speaks to the need for accurate diagnosis
Real world
But if we are sure about the diagnosis there is a greater
positive impact on treatment
Evidence Against
Observation Option
Lack of rigor in studies demonstrating limited
benefit from antibiotics (Wald, Ped Infect Dis
J, 2003)
Complication rate increased versus universal
antibiotic treatment
Mastoiditis
3.8/100 000 per year in Netherlands
1.2-2 /100 000 per year in higher prescribing
nations (Van Zuijlen, Ped Inf Dis J, 2001)
Evidence Against
Observation Option
Antibiotic treatment is the current standard of care:
Medical-legal issues
Delays symptomatic relief
Days 2-7 pain decreased by 41% (Del Mar, BMJ, 1997)
May place young children at added risk for serious
sequelae
We should treat real infections with antibiotics and
focus our antibiotic reductions in areas that we know
won’t help
21% prescription rate for “common cold”, 46% for bronchiolitis
(El Sayed, Eur J Ped, 2009)
44% - common colds, 75% bronchiolitis (Nyquist, JAMA, 1998)
Follow-up and Communication
You SHOULDN’T use this option unless
Caregiver understands the risks and benefits of
this treatment – specifically the need to contact
PMD with progressive course
Caregiver has reliable means of communicating
with PMD and vice-versa
Follow-up can be assured in the next 2-3 days
Antibiotics DO have a role in the
management of AOM
Observation is more work!
Individual Patient Data Meta-Analysis
RCTs on AOM and Antibiotics
Burke
Appelman
Damoiseaux
Little
Le Saux
McCormick
Country
year
n
UK
NL
NL
UK
Canada
USA
1991
1991
2000
2001
2005
2005
232
121
240
315
512
223
Rovers et al. Lancet 2006
Results for Pain and/or Fever at 37 days Subgroups
Rate Difference (95% CI)
NNT
< 2 years + bilateral AOM
< 2 years + unilateral AOM
≥ 2 years + bilateral AOM
≥ 2 years + unilateral AOM
25% (20 - 30)
5% (2 - 8)
12% (7 - 17)
4% (2 - 6)
4
20
9
25
Otorrhea
yes
no
36% (27 - 45)
14% (11 - 17)
3
8
Rovers et al. Lancet 2006
Impact of AOM Guidelines
Coco A, et al Pediatrics 2010;125: 214-220.
30 month period before and after guideline
publication using ambulatory medical care survey
Antibiotics
Has made a negligible impact on the overall amount of
antibiotics prescribed for AOM = 11%-16% not treated
Mild infections are being Rx’d less commonly
Absence of pain or fever
Pain
71% increase in the use of analgesics for AOM
Increased further in patients managed with observation
option
Risk Factor (RF) Reduction
Modifiable
Tobacco exposure
Breast feeding
Vaccines
Influenza – Benefit unclear (Hoberman A, JAMA, 2003)
Pneumococcal – Clear but small benefit
Child care arrangements
Bottle/pacifier use
?? – Early onset first infection
GERD
Allergy
Risk Factor (RF) Reduction
Not Modifiable
Anatomic considerations
Syndromic
Craniofacial
Down
Gender
Socioeconomic status
Family History
Race – Indigenous
Immune deficiency
Only 2nd large scale
study looking at
caregiver knowledge
regarding OM RF
Significant
opportunities to educate
caregivers
Significant willingness
to modify behaviors to
lessen OM risk
Viruses
Increased interest due to potential for
vaccines
Major players
RSV
Influenza
Parainfluenza
Adenovirus
Rhinovirus
Viral Otitis Media
Sole causative agent
30%
“Mixed” Infections
Significant precursor to bacterial infections
RSV identified in 53% of MEE by PCR
(Okamoto, J Infect Dis, 1993)
Viral Effects
Eustachian Tube Dysfunction
Cytokine mediated inflammation
Immunosuppression
Increase in bacterial colonization and
adherence
Severity of “Mixed” Infections
Mucosal damage
Immune changes with potential for poor
bacterial clearance
Changes in antibiotic pharmacokinetics
Viruses decrease amoxicillin concentration
in MEE (Canafax, infect Dis J, 1998)
Changes in cytokine mediators
Vaccines
Viral
Influenza A
Clinically available
Reduction in AOM by 36% in daycare setting
during influenza season
(Heikkinen, Am J Dis child, 1991)
RSV
Most commonly associated with OM
Invades ME readily
Vaccines
Pneumococcal conjugate (7-valent)
Efficacy
Finland (2001) - 6% reduction in OM (CI -4 - 16)
California (2000) - 7% reduction in OM (CI 4-10)
Meta-analysis not possible on multiple studies
Follow-up
6% reduction (Fireman, 2003)
Diagnosis and definitions are important
Replacement with non-covered serotypes
Overall Impact for Otitis Media – Modest
Cost – not really very cost effective for OM
NTHI – likely around the corner
Holy grail – There will be the need for antibiotics
and surgeons in the future
http://pediatrics.aappublications.org/
cgi/reprint/113/5/1412
OME - Children at Risk
At risk for speech, language , learning
difficulties
Need early assessment of hearing
levels, speech and language
progression and need early intervention
Just finished work on recommendations
for OME of short duration
Children at Risk
Underlying hearing loss not associated with
OME
Congenital
Anatomic – unilateral microtia
Suspected or diagnosed language delay
Cleft palate
Visual impairment
Syndromes or craniofacial disorders with
cognitive, speech or language delays
Autism and other pervasive developmental
disorders
Watchful Waiting
3 months from date of onset/diagnosis
Most OME is self-limited
80% of effusions with AOM resolve by 3 months
Need to consider
Hearing levels
Recurrent infections
Development
Not mutually exclusive from RecOM
54% of patients referred for OME
Pediatrician screening device
Medications
Antihistamines
Decongestants
Corticosteroids
Antimicrobials
No evidence of benefit with OME
Hearing and Language
Hearing testing
Minimum intervention after 3 months OME
Sooner with speech or other
developmental delay
Primary care screening
4 years and older
4 frequency testing (500, 1000, 2000, 4000 Hz)
Formal audiological testing
Children younger than 4
Older children with a failed screen
Language Testing
Assessed in all children with persisting
hearing loss
Language Development Survey (caregiver
only)
Early Language Milestone Scale
Denver Development Screening Test II
Surveillance
Most Controversial Point
When to place
tympanostomy tubes (TT)?
Follow-up every 3 months
until:
Fluid resolves
Significant hearing loss
develops
Structural abnormalities of
the ear are suspected
Tympanostomy tubes are
generally mandated if
patient develops
Retraction pocket
Adhesive atelectasis
Ossicular erosion
“Significant” Hearing Loss
HL > 40dB = Moderate hearing loss
Tympanostomy tubes
Clear evidence of negative impact on speech
language and academic performance
HL of 21 to 39dB = Mild hearing loss
Still significant
Evidence of negative impact on speech, language
and school performance in children with
permanent SNHL
Need to optimize listening and learning
environment
Optimizing Hearing and Listening
TABLE 4. Strategies for Optimizing the Listening-Learning
Environment for Children With OME and Hearing Loss*
Get within 3 feet of the child before speaking.
Turn off competing audio signals such as unnecessary music and
television in the background.
Face the child and speak clearly, using visual clues (hands, pictures) in
addition to speech.
Slow the rate, raise the level, and enunciate speech directed at the child.
Read to or with the child, explaining pictures and asking questions.
Repeat words, phrases, and questions when misunderstood.
Assign preferential seating in the classroom near the teacher.
Use a frequency-modulated personal- or sound-field-amplification
system in the classroom.
*
Modified with permission from Roberts et al.
“Significant” Hearing Loss
<20 dB hearing = Normal hearing
Assess unilaterality – even in younger
children
Assess speech and language
Assess “additive” or “risk factors”
Caregiver environment
Socioeconomic environment
Assess behavioral issues
Attention
Balance
Otalgia
OME/Language Studies
Some studies have questioned the impact of
OME on speech/language (Paradise JL, et al. NEJM,
2007)
Significant methodolical errors
Intense screening process
Not equivalent to real world
Impact of TT is greatest on patients who are symptomatic
(hearing, balance) and seek treatment
Very mild disease in treatment group
Most kids had unilateral disease
Eliminated patients most likely to benefit
Patients with speech delay, ADHD, developmental delay,
other chronic illnesses, poor socioeconomic factors
OME
Cochrane review 2010
Looked for randomized trials
Primary outcome was hearing level
Many of the studies had mild disease
3 studies with persistent bilateral OME- more
severe
Difference at 3 months = 12 dB
Difference at 6-9 months = 4dB
Short acting tubes
Leaving out children with development issues
Surgery
Tympanostomy tubes for initial surgery
Consideration of adenoidectomy for
secondary procedures
National Institute for Health and Clinical
Excellence
National
Institute for
Health and
Clinical
Excellence-2008
www.nice.org.uk
Surgery
based on
Hearing
Development
Education
Different
pathways
Down’s
Cleft
Ear Tube Otorrhea
Post tympanostomy tube placement
Ototopical drops only required if middle
ear fluid is present at time of tube
placement
Decreases post-operative otorrhea and
tube plugging
Poetker DM, et al. Ofloxacin otic drops
versus neomycin/polymyxin b otic
drops as prophylaxis against posttympanostomy tube otorrhea. Archives
of Otolaryngology – Head and Neck
Surgery 2006;131(6):1294-1298.
Ototopical Therapy
Character of otorrhea
Drop administration
Microbiology of infection
NEED CULTURE!!
Fungal infections
Lotrimin drops
Diflucan®
Martin TJ, Kerschner JE, Flanary VA. IJPO
2005;69:1503-1508.
Eustachian Tube
Eustachian Tube Dysfunction Model of Otitis
Viral infection – edema – poor opening – negative pressure –
transudate – when tube does open “sucks in bacteria from
nasopharynx
“A key component” in OM
“Developmentally immature”
“It is important to describe the growth and development of the
tube to understand why infants and young children have more
middle-ear infections than older children and adults.”
“Convincing evidence”
Bluestone CD, Klein JO. Otitis media and eustachian tube dysfunction. In:
Bluestone CD, Stool SE, eds. Pediatric Otolaryngology, Philadelphia, PA:
Saunders; 2003:497.
Commonly referenced as cause and solution to difficulties with
OM in children
Eustachian Tube
Eustachian Tube Dysfunction Model of Otitis
Viral infection – edema – poor opening – negative pressure –
transudate – when tube does open “sucks in bacteria from
nasopharynx
“A key component” in OM
“Developmentally immature”
“It is important to describe the growth and development of the
tube to understand why infants and young children have more
middle-ear infections than older children and adults.”
“Convincing evidence”
Bluestone CD, Klein JO. Otitis media and eustachian tube dysfunction. In:
Bluestone CD, Stool SE, eds. Pediatric Otolaryngology, Philadelphia, PA:
Saunders; 2003:497.
Commonly referenced as cause and solution to difficulties with
OM in children
What Is The Evidence?
Eustachian Tube Dysfunction
Anatomic - ET does change from infancy
Length
50% as long as adult (~40mm)
Age 7 reaches adult length
“Too short to protect from nasopharyngeal secretions”
Width
Cartilage, lumen and levator veli palatini (TVP) m. increase in overall
cross-sectional area and volume
Very little actual change in width of lumen itself
Orientation
10 angle to the horizon in infants
45% in adults
TVP angle to cartilage is larger in children
“Tube won’t open” increasing incidence of OM
Cartilage composition
Infants with increased cartilage cell density but less elastin
“Too floppy or compliant” impairing protection from nasopharynx and
decreasing ability to open
“Cartilage does not provide adequate support during attempts at
opening and may buckle”
What Is The Evidence?
Muscular attachments
Passively closed at rest with active muscular
opening and cartilage recoil to close again
TVP – attributed as primary ET muscle
2 distinct bundles – lie mediolateral to the tube
TVP – more lateral
Dilator tubae – cartilagenous insertion
Internal pterygoid – help with closure
Especially for abnormal populations
Tensor tympani – interacts with the TVP
Levator veli palatini – close proximity but no
consensus as to ability to affect ET
Functions – Pressure Regulation
Adults clear pressure changes more
efficiently
Negative pressure chamber
35% children could not clear verses 5% adults
Bylander A, et al. Acta Otolaryngol 1983;96:255.
Increased incidence of “normal” children
with negative pressure on tympanogram
Experimental Evidence?
TVP muscle inactivation
Muscular destruction or inactivation (botulinum)
Produces middle ear effusions (MEE) - reversible
Casselbrant ML, et al, Acta Otolaryngol 1988;106:178–185.
Infectious implications ?
Nasal viral challenges – human
Influenza A
ETD – negative pressure
Small percentage developed MEE
Buchman CA, et al, J Infect Dis 1995;171:1348
Special Populations
Cleft palate and Down Syndrome
Shorter tubes
Decreased TVP musculature insertion into
cartilagenous tube
Greater cartilage cell density
Increased TVP angle with ET
Daycare populations
? Role of ET
Hypothesis
ET dysfunction or obstruction may result during the events of
OM but ETD is not the primary underlying cause of OM and
development of the ET is not the major event responsible for
resolution of OM as children get older.
Immunology, Inflammation and Genetics - Not Anatomy
Children with early first infection
Children in daycare
Genetics/family history
Polymorphisms
Mucins
Biofilms
GERD
Biofilms
Bacterial biofilms
Complex organization of bacteria
Anchored to a surface
Surrounded by exopolysaccharide – Matrix –
secreted by bacteria
Low metabolic rate
Escape host immune surveillance
Opposed to planktonic concept of bacteria
Biofilms
Bacteria growing as biofilms display a different phenotype
than free-living, planktonic, bacteria
Reduced metabolic rates that render them resistant to
antimicrobial treatment
Exopolysaccharide matrix that provides protection from
phagocytosis and other host defense mechanisms due to a lack
of accessibility by immunoglobulin and complement
Reliance on complex intracellular communication system that
provides for organized growth characteristics, “quorum sensing”
Resistant to standard culture techniques because of altered
metabolism
Altered genetic expression and ability to rapidly share genetic
information
Background
Many chronic infectious processes in humans have been
demonstrated to be dependent upon the development of
biofilm formation
Dental
Chronic bacterial prostatitis
Cystic fibrosis
Medical Implants
Orthopedic implants
Heart valves
Catheters
Native valve endocarditis (NVE)
Biofilms form on cardiac valves
streptococci (including pneumococci)
staphylococci g
gram-negative bacteria
fungi (Candida and Aspergillus spp.)
Interactive biofilm model: www.erc.montana.edu
OM as a Biofilm Disease?
Chronic infectious process
Difficulties with culturing effusions
Recalcitrant to antibiotic therapy
Indirect Evidence of Bacterial Biofilm
in Otitis Media with Effusion
Evidence suggesting that otitis media with effusion is not a
sterile inflammatory effusion, but rather a vibrant, active
bacterial process
Bacterial DNA is present in pediatric culturally “sterile” effusion
Purified bacterial DNA are cleared within hours while DNA from
live infectious bacterial DNA persist in sterile effusion for up to 4
weeks
Bacterial mRNA is present in culturally sterile, DNA-positive
middle ear effusions in children indicating that the bacteria are
intact and metabolically active.
Bacteria-synthesized proteins are present in sterile effusions
Rayner MG, et al. JAMA. 1998;279:296-9.
Direct Evidence of Bacterial Biofilms in
Otitis Media
Experimental chinchilla model of OM
H. influenzae injected via transbullar approach
bilaterally
Confocal and electron microscopic evidence of
biofilm formation
Ehrlich GD, et al, JAMA 2002;287:1710
Biofilms
JAMA 2006;296(2):202-211.
Hypotheses
Otitis media in humans is biofilm mediated
Otitis media with effusion (OME)
Recurrent otitis media (ROM)
Direct evidence of Streptococcus
pneumoniae (SP) and Haemophilus
influenzae (HI) biofilms is available in
children undergoing tympanostomy tube
(TT) placement for OM
Mucin
Laryngoscope
2007;117(9):1666-1676.
Mucin
20 human mucin genes
5 previously well-studied in the middle ear
Mucins can be membrane bound – MUC 1
Mucins can be secretory (gel forming) – MUC 2, MUC 4, MUC 5AC, MUC 5B
Additional 10 identified in middle ear in our laboratory and undergoing further
characterization
Variation in quantity and quality of mucin is important in the pathophysiology
of OM
Mucin determines the viscosity of middle ear fluid and mucociliary clearance
Mucin responsible for hearing loss in COME
Mucins perform important host-defense functions
Mechanical protection
Affect pathogen adherence and clearance
Biofilm interactions
Mucin
MUC5B in Otitis Media
Relative Fold Change
200.00
150.00
100.00
50.00
0.00
control
RecOM
COME
Data demonstrating a strong
correlation between increased
MUC2, MUC5AC and MUC5B
expression and poorer hearing
(higher dB levels).
Summary
Diagnosis of patients with OM is still one of
the most important aspects of OM
It is a very prevalent and expensive
disease to manage
This is unlikely to change in the near future
Basic and clinical research continues to
hone who benefits most from which
interventions
Feedback – time