BURDEN OF OTITIS MEDIA IN DEVELOPING AND DISADVANTAGED POPULATIONS
Otitis media (OM) is a common but complex disease affecting many children and families across the globe. The burden of OM, its frequency and severity, varies among populations and risk groups and estimates of disease burden can be strongly influenced by definitions. In 1993 the World Health Organization (WHO) and the World Bank estimated that OM causes 51,000 deaths per year in children less than 5 years of age, mainly due to complications of chronic suppurative otitis media (CSOM).1 CSOM is estimated to affect between 65 and 330 million people, 60% of whom suffer significant hearing loss.2 The majority of this burden is in South East Asia, Western Pacific, Africa, and ethnic minorities. The WHO defines populations where the childhood prevalence of CSOM is ≥4% as having a public health emergency requiring immediate attention.3 Children with CSOM living in developing countries frequently require long-term (16 weeks) topical and/or systemic antibiotics to resolve the offensive discharge and improve hearing,4 some also require surgery to repair persistent perforation(s) in the tympanic membrane.5
BURDEN OF OM IN DEVELOPED AND AFFLUENT POPULATIONS
In developed countries, CSOM is now so rare that prevalence rates are not reported in the current literature.6 Most cases of CSOM in children are adverse events associated with surgical insertion of tympanostomy tubes.7 The major burden of OM is attributed to episodes of acute otitis media (AOM) and persistent otitis media with effusion (OME). Many children with AOM experience pain requiring oral analgesics. Many also require doctor visits and antibiotic therapy,8 particularly children less than 2 years of age with bilateral disease, and children with tympanic membrane perforation.9 Estimates of the incidence of AOM from longitudinal birth cohort studies range from 0.125 to 1.2 episodes per child year.10–12 For children prone to recurrent episodes of AOM, up to 7.3 episodes annually has been reported.13 In 60% of children with AOM, asymptomatic OME may persist for 3 months or more.6 The burden of OME is related to the associated conductive hearing loss that may affect language development as well as have social and educational outcomes. Management options for persistent OME with hearing loss include audiologic and medical interventions (antibiotic therapy and possibly surgery) to resolve the effusion and restore hearing.14,15
BURDEN OF OM IN INDIGENOUS POPULATIONS
Indigenous children (including those residing in industrialized countries) experience high rates of acute and chronic suppurative OM in addition to recurrent OM and persistent OME.16–19 Australian Aboriginal children living in remote communities have the highest published rates of CSOM and AOM with perforation.18 In 2001, a community-based survey that examined 709 (78%) of 914 eligible children between the age of 6 months and 2.5 years and living in 29 remote Aboriginal communities identified 24% as having perforated tympanic membranes (15% had CSOM, 2% dry perforation, and 7% AOM with perforation).18 An additional 26% had AOM (bulging tympanic membrane) without perforation and only 8% had bilaterally normal middle ears.
MODEL TO EXPLAIN HIGH PREVALENCE OF CSOM
In Australian Indigenous children, respiratory tract infections commence early in life and involve multiple bacterial species that result in recurrent episodes of AOM and progression to CSOM.20,21 Infants colonized with mixed pathogens, specifically those colonized with Streptococcus pneumoniae and Haemophilus influenzae, were at greater risk of OM [odds ratio (OR) = 33.6; 95% confidence interval (CI), 8–144] compared with those colonized with Moraxella catarrhalis alone (OR = 6.5; 95% CI, 2–29). Culture of ear discharge from acute perforations support a mixed bacterial etiology in this population; 57% cultured H. influenzae, 34% S. pneumoniae, and 21% cultured both pathogens (Table 1)22
A vicious circle of inflammation was hypothesized by Cole to explain the pathogenesis of chronic suppurative lung disease in adults with bronchiectasis.23 We believe that an extension of this model also explains the high rates of OM and other respiratory infections such as bronchiectasis in Aboriginal children.24,25 Dense and diverse bacterial nasopharyngeal colonization causes neutrophilic infiltration, tissue damage, increased mucus secretion, decreased mucociliary clearance, and leads to chronic suppurative lung disease in adults.23 However in the infant these events may also lead to CSOM and persistent nasal discharge. The persistent nasal discharge perpetuates the vicious circle, particularly where there is poor hygiene and overcrowding, by increasing opportunities for transmission among young infants. This includes transmission via hand contamination (in a community-based survey, 40% of children were found to have pneumococcal hand contamination).26 High rates of transmission events result in an accumulation of strains at a rate greater than can be cleared by the infant immune response or by damaged mucosa, and the vicious circle is repeated. For the middle ear, the high density of organisms and damaged mucosa are likely risk factors for failed therapy, recurrent AOM, and progression to perforation and CSOM. A role for respiratory viruses in AOM or failed therapy in these populations has not been described.
OUTCOME OF INTERVENTIONS FOR PREVENTION AND TREATMENT OF OM
Antibiotics for Prevention/Treatment of AOM
A meta-analysis of long-term antibiotic therapy found modest benefits in the prevention of AOM [Relative Risk (RR) = 0.62; 95% CI, 0.52–0.75] or AOM episodes [Incidence Rate Ratio (IRR) = 0.48; 95% CI, 0.37–0.62].13 Few randomized controlled trials of prolonged antibiotic therapy have been conducted in high-risk populations (rate of CSOM >4%); however, in a subgroup analysis the benefit of long-term antibiotics in preventing perforation in a high-risk population17 was substantial (RR = 0.61; 95% CI, 0.44–0.84; IRR = 0.52; 95% CI, 0.39–0.70) for preventing AOM in the subgroup of studies conducted primarily in the United State and Europe (RR = 0.62; 95% CI, 0.51–0.76; IRR = 0.51; 95% CI, 0.30–0.87).13
Evidence from systematic reviews shows minimal benefit of antibiotics over placebo for pain associated with AOM at 2 to 7 days; antibiotic use was associated with an absolute reduction of 7% (95% CI, 4–10), (OR = 0.57; 95% CI, 0.45–0.73).8 Two studies reported perforation rates and these occurred in 7% of controls and in 4% of children receiving antibiotics (OR = 0.51; 95% CI, 0.2–1.3).8 A subsequent analysis of individual patient data from several of the studies in this meta-analysis and several new trials permitted secondary analysis to identify subgroups of children with CSOM most likely to benefit. In children younger than 2 years of age with bilateral AOM, 55% of controls and 30% on antibiotics still had pain, fever, or both at 3 to 7 days. The risk difference between these groups was 25% (95% CI, −36 to −14), resulting in a number-needed-to-treat (NNT) of 4 children. In children with otorrhoea, the risk difference and NNT, respectively, were −36% (95% CI, −53 to −19) and 3, whereas in children without otorrhoea the equivalent values were −14% (95% CI, −23 to −5) and 8.9
Vaccines for Prevention of AOM
Pneumococcal Polysaccharide Vaccine (PPV: 8- or 14-Valent).
In the Cochrane systematic review of vaccines for preventing OM, the overall pooled rate ratio for PPV vaccination in prevention of AOM in the group of healthy children (no previous documented AOM episodes) was 0.92 (95% CI, 0.85 to 0.99).27 AOM episodes due to vaccine types (3 studies) was not significantly reduced (RR = 0.72. 95% CI, 0.43–1.21). The rate ratio in children younger than 24 months of age was 0.93 (95% CI, 0.83–1.05) and the rate ratio was 0.78 (95% CI, 0.63–0.97) for children older than 24 months. There was a significant reduction in AOM episodes in vaccinated children with previous AOM episodes (RR = 0.8; 95% CI, 0.69–0.93). Subgroup analysis shows a pooled rate ratio in the younger age group of 0.85 (95% CI, 0.74–0.98). The RR in the older age group was 0.74 (95% CI, 0.62–0.90).
Pneumococcal Conjugate Vaccine (PCV).
Two randomized controlled trials (RCT) of infant schedules of 7-valent PCV were reported before licensure in the United States.12,28 Efficacy of PCV for prevention of vaccine serotype pneumococcal OM was 54% (95% CI, 41–64) in the FinOM RCT.12 Serotype replacement reduced efficacy for all serotype pneumococcal OM to 34% (95% CI, 21–45). Overall efficacy for clinical AOM was only 6% (95% CI, −6 to 16). The FinOM study also reported a nonsignificant increase in culture-confirmed H. influenzae AOM episodes (VE = −11%; 95% CI, −34 to 8). In the Northern California Kaiser Permanente study, per protocol efficacy for OM against visits, episodes, frequent otitis, and ventilatory tube placement was 8.9% (95% CI, 6–12), 7.0% (4–10), 9.3% (3–15), and 20.1% (2–35), respectively, with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype-specific effectiveness was 66.7% (based on a relatively small number of specimens).28
The authors of the Cochrane Systematic Review concluded that the effects of PPV and PCV on the prevention of AOM are minimal. Irrespective of age, PPV would prevent 10% and PCV would prevent 8% of the AOM episodes, respectively.27 Approximately 32 children should be vaccinated with PPV or PCV to prevent 1 child from having an AOM episode during 1 year. To prevent 1 child younger than 24 months from having an AOM episode during 1 year, around 57 children should be vaccinated with PPV. PCV seemed a bit more effective compared with PPV—around 33 children need to be vaccinated with PCV to prevent 1 child from having AOM within a period of 1 year. Administering these vaccines on a large scale to prevent AOM cannot be recommended based on the currently available results.
An ecologic evaluation of PCV for prevention of OM in Australian Aboriginal children compared OM prevalence before and after a universal PCV program. In comparison with the 2001 data quoted above,18 in 2003, of 644 well children from 29 communities, 98% of whom had received 2 doses of pneumococcal conjugate vaccine, no significant reductions were found. An average of 21% had perforations (16% CSOM, 4% AOM with perforation, and 1% dry perforation), 24% had AOM without perforation, and a further 29% had OME. Bilateral normal ears were diagnosed in only 12% children. The microbiologic assessment supports the view that clinical failure in PCV-vaccinated children is most likely due to multiplicity of bacterial pathogens involved in AOM with perforation (AOMwiP), and to serotype replacement in pneumococcal AOMwiP. H. influenzae remains the major pathogen in AOMwiP (Table 1).22
COMPARISON OF AAP/AAFP AND OATSIH GUIDELINES FOR MANAGEMENT OF AOM
In high-risk populations where the childhood rate of CSOM is greater than 4% it is valuable to be able to identify those children at greatest risk of perforation. In community-based screening, around 20% to 30% of Australian Aboriginal children have bulging eardrums.29 Only 10% have typical symptoms that define AOM in low-risk populations (sudden onset of middle ear effusion with pain or redness).30 The value of bulging as a predictor of AOM has been confirmed in several high-quality studies but has not been emphasized in the AAP and AAFP guidelines.31 The implications of withholding antibiotic therapy in children with asymptomatic bulging ear drums have also not been evaluated in high-quality studies. However, our data from a randomized controlled trial of short-term antibiotics for AOM (bulging or perforated tympanic membrane) in a high-risk population indicated that AOM persists in around 50% of children.29 Guidelines for management of AOM in Indigenous children therefore define AOM as middle ear effusion with either bulging of the tympanic membrane, recent discharge, ear pain, or redness.32 There is no option to withhold antibiotics in an Aboriginal child with AOM, and for children with AOM with perforation, longer courses of antibiotics are recommended.
The burden of respiratory disease is extremely high in Indigenous children. Bacterial colonization within weeks of birth and persistent exposure to multiple pathogenic species and strains are the greatest predictors of persistent and progressive disease. AOM does not resolve spontaneously if untreated, and may progress to perforation and CSOM in 25% of children. Long-term antibiotics are beneficial but are difficult for families, and antibiotic resistance may be a problem. Currently licensed vaccines have not had much impact on rates of OM. Although conjugate vaccines seem to prevent vaccine serotype-specific OM and carriage, replacement with nonvaccine serotypes negates much of the benefits. Vaccines that reduce infection to both S. pneumoniae and H. influenzae will be needed to substantially reduce the burden of disease in Indigenous children.10
1.World Health Organisation. World Development Report 1993: Investing in Health.
Oxford: Oxford University Press; 1993:215–222.
2.Acuin J. Chronic suppurative otitis media
: burden of illness and management options. World Health Organization
(WHO). 2006 update.
3.WHO/CIBA Foundation Workshop. Prevention of Hearing Impairment From Chronic Otitis Media
. WHO/PDH/98. 4. 1996. London: CIBA Foundation; 1996;11–19.
4.Smith AW, Hatcher J, Mackenzie IJ, et al. Randomised controlled trial of treatment of chronic suppurative otitis media
in Kenyan schoolchildren. Lancet
5.Mak D, MacKendrick A, Bulsara M, et al. Outcomes of myringoplasty in Australian Aboriginal children and factors associated with success: a prospective case series. Clin Otolaryngol
6.Rosenfeld R, Bluestone C. Evidence-Based Otitis Media.
Hamilton: BC Decker; 2003.
7.van der Veen EL, Schilder AG, van Heerbeek N, et al. Predictors of chronic suppurative otitis media
in children. Arch Otolaryngol Head Neck Surg
8.Glasziou PP, Del Mar CB, Hayem M, et al. Antibiotics for acute otitis media
in children. Cochrane Database Syst Rev.
9.Rovers MM, Glasziou P, Appelman CL, et al. Antibiotics for acute otitis media
: a meta-analysis with individual patient data. Lancet
10.Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media
caused by both Streptococcus pneumoniae
and non-typable Haemophilus influenzae
: a randomised double-blind efficacy study. Lancet
11.Teele DW, Klein JO, Rosner B. Epidemiology of otitis media
during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis
12.Eskola J, Kilpi T, Palmu A J, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media
. N Engl J Med
13.Leach AJ, Morris PS. Antibiotics for the prevention of acute and chronic suppurative otitis media
in children. Cochrane Database Syst Rev.
14.Stool SE, Berg AO, Berman S, et al. Otitis Media With Effusion in Young Children
. Clinical Practice Guideline, Number 12. 1994. Rockville, MD: United States Department of Health and Human Services.
15.Berman S, Roark R, Luckey D. Theoretical cost effectiveness of management options for children with persisting middle ear effusions. Pediatrics
16.Curns AT, Holman RC, Shay DK, et al. Outpatient and hospital visits associated with otitis media
among American Indian and Alaska native children younger than 5 years. Pediatrics
17.Maynard JE, Fleshman JK, Tschopp CF. Otitis media
in Alaskan Eskimo children: prospective evaluation of chemoprophylaxis. JAMA
18.Morris PS, Leach AJ, Silberberg P, et al. Otitis media
in young Aboriginal children from remote communities in Northern and Central Australia: a cross-sectional survey. BMC Pediatr
19.Costa OA, Swenson RC, Ribeirio NO, et al. Secretory otitis media
and its sequelae in children living in charitable institutions. Scand Audiol Suppl
20.Leach AJ, Boswell JB, Asche V, et al. Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media
in Australian aboriginal infants. Pediatr Infect Dis J
21.Smith-Vaughan HC, Byun R, Nadkarni M, et al. Measuring nasal bacterial load and its association with otitis media
. BMC Ear Nose Throat Disord
22.Leach AJ. Microbiology of acute otitis media
with perforation in indigenous children. Streptococci—new insights into an old enemy. In: Sriprakash KS, ed. Proceedings of the XVIth Lancefield International Symposium on Streptococci and Streptococcal Diseases.
Cairns, Australia: Elsevier; 2006;89–92.
23.Cole PJ. Inflammation: a two-edged sword—the model of bronchiectasis. Eur J Respir Dis Suppl
24.Leach AJ, Morris PS. Perspectives on infective ear disease in indigenous Australian children. J Paediatr Child Health
25.Chang AB, Grimwood K, Mulholland EK, et al. Bronchiectasis in indigenous children in remote Australian communities. Med J Aust
26.Stubbs E, Hare K, Wilson C, et al. Streptococcus pneumoniae and noncapsular Haemophilus influenzae nasal carriage and hand contamination in children: a comparison of two populations at risk of otitis media
. Pediatr Infect Dis J
27.Straetemans M, Sanders EA, Veenhoven RH, et al. Pneumococcal vaccines for preventing otitis media
(Cochrane Review). Cochrane Database Syst Rev.
28.Black S, Shinefield H. Safety and efficacy of the seven-valent pneumococcal conjugate vaccine: evidence from Northern California. Eur J Pediatr
. 2002;161(suppl 2):S127–S131.
29.Gadil G, Leach AJ, Morris PS, et al. Azithromycin versus Amoxycillin for Acute Otitis Media
in Aboriginal Children (AATAAC): a double blind randomised controlled trial. Paper presented at: International Symposium on Pneumococci and Pneumococcal Diseases; April 2–6, 2006; Alice Springs, Central Australia. Abstract No. SY12.06.
30.Subcommittee on Management of Acute Otitis Media
. Diagnosis and management of acute otitis media
31.Hoover H, Roddey OF. The overlooked importance of tympanic membrane bulging. Pediatrics
32.Morris P, Ballinger D, Leach A, et al. Recommendations for Clinical Care Guidelines on the Management of Otitis Media in Aboriginal and Torres Strait Islander Populations
. Canberra: Office of Aboriginal and Torres Strait Islander Health; 2001.