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 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 Pneumatic otoscopy Tympanometry

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 High-dose amoxicillin-clavulanate has become drug of choice in these settings Cost Safety profile

Casey, JR Ped Inf Dis J, 2010

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

2

nd

-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

3

rd

-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.



24 mos.

Certain AOM Antibiotics 6-23 mos.

Antibiotics Uncertain AOM Antibiotics Antibiotics if severe Observe if non-severe 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

Country year n Burke Appelman Damoiseaux Little Le Saux McCormick 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 3 7 days Subgroups

Rate Difference (95% CI) NNT < 2 years + bilateral AOM 25% (20 - 30) < 2 years + unilateral AOM 5% (2 - 8) ≥ 2 years + bilateral AOM 12% (7 - 17) ≥ 2 years + unilateral AOM 4% (2 - 6) Otorrhea yes no 36% (27 - 45) 14% (11 - 17) 4 20 9 25 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 2 nd 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 post tympanostomy 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 S

treptococcus 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

200,00 150,00 100,00 50,00 0,00 control RecOM COME

D

ata 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