Epidemiology of otitis media in children from developing countries: A systematic review

International Journal of Pediatric Otorhinolaryngology 85 (2016) 65–74

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Review Article

Epidemiology of otitis media in children from developing countries: A systematic review Rodrigo DeAntonio a, Juan-Pablo Yarzabal b, James Philip Cruz c, Johannes E. Schmidt b, Jos Kleijnen d,e,* a

GSK Vaccines, Ciudad del Saber, Panama GSK Vaccines, Wavre, Belgium GSK Vaccines, United Kingdom d School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, The Netherlands e Kleijnen Systematic Reviews Ltd, York, United Kingdom b c

A R T I C L E I N F O

Article history: Received 25 January 2016 Received in revised form 23 March 2016 Accepted 24 March 2016 Available online 11 April 2016 Keywords: Otitis media Systematic review Epidemiology Children Developing and newly industrialised countries

A B S T R A C T

Objective: This systematic review examined the epidemiology of otitis media (OM) in children <6 years within 90 developing and newly industrialised countries. Methods: Literature searches (1992–2011), based on MEDLINE, EMBASE, WHO, Index Medicus, countryspecific websites, conferences, and the reference lists of included studies, yielded 11,413 records; 59 of 344 studies analysed were included in this review. Results: The majority of the identified studies provided only a single timepoint for OM. In children <6 years of age, OM prevalence was found to be 9.2% in Nigeria, 10% in Egypt, 6.7% in China, 9.2% in India, 9.1% in Iran and 5.1–7.8% in Russia. Few studies examined the etiology of OM and the antibacterial resistance. The most common bacterial pathogens were S. pneumoniae, H. influenzae and S. aureus. A high resistance to penicillin was reported in Nigeria and Turkey. Conclusions: Despite the variability between the identified studies, this review indicates that OM and its various sub-types remain a significant burden in different settings. However, the heterogeneity of studies and a general lack of reliable data made generalisation very difficult. ß 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . Search strategy and eligibility criteria . . . . 2.1. Screening and data abstraction . . . . . . . . . 2.2. 2.3. Assessment of methodological quality. . . . Data synthesis and analysis . . . . . . . . . . . . 2.4. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence and prevalence . . . . . . . . . . . . . . 3.1. Africa . . . . . . . . . . . . . . . . . . . . . . 3.1.1. China and Hong Kong . . . . . . . . . 3.1.2. India and South Asia . . . . . . . . . . 3.1.3. 3.1.4. Middle East . . . . . . . . . . . . . . . . . Russia . . . . . . . . . . . . . . . . . . . . . . 3.1.5. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Antibacterial resistance and susceptibility 3.3.

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* Corresponding author at: Kleijnen Systematic Reviews Ltd, 6 Escrick Business Park, Riccall Road, Escrick, York YO19 6FD, United Kingdom. E-mail address: [email protected] (J. Kleijnen). http://dx.doi.org/10.1016/j.ijporl.2016.03.032 0165-5876/ß 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

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4. 5.

R. DeAntonio et al. / International Journal of Pediatric Otorhinolaryngology 85 (2016) 65–74

Discussion . . . . . . . Conclusions . . . . . . Acknowledgements References . . . . . . .

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1. Introduction Otitis media (OM) is one of the most common childhood infections in pre-school aged children [1] and a major cause of childhood morbidity [2–5]. OM also represents the most frequent reason why children are prescribed with antibiotics or undergo surgery in the developed countries [6,7]. Moreover, in most of the countries belonging to developing countries, no guidelines regarding the use of antibacterial treatment in OM and respiratory tract infections exist and in several countries, parents can purchase any antibacterial drug in pharmacies without mandatory medical prescriptions. OM is subdivided into several disease sub-categories: acute otitis media (AOM), recurrent AOM, OM with effusion (OME) and chronic suppurative OM (CSOM). AOM presents with local and systemic signs and has a rapid onset [8,9], and is a leading cause of antibacterial treatment for children in developed countries [10,11]. OME can occur during the resolution of AOM once the acute inflammation has resolved but bacteria may still be present [12], while CSOM requires ongoing inflammation of the middle ear leading to otorrhea persisting for at least two weeks and perforation of the tympanic membrane [13]. In general, OM can be caused by bacteria or viruses [14]. The two leading bacterial pathogens are Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) [14–16]. Other important bacterial causes of OM are Staphylococcus aureus, Moraxella catarrhalis and S. pyogenes [14,16]. In terms of causative agent, the difference between OME and AOM is that the frequency of S. pneumoniae is not as high, and H. influenzae and M. catarrhalis are moderately more common. It has been estimated recently that around 20,000 people die annually from complications associated with OM, with the highest mortality rates in the children <5 years of age [4]. Recurrent or chronic forms of the disease can lead to considerable hearing loss and negatively affect learning ability and scholastic achievement [17]. It is well known that the prevalence of OM is increasing over time; Auinger et al. have reported this observation from the US during the 80s, attributed in part to the increase in child care and in higher prevalence of allergic conditions [1,18]. While there is a considerable body of work examining the treatment of OM [19– 21], limited research has been undertaken on the burden of OM in developing and newly industrialised countries. A systematic review of AOM in children from Latin America and the Caribbean [2], a review of OM burden in children from Asia-Pacific [5], and a systematic review on global estimates for OM and related conditions [4] were published previously. To build on this work, we conducted a systematic review of the epidemiology of OM, including all sub-categories, in children <6 years of age from 90 developing and newly industrialised countries covering Africa, China, India and South Asia, Russia and the Commonwealth of Independent States (CIS), and the Middle East. Our review focussed on incidence, prevalence, distribution of pathogens and antimicrobial resistance in children with OM.

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70 72 73 73

Appendix A for a list of the countries included). These countries covered 5 regions of interest: Africa, China, India and South Asia, Russia and CIS, and the Middle East. Children <6 years of age with a diagnosis of OM (any subcategory) were the population of interest. Studies including a wider age-range for participants were only included when they reported separate results for those aged <6 years. Searches were not limited by language or publication status. Twenty-three electronic databases were searched from 1992 to October 2011, including MEDLINE, EMBASE, African Index Medicus, Index Medicus for the Eastern Mediterranean Region, Index Medicus for South Asia Region, Western Pacific Region Index Medicus. Conference abstracts and relevant websites (e.g. Health Ministry websites) were also searched. An example of search strategy for MEDLINE is included in Supplementary Material, Appendix B. The current review reports on the following outcomes: incidence or prevalence or count of OM (any sub-category), distribution of pathogens causing OM and antimicrobial resistance and susceptibility of pathogens causing OM. Otitis externa and labyrinthitis were excluded from this review. Any study or data source reporting relevant outcome data were included, for example, observational studies (e.g. cohort studies, case-control studies, case series), country-specific/regional trials, registries, guideline/guidance documents, and statistical databases. We planned to investigate various subgroups of interest (disease sub-categories, age-groups, vaccination status, HIV status, malnutrition, diagnostic approach), but a paucity of data made these analyses unfeasible. 2.2. Screening and data abstraction

2. Materials and methods

Pairs of reviewers working independently screened the titles and abstracts of the retrieved references for relevance and any disagreements were resolved through consensus. Studies that were potentially relevant (prevalence, incidence and mortality of OM in children [aged <6 years] in the countries of interest, both overall and in different patient groups; distribution of pathogens and serotypes causing OM in the countries under consideration; seasonal variation in the incidence rate of OM; rate of treatment failure, antibiotic resistance, and hearing impairment from OM for the countries under consideration; health resource use for OM; health related quality of life for OM patients, parents or care givers; vaccination programmes and recommendation) or studies that were in disagreement were ordered and the full article was assessed for inclusion by one reviewer and checked by a second reviewer. Any disagreements were resolved through discussion or were checked by a third reviewer. Justifications for excluding papers from the review were documented for all full papers ordered for further inspection. Studies fulfilling all inclusion criteria were included in the review. Data abstraction sheets Microsoft Excel (version 2010) were first piloted on a small selection of studies. Subsequently, for each study, data were abstracted by one reviewer and checked by a second reviewer. Any disagreements were resolved by consensus.

2.1. Search strategy and eligibility criteria

2.3. Assessment of methodological quality

This review was restricted to a pre-defined list of 90 developing and newly industrialised countries (see Supplementary Material,

The risk of bias for included studies was assessed using the Downs and Black 27 item checklist for the methodological quality

R. DeAntonio et al. / International Journal of Pediatric Otorhinolaryngology 85 (2016) 65–74

assessment of non-randomised studies [22]. The checklist items for observational studies focused on the use of an appropriate recruitment strategy, response rates, sample representativeness of the general population, objective and reliable outcome measures, use of a power calculation, appropriate use of statistical methods and evidence of bias within the studies. The checklist was completed independently by pairs of reviewers and any disagreements were resolved by discussions. The results of the risk of bias assessment were used for descriptive purposes to provide an evaluation of the overall quality of the included studies and yield a transparent method of recommendation for the design and conduct of future studies. The results of the study quality assessment carried out are detailed in Supplementary Material, Appendix C. 2.4. Data synthesis and analysis The heterogeneity of the included studies precluded statistical pooling of data. Instead, results have been narratively analysed, grouped into AOM and chronic/other OM, and ordered by region and country to aid interpretation.

3. Results A total of 11,413 records were retrieved through the searching of 23 electronic databases and loaded into an EndNote library, from which 59 publications (journal articles and governmental statistics) were included in the review (Fig. 1). Publication dates ranged from 1992 to 2011 and reported data for locations in Africa, India and South Asia, China and Hong Kong, Middle East, and Russia [3,23–80].

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3.1. Incidence and prevalence Fifty-nine publications were identified which provided some measure of OM incidence and/or prevalence across five regions and 16 countries (Egypt, Nigeria, Ethiopia, China, Hong Kong, India, Bangladesh, Pakistan, Saudi Arabia, Turkey, Oman, United Arab Emirates, Iran, Yemen, Bahrain and Russia) [3,23–80]. For AOM, there were five studies conducted in Africa, all from Nigeria [49– 53], 2 studies from India and South Asia [3,28], and 9 studies from the Middle East [31–34,36,54–57] (Table 1). For chronic/other OM, 12 studies were from Africa [23,24,53,58–66], 3 were from China and Hong Kong [25,26,74], 9 from India and South Asia [3,27,67– 73], 24 from the Middle East [30–47,56,75–79], and 1 from Russia [48] (Table 2). These studies included different sub-categories of OM, different study designs and ways of measuring OM. The majority of studies consisted of small sample sizes and few provided estimates of incidence or prevalence, but rather a count of the number of OM cases over a single timepoint. 3.1.1. Africa A study by Amusa et al. [23] aimed to measure community prevalence of OM in a sample of 600 Nigerian children aged <12 years. This study found the prevalence of OM to be 14.7% (88/600), with a peak in children 1–4 years of age (55/600; 9.2%). OM was diagnosed as AOM, CSOM and OME in 11.8%, 2.5% and less than 1% of children <12 years of age, respectively. Khallaf et al. [24] used a data set of 75,789 acute respiratory infections from 5 regions across Egypt among children <4 years of age, and found that the prevalence of OM cases was about 10% (8078/75,789), ranging from 8.2% (258/3145) for those <2 months of age to 10.6% (2413/22,649) for the 2–11-month-olds and 10.8% (5407/49,995) for the 1–4-year-olds. Another eleven studies were found to report measures of OM for Nigeria [49–53,58–63]; however, many of these were hospitalbased rather than population-based and contained small samples (Tables 1 and 2). 3.1.2. China and Hong Kong There were 2 studies from China included [25,26]. Both were population-based and included relatively large samples. Wang et al. and Zhang et al. found OME prevalence to be 6.7% (children 3–6 years of age) and 6.3% (91/1431; children 2–6 years of age), respectively [25,26]. By age group, the prevalence was reported at 14.0% in 2-year-olds, 8.3% in 3-year-olds, 5.0% in 4-year-olds, 4.9% in 5-year-olds and 2.8% in 6-year-olds [26]. 3.1.3. India and South Asia A study by Sophia et al. of pre-school children in rural India provided population-based data from a relatively large sample of 800 children and found the prevalence of OM to be 9.2% (54/587) in children 0–5 years old [27]. In Pakistan, Tariq et al. provided data from an observational hospital-based study on the prevalence of AOM in 1724 children <2 years of age [28]. The prevalence of AOM was reported at 4.4% (75/1724) [28].

Fig. 1. Flow of studies retrieved through electronic database searches.

3.1.4. Middle East A study by Zakzouk et al. (2002) from Saudi Arabia used data from a large sample of 9540 children <12 years of age (2054 children <4 years of age), collected from 70 health centres across the kingdom [29]. The prevalence of AOM (otoscopic criteria) was 1.05% (100/9540) in children <12 years of age, with a higher value in children <4 years of age (1.95%; 40/2054). A study by Naini et al. examined the link between parental smoking and OME prevalence among children in Iran [30]. This study used a large population-based sample of 3833 children aged 2–11 years (1833 pre-school children [2–6 year-olds]) and the

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Table 1 Summary of studies reporting counts or incidence of AOM in children <6 years of age. Region

Country (study design)

N

Diagnosis

Age; Count (%)

Source

Africa

Nigeria (cross-sectional)

617

AOM

[49]

200

AOM

114 200

AOM AOM

361

ASOM

0–12 m; 23/53 (43.4%) 13–24 m; 23/53 (43.4%) 25–36 m; 7/53 (13.2%) 0–1 y; 12/64 (18.8%) 2–3 y; 24/64 (37.5%) 4–5 y; 16/64 (25.0%) 0–5 y; 77/114 (67%) 0–11 m; 13/200 (6.5%) 12–23 m; 19/200 (9.5%) 24–35 m; 2/200 (1%) 36–47 m; 2/200 (1%) 48–60 m; 1/200 (0.5%) 0–1 y; 46/83 (55.4%) 2–5 y; 48/151 (31.8%)

[50]

[51] [52]

[53]

South Asia

Bangladesh (case series) Pakistan (cross-sectional)

252 1724

AOM AOM

0–24 m; 0.9 episodes per child-year 0–2 y; 75/1724 (4.3%)

[3] [28]

Middle East

Saudi Aabia (cross-sectional) Turkey (case series)

9540 120

AOM AOM

[54] [55]

Oman (cross-sectional state surveillance)

NR NR NR NR NR NR 429

AOM AOM AOM AOM AOM AOM AOM

<4 y; 40/2045 (1.96%) <1 y; 32 cases 1–2 y; 18 cases 2–4 y; 47 cases 4–6 y; 13 cases <5 y; 20,824 cases <5 y; 18,376 cases <5 y; 16,720 cases <5 y; 14,489 cases <5 y; 13,758 cases <5 y; 10,970 cases <2 y; 145 cases 3–5 y; 101 cases

Yemen (cross-sectional)

[31] [32] [33] [34] [56] [36] [57]

AOM, acute otitis media; ASOM, acute suppurative otitis media; m, month; y, year; N, sample size; NR, not reported.

prevalence of OME was found to be 9.1% (167/1833) in preschoolers and 14.1% (283/2000) in school-aged children. Slightly more children with OM had smoking parents (54%; 243/450). Annual health reports from Oman, based on state surveillance, provided reliable data for the total number of AOM and chronic OM (COM) cases for 2003, 2004, 2005, 2007, 2008 and 2009 [31–37]. Oman’s total AOM cases in children <5 years of age decreased from 20,824 in 2003 to 10,970 in 2009 and cases of COM from 2951 in 2003 to 722 in 2009. Importantly, the 7-valent pneumococcal conjugate vaccine (PCV) was introduced in Oman’s National Immunization Program (NIP) in 2008 [81]. In Bahrain, similar surveillance data to Oman is provided by the Salmaniya Medical Complex and covers suppurative unspecified OM and OME (non-suppurative OM) for children <1 year relative to all discharges for that age group (Table 2) [38–47]. Similarly to Oman, PCV was introduced in Bahrain’s NIP in 2008 [81]. The vaccine is recommended to be administered in a 2-dose schedule at 2 and 6 months of age followed by a booster at 15 months of age [82]. 3.1.5. Russia Lebedeva et al. provided both prevalence and incidence estimates for 1991 and 1996 from Orenburg, Russia [48]. They reported an overall prevalence estimate for all sub-categories of OM between the ages 0–7 years at 5.1% for 1991, increasing to 7.8% for 1996. They also reported separate prevalence estimates for boys and girls and for different age groups: <1 year, 1–3 years and 4–7 years. Between 1991 and 1996 there were considerable increases in OM incidence and prevalence overall and for each age group and gender. The incidence estimates increased from 13.6 per 1000 children to 34.5 per 1000 children aged 0–7 years (Table 2). The largest increases were in the <1 year age group, with 41.9% increase for boys and 37.5% for girls, and 6.7% for boys and 4.9% for girls, for incidence and prevalence, respectively. To account for

these relatively large increases in incidence and prevalence, the authors point to improvements in surveillance activities, the use of sensitive OM case definitions and improvements in access to care. Of note, Russia introduced PCVs into its NIP in the beginning of 2014 [81]. 3.2. Etiology Six studies described the bacterial etiology of OM (the number of cases of OM or its sub-categories where a pathogen could be identified) in children <6 years of age [49,55,64,69,76,80] (Table 3). These studies covered 3 regions and 5 countries (Nigeria, Ethiopia, India, Saudi Arabia and Turkey) and included patients with different subtypes of OM, used a range of study designs and reported outcomes for several different age groups. The majority of studies were relatively small in terms of sample size. All studies were conducted before the introduction of PCVs into the countries’ NIPs [81]. The most common bacterial pathogens were S. pneumoniae, H. influenzae and S. aureus. The estimates from 4 studies reporting data on S. pneumoniae ranged from 8.8% to 38% with little consistency observed between the studies or between subcategories of OM [49,55,76,80]. H. influenzae prevalence estimates from the same studies ranged between 7.4% (AOM) and 24.6% (secretory OM) [49,55,76,80], with 3 percentage estimates 20% [55,76,80]. S. aureus estimates from 5 studies ranged from 4% to 25% [49,55,64,76,80], with reasonable consistency seen within 3 of the studies with percentage estimates >19% [49,76,80]. Bulut et al. was the only study found to describe viral isolates of AOM in children <6 years of age in Turkey [55]. Among children aged 6–24 months, 26% (13/50) were infected with respiratory syncytial virus (RSV) and 12% (6/50) were infected with human rhinovirus (HRV) (2 children were positive for both RSV and HRV) [55].

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Table 2 Summary of studies reporting counts or incidence of chronic and other OM for children <6 years of age. Region

Country (study design)

N

Diagnosis

Age; count (%)

Source

Africa

Egypt (cross-sectional)

75,789

OM

[24]

Nigeria (case series) Nigeria (cross-sectional)

74 500 569 600

CSOM OM OME OM

375

CSOM

703 361

OM CSOM

112

CSOM

391

CSOM

Coˆte d’Ivoire (cross-sectional)

653

OM

<2 m; 258/3145 (8.2%) 2–11 m; 2413/22,649 (10.7%) 1–4 y; 5407/49,995 (10.8%) 1–5 y; 41/74 (55.4%) 0–5 y; 69/88 (78.41%) <5 y; 185/569 (32.5%) <1 y; 10/69 (14.5%) 1–4 y; 55/245 (22.45%) 0–5 y; 109 specimens positive for bacterial isolates 0–6 y; 42/144 (29.2%) 0–1 y; 35/83 (42.2%) 2–5 y; 98/151 (64.9%) <2 y; 43 cases 2–4 y; 20 cases <6 m; 5/167 (3%) 6–11 m; 17/167 (10.2%) 12–23 m; 50/167 (29.4%) 24–59 m; 95/167 (58.9%) 0–4 y; 15.3%

India (cross-sectional)

296 100 800

CSOM OM OM

278 252 203

CSOM CSOM CSOM

Pakistan (cross-sectional)

197 87 156

Exudative OM Secretory OM CSOM

China (cross-sectional)

2902

OME

7469

OME

Hong Kong (cross-sectional)

797

Secretory OM

Saudi Arabia (cross-sectional)

1800

OM OM (complications) Secretory OM OME COM

<5 y; 463 cases <5 y; 45 cases 0–4 y; 47 cases 5–6 y; 16/105 (15.2%) <5 y; 2951 cases

[75]

<5 y; 2478 cases <5 y; 2074 cases <5 y; 1633 cases <5 y; 981 cases 98/654 (15%) 33/654 (5%) <4 y; 748 (per 10,000) <5 y; 722 cases 83/688 (12.1%) 51/688 (7.4%) <4 y; 658 (per 10,000) 0–5 y; 21/739 (2.8%) 2–6 y; 167/1833 (9.1%) 0–6 y; 31% <1 y; 1/188 discharges

[32] [33] [34] [56]

NR 739 1833 856 188

COM COM COM COM Secretory OM Supp. OM OM COM Secretory OM Supp. OM OM OM OME Serious OM Non-supp.OM

157 109 242 149 129 185

Non-supp.OM Supp. & unsp. OM Non-supp.OM Supp. & unsp. OM Non-supp.OM Supp. & unsp. OM

<1 <1 <1 <1 <1 <1

Ethiopia (cross-sectional)

India and South Asia

Bangladesh (case series) Bangladesh (cross-sectional)

China and Hong Kong

Middle East

Oman (cross-sectional state surveillance)

321 1077 NR NR NR NR NR 654 NR NR 688

UAE (cross-sectional) Iran (cross-sectional) Bahrain (cross-sectional hospital surveillance)

[58] [59] [60,61] [23] [62] [63] [53] [64] [65]

[66]

2–5 y; 17/296 (5.7%) 1 m–3 y; 5/100 (5%) <1 y; 1/8 (12.5%) 1–2 y; 11/83 (13.3%) 2–3 y; 14/161 (8.7%) 3–4 y; 13/170 (7.6%) 4–5 y; 15/165 (9.1%) 0–2 y; 29 cases NR; 19/252 (7.5%) <1 y; 2/12 (17%) 2–5 y; 8/62 (13%) <1 y; 8 cases 2–4 y; 9 cases <1 y; 55 casesa 1–5 y; 45 casesa

[67] [68] [27]

2–3 y; 8/57 (14%) 3–4 y; 38/457 (8.2%) 4–5 y; 18/364 (5%) 5–6 y; 27/553 (4.9%) 3 y; 90/742 (12.13%) 4 y; 162/3101 (6.93%) 5 y; 200/3250 (6.46%) 2–3 y; = 66 (21.6%)b 4–5 y; = 35 (7.1%)b 2–3 y; = 94 (30.7%)c 4–5 y; = 68 (13.8%)c

[26]

y; y; y; y; y; y;

5/157 discharges 26/109 discharges 6/242 discharges 22/149 discharges 1/129 discharges 18/185 discharges

[69] [3] [70] [71] [72] [73]

[25]

[74]

[76] [77] [31]

[35] [36]

[37] [78] [30] [79] [38] [39] [40] [41] [42]

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R. DeAntonio et al. / International Journal of Pediatric Otorhinolaryngology 85 (2016) 65–74

Table2 (Continued ) Region

Russia and CIS

Country (study design)

Russia (cross-sectional)

N

Diagnosis

Age; count (%)

110 123 102 132 119 105 97 103 92

Non-supp. OM Supp. & unsp. OM Non-supp. OM Supp. & unsp. OM Non-supp. OM Supp. & unsp. OM Non-supp. OM Non-supp. OM Non-supp. OM

<1 <1 <1 <1 <1 <1 <1 <1 <1

130,278d

All types

0–7 y; 13.6 (per 1000) <1 y; 9.3 (per 1000)f 1–3 y; 7.2 (per 1000)f 4–7 y; 15.5 (per 1000)f <1 y; 12.3 (per 1000)g 1–3 y; 10.3 (per 1000)g 4–7 y; 17.3 (per 1000)g 0–7 y; 34.5 (per 1000) <1 y; 51.2 (per 1000)f 1–3 y; 32.1 (per 1000)f 4–7 y; 32.9 (per 1000)f <1 y; 49.8 (per 1000)g 1–3 y; 38.4 (per 1000)g 4–7 y; 29.4 (per 1000)g

115,828e

y; y; y; y; y; y; y; y; y;

1/110 discharges 13/123 discharges 4/102 discharges 24/132 discharges 2/119 discharges 8/105 discharges 5/97 discharges 1/103 discharges 8/92 discharges

Source [43] [44] [45] [46] [47] [48]

OM, otitis media; COM, chronic otitis media; CSOM, chronic suppurative otitis media; OME, otitis media with effusion; N, sample size; supp., suppurative; unsp., unspecified; m, month; y, year; NR, not reported; UAE, United Arab Emirates. a Read from a graph. b Otoscopic diagnosis. c Tympanometric diagnosis. d 1991. e 1996. f Males. g Females.

3.3. Antibacterial resistance and susceptibility Only few studies reported on antimicrobial resistance for OM patients <6 years of age [49,80]. In Nigeria, Ako-Nai et al. [49] reported on the high levels of resistance for all 35 isolates, including S. pneumoniae, H. influenzae and S. aureus, to one or more antibiotics (74.2% resistant to penicillin, 62.8% to streptomycin, 57.0% to gentamicin, 68.0% to chloramphenicol, and 77.7% to nalidixic acid). All 35 isolates were sensitive to ofloxacin [49]. Similarly, Guven et al. [80] reported on the considerable resistance to penicillin amongst the same pathogens in Turkey (22/46 (48%) S. pneumoniae, 16/24 (67%) of H. influenzae and 8/16 (50%) S. aureus isolates). All of these, except for 4/16 (25%) S. aureus isolates, were susceptible to amoxicillin-clavulanate. They also note that a significant proportion (40%) of bacteria resistant to penicillin came from children 2 years of age [80]. Again, both studies were conducted before PCVs being introduced in NIPs (Nigeria–end of 2014, Turkey–end of 2008) [81]. 4. Discussion This review has investigated the epidemiology, etiology and antibiotic resistance of OM across 90 developing and newly industrialised countries and found that OM remains associated with a high disease burden and costs for the payer and for the society. These data are valuable for vaccine decision-makers to evaluate the potential health impact of vaccines in their countries. They are also relevant in the context of antibiotic treatment and potential antibiotic resistance. The current review covered a variety of outcomes relating to OM including incidence and prevalence, distribution of causing pathogens and antimicrobial resistance. However, the relative paucity of data and the heterogeneity on study designs, OM case definitions and settings where most of the literature was identified, made generalisations very difficult and conclusions should be drawn with caution.

In total, 59 publications were included in the review, covering the 1992–2011 period. This might be the best evidence considering prospective follow-up at population level. These publications were found to address the question of OM count and/or prevalence and/ or incidence in the relevant countries. Several population-based studies were found [23–27], along with single-centre studies which used relatively large samples [28–30]. Oman and Bahrain were well-served by health system or hospital surveillance data which was reported consecutively over several years [31–47]. Data coverage was featuring prominently within some countries like Nigeria, while others, like Russia, had only one study reporting data from one city [48]. A number of reviews were recently published, assessing OM data in children from different regions of the world [2,4,5]. In a systematic review aimed to provide global estimates for OM and related conditions, the AOM incidence rate was estimated at 10.85% (709 million cases each year, 51% of these occurring in <5 yearolds) [4]. In another review, Bardach et al. reported an incidence range for AOM of 1171–36,000 episodes/100,000 children, for children aged <5 years of age from Latin America and the Caribbean [2]. In Asia Pacific countries, OM prevalence in school-age children was reported to vary between 3.25% (Thailand) and 12.23% (Philippines) [5]. Our results are in agreement with recently published data [2,4,5]; the reported prevalence of OM in population-based studies was between 6.3% and 10.7%. In several studies included in the review, the OM prevalence values were higher at younger ages (<3 years of age) [23,24,26,27]. The reported values included here are however much lower than those from comparable studies in other world regions. Auinger et al. reported the prevalence of OM in the US from 1988–1994 for children <6 years of age to be 68.2% (95% CI: 66.3%, 70.1%) [1]. The prevalence of early onset of OM (<1 year of age) was reported to be 56.8% (95% CI: 52.9%, 60.7%), while repeated OM prevalence was 36.1% (95% CI: 32.8%, 39.3%) [1].

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Table 3 Summary of included studies reporting the distribution of pathogens and isolates causing OM in children <6 years of age. Region

Country (study design; year)

N

Diagnosis

Pathogens isolated

PCV introduction (year)

Source

Africa

Nigeria (cross-sectional; 2002)

617 (53a)

AOM

2014 (phasedc)

[49]

Ethiopia (cross-sectional; 2001)

63d

CSOM

S. pneumoniae; 6/68b (8.8%) H. influenzae; 5/68 (7.4%) S. aureus; 17/68 (25%) Bacillus spp; 10/68 (14.7%) Corynebacterium spp; 3/68 (4.4%) P. mirabilis; 11/68 (16.2%) P. aeruginosa; 5/68 (7.4%) K. oxyotoca; 4/68 (5.9%) Citrobacter spp; 1/68 (1.4%) S. aureus; 9 (8.0%) single, 4 (3.6%) mixed P. mirabilis; 12 (10.7%) single, 8 (7.1%) mixed E. coli; 6 (5.3%) single, 6 (5.3%) mixed Klebsiella; 3 (2.7%) single, 5 (4.5%) mixed Others: 7 (6.2%) single, 10 (8.9%) mixed

2011

[64]

India and South Asia

India (cross-sectional; 2004)

278

CSOM

P. aeruginosa; 3/29c (10.3%) S. aureus; Klebsiella and Citrobacter (NA)

No decision

[69]

Middle East

Turkey (case series; 2006–2007)

120

AOM

2008

[55]

180

AOM

321

Secretory OM

S. pneumoniae; 18 (36%) H. influenzae; 8 (16%) S. aureus; 2 (4%) M. catarrhalis; 1 (2%) E. coli; 2 (4%) S. pneumoniae; 16/42e (38%) H. influenzae; 10/42e (24%) S. aureus; 8/42e (19%) S. aureus 15 (24.6%) H. influenzae; 15 (24.6%) Pseudomonas spp; 9 (14.8%) Proteus spp; 1 (1.6%) S. pneumoniae 6 (9.8%) S. pyrogenes 4 (6.6%) Others 3 (4.9%)

Saudi Arabia (cross-sectional; 1998)

[80]

2009

[76]

a

Children with AOM. Number of isolates. c Children <2 years of age. d Children <4 years of age. e Children <2 years of age for which bacteria were isolated. OM, otitis media; AOM, acute otitis media; CSOM, chronic suppurative otitis media; OME, otitis media with effusion; N, sample size; NA, not available b

In some areas, data covering the screening period for the current review (1992–2011) were very limited. However, more recent data are currently available. For example, a review published in 2014 evaluated the pneumococcal serotype distribution in Russia [83]. In one of the studies included in that review, the incidence of severe AOM (requiring tympanocentesis) was reported at 12.2 per 1000 in children <3 years old, and 9.7 per 1000 children 4–7 years old from Saint Petersburg [83]. Another very recent study from Kenya [84], which included 13.109 children <15 years of age (1702 <6 years of age) from 58 urban and rural schools, reported the following OM rates (per 1000 children [with 95% confidence intervals]) in children <6 years of age: AOM urban, 19.3 (6.3– 45.1); AOM rural, 27.7 (19.1–36.3); OME urban, 54.1 (25.7–82.4); OME rural, 35.3 (25.6–45); CSOM urban, 30.9 (13.3–60.8); CSOM rural, 12.5 (6.7–18.2). For the current review, only 6 studies (5 AOM and 1 CSOM) were found to address the bacterial etiology of OM in children <6 years of age [49,55,64,69,76,80]. It should be noted that all results were based on a small number of cases. Some overlap in results was identified between the estimates of S. pneumoniae, H. influenzae and S. aureus in Nigeria, Turkey and Saudi Arabia: S. pneumoniae estimates in children with AOM were reported between 8.8% [49] and 36–38% [55,80]; H. influenzae prevalence was reported at 16–24.6% in 3 studies (2 AOM and 1 CSOM) [55,76,80]; and S. aureus estimates were between 19–25% in 3 studies (2 AOM and 1 CSOM) [49,76,80]. In addition to the 6 studies initially included in this review, 2 very recent papers (outside the screening period) reported on the

bacterial etiology and the antimicrobial susceptibility of AOM in children from China [85] and Saudi Arabia [86]. In the Chinese study of children <18 years of age, Ding et al. reported that the leading cause of AOM was S. pneumoniae (47.2%; 108/229), followed by S. aureus (18.8%; 43/229) and H. influenzae (7.4%; 17/229) [85]. In Al-Mazrou et al. 21% (14/66) of AOM episodes recorded in Saudi children 3–60 months of age were positive for either S. pneumoniae or NTHi and 26% (17/66) for S. aureus. The authors suggested that even if S. aureus is an uncommon cause of AOM, it might become an important contributor to AOM in these regions following the introduction of routine pneumococcal vaccination [86]. Importantly, the relative consistency seen within 3 of our included studies [49,76,80], highlight the importance of screening for S. aureus as a pathogen in AOM. In comparison with the data reviewed here, a systematic review by Coker et al. included 6 studies undertaken in the US, Finland, and the Netherlands [20]. These studies reported percentage estimates of pathogens causing AOM, in children 4 weeks to 18 years of age, ranging from 23% to 48% for S. pneumoniae and 41% to 57% for H. influenzae. Bardach et al. estimated that S. pneumoniae (32.4%) and H. influenzae (26.0%) including NTHi (18.3%), were the most prevalent AOM bacterial pathogens in children <6 years of age from Latin America and the Caribbean [2]. In this meta-analysis, S. aureus prevalence was estimated at only 2.77% [2]. Antimicrobial resistance is a major problem in countries with higher density populations where antibiotics are easily obtained over the counter [87,88]. For example, in China, India and Nigeria,

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antibiotic sales have recently increased with the number of the wealthy middle class individuals [89]. Therefore, concerns still remain about combating the spread of antimicrobial resistance especially in children with pneumonia and OM. Concerning antimicrobial resistance, only 2 studies included in the current review reported data from OM samples for children <6 years of age. Ako-Nai et al. and Guven et al. reported high levels of resistance to penicillin [49,80]. Similarly, in the recent aforementioned study from China, the antibiotic resistance rates of S. pneumoniae isolates to erythromycin were 99.1%, and the non-susceptibility rate to penicillin was 54.6% [85]. In another recent study from Russia, the rate of multidrug-resistant pneumococci was reported at 22%, while the resistance rate to penicillin and erythromycin was 28% and 26%, respectively [90]. A recent study from South Africa suggests that managing comorbidities associated with CSOM (malnutrition, HIV infection and anemia), especially in children from Africa, can significantly improve the treatment outcomes [91]. This study points out the fact that all children presenting with CSOM should receive a comprehensive clinical examination, with a nutritional assessment, an HIV test and other clinical investigations [91]. Moreover, as shown in a recent systematic review, early breastfeeding, smoking avoidance during and after pregnancy, and reduction of exposure to indoor air pollution are crucial in prevention of AOM and its complications and sequelae [4]. PCVs have been shown to have a direct impact against OM [92–94]. Moreover, the development and widespread use of H. influenzae type b (Hib) conjugate vaccines have nearly eradicated invasive Hib disease in children in countries where the vaccines are used widely [95]. However, the majority of H. influenzae strains currently causing AOM are NTHi. Interestingly, a PCV incorporating a carrier protein (protein D) derived from NTHi was shown to have modest efficacy against NTHi AOM [93,94]. A recent study from the US aimed to determine the microbiology of OM in children at 2–3 years post-introduction of the 13valent pneumococcal conjugate vaccine (PCV13) in February 2010 [96]. A single (1/39) non-vaccine S. pneumoniae (serotype 16) isolate was obtained from a 7-valent pneumococcal (PCV7)-only vaccinated patient and was penicillin susceptible, indicating that PCV13 has had a significant impact on pneumococcal infections during these initial years following licensure [96]. Concerning the impact of PCV7, a systematic review by Taylor et al. concluded that this vaccine provides some protection against OM, but more data with comparisons pre- to post-vaccination are needed to estimate the true impact of vaccination on AOM [97]. Although these data are essential, as of December 2012, PCV was introduced into the NIP in only 44% (86/194) of the WHO member states, with 41% (19/46) of member states in the African Region, 33% (9/27) of member states in the Western Pacific Region, and none of 11 member states in the South East Asia Region [98]. As of 2015, 127 countries (65%) have introduced PCV into their NIP (including 119 universal, 2 phased, and 6 at-risk programs) and 23 additional countries have announced plans to introduce PCV into their NIP [81]. A summary of the findings on the availability of pneumococcal and Hib vaccinations in the relevant countries considered for the current review is presented in Supplementary materials, Appendix D. This information was mainly obtained from a WHO/UNICEF survey in 2011 [99]; additional resources included country-specific ministry of health websites. The strength of this review lies in its adherence to established methods for conducting systematic reviews, extensive searching, an inclusive date range, and the searching, screening and inclusion of multi-language papers, combined with a quality assessment of the included studies. Compiling all available evidence on this matter will help stakeholders to make informed decisions on prevention measures.

However, our review has several limitations. Firstly, there was a lack of reliable data, mainly associated with the variability in case definitions for OM, to confidently address the research questions for the relevant countries. Few studies were population-based or reported estimates for incidence or prevalence. Instead, most provided one-off measures of OM for a single site over a single timepoint. Most studies also only included small or modest sample sizes. The included studies employed different study designs including parental reports of physician’s diagnosis; recall bias is always a potential factor in survey questionnaires. The studies used a variety of means to diagnose OM and included a wide range of OM case definitions, leading to overestimation of reported prevalence. Due to the heterogeneity in reporting the outcomes, statistical pooling or a meta-analysis could not be performed. Another limitation of this review relates to the screening of titles and abstracts. Given the volume of results to be screened we frequently relied on the first author’s correspondence address as a means of judging whether the study was conducted in a country of interest when it was not clear from the title or abstract. Finally, a further limitation of this review is that 75 full papers could not be retrieved, despite extensive efforts. It is difficult to assess the impact of not having seen these papers, though based on the exclusion pattern it seems likely that many would not have met the inclusion criteria. While there are clear and substantial obstacles to undertaking research in many of the countries included in this review, future studies should endeavour to be population-based and/or provide repeated measures to add further reliability to the data. When studies include a broad age range (children and adults), it would be beneficial to report the results for adults and children separately, as the health implications may vary depending on the age group. Future studies should also aim to use strict and harmonized OM diagnostic criteria in assembling a sample and adequately report this in publications. Studies of bacterial etiology and antimicrobial resistance should include much larger samples to add further reliability to the evidence-base. 5. Conclusions The studies included in this review indicate that OM and its various sub-types are prevalent and a burden across the 90 developing and newly industrialised countries. The data presented provided an overview of the best available evidence on the burden of OM data up to 2012, prior to Hib and pneumococcal vaccines being widely used in these countries. Although in the majority of these countries Hib and pneumococcal vaccines have been licensed, only some countries have introduced them in the NIP. These key data would be essential for any discussion with decision makers within these countries on potential introduction and impact of Hib and pneumococcal conjugate vaccines in prevention of OM. Funding This systematic review was sponsored and funded by GlaxoSmithKline Biologicals SA. GlaxoSmithKline Biologicals SA was involved in all stages of the study conduct and analysis; and also took charge of all costs associated with the development and the publishing of the manuscript. Contributors All authors were involved in the conception or the design of the review; participated in the analysis and interpretation of the data, and the development of this manuscript. JK participated in the collection or assembling of data. All authors had full access to the

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data, gave final approval before submission and are accountable for all aspects of the work. Conflict of interest RDA, JPY, JPC and JES are employees of GSK group of companies and hold stock options/restricted shares from the sponsoring company. JK reports grants from GSK group of companies during the conduct of the systematic literature review. Acknowledgements The authors would like to thank the staff at Kleijnen Systematic Reviews Ltd for carrying out the literature search and the data extraction for the review. The authors also thank Vasile Coman, Abdelilah Ibrahimi and Angeles Ceregido (from XPE Pharma & Science on behalf of GSK) for editing and coordinating the publication development.

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