National impact of 13-valent pneumococcal conjugate vaccine on ambulatory care visits for otitis media in children under 5 years in the United States

Accepted Manuscript National Impact of 13-Valent Pneumococcal Conjugate Vaccine on Ambulatory Care Visits for Otitis Media in Children under 5 Years in the United States Xiaofeng Zhou, Cynthia de Luise, Michael Gaffney, Catharine W. Burt, Daniel A. Scott, Nicolle Gatto, Kimberly J. Center PII:

S0165-5876(19)30034-5

DOI:

https://doi.org/10.1016/j.ijporl.2019.01.023

Reference:

PEDOT 9348

To appear in:

International Journal of Pediatric Otorhinolaryngology

Received Date: 13 November 2018 Revised Date:

16 January 2019

Accepted Date: 16 January 2019

Please cite this article as: X. Zhou, C. de Luise, M. Gaffney, C.W. Burt, D.A. Scott, N. Gatto, K.J. Center, National Impact of 13-Valent Pneumococcal Conjugate Vaccine on Ambulatory Care Visits for Otitis Media in Children under 5 Years in the United States, International Journal of Pediatric Otorhinolaryngology, https://doi.org/10.1016/j.ijporl.2019.01.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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National Impact of 13-Valent Pneumococcal Conjugate Vaccine on Ambulatory Care Visits for Otitis Media in Children under 5 Years in the United States Xiaofeng Zhou, PhD,1 Cynthia de Luise, PhD,1 Michael Gaffney, PhD,2 Catharine W. Burt, EdD,3 Daniel A. Scott, MD,4 Nicolle Gatto, PhD,1 Kimberly J. Center, MD4 Epidemiology, Worldwide Safety and Regulatory, Pfizer Inc, New York, NY, USA; 2Statistical Research and Consultation Center, Pfizer Inc, New York, NY, USA; 3Biostatistician Consultant, Pittsboro, NC, USA; 4Vaccine Clinical Research and Development, Pfizer Inc, Collegeville, PA, USA

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1

Corresponding author:

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Xiaofeng Zhou, Worldwide Safety and Regulatory, Pfizer, 219 E 42nd Street, Mail Stop 219/9/01, New York, NY 10017 USA

Funding source: Funding for this work was provided by Pfizer, Inc.

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Conflicts of interest: XZ, CL, MG, DS, NG and KC are employees of Pfizer and may hold stock and/or other investments in the company. CB was a consultant to Pfizer for this study and was compensated for participating in manuscript development.

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Contributors’ statement: Xiaofeng Zhou, Cynthia de Luise, Michael Gaffney, Catharine W. Burt, Daniel A. Scott, Nicolle Gatto, and Kimberly J. Center have contributed to more than one following activities: conception and design of the study, acquisition of data, analysis and interpretation of data, participation in drafting, or revision of the submitted article.

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Abbreviations: AAP – American Academy of Pediatrics; AOM – acute otitis media; CHC - Community Health Center; ICD-CM - International Classification of Diseases, Clinical Modification; NAMCS National Ambulatory Medical Care Survey; NHAMCS - National Hospital Ambulatory Medical Care Survey; NHCS - National Center for Health Statistics; NPC – nasopharyngeal carriage; OM – otitis media; OPD - outpatient department data; PCV – pneumococcal conjugate vaccine; RD - rate differences; RR - rate ratios; VE – vaccine efficacy.

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Abstract Objective: The 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) were approved in

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the US in 2000 and 2010, respectively, for active immunization against invasive disease caused by all vaccine serotypes and otitis media (OM) caused by 7 serotypes common to both vaccines, starting at ~6 weeks of age. This study assessed the impact of PCV13 on OM by evaluating changes in US ambulatory care visit rates between the period before PCV7 (1997-1999), during PCV7 (2001–2009), and after the

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introduction of PCV13 (2011-2013) among US children <5 years old.

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Methods: This ecological study used US National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data. Trend analyses using weighted least-squares regression and mean visit rates were calculated for OM and two control endpoints not likely to be related to either vaccine (skin rash and trauma).

Results: Among children <5 and <2 years old, the observed reduction in OM visit rates was 22% (95%CI:

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12%-32%) and 24% (95%CI: 13%-35%) when comparing PCV13 to PCV7 periods, and 41% (95%CI: 30%-52%) and 48% (95%CI: 37%-59%) when comparing PCV13 to pre-PCV7 periods. Visit rates for

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skin rash and trauma remained stable.

Conclusion: Significant reductions in US ambulatory care visit rates for OM were observed among

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children aged <5 years after introduction of PCV13 compared to the periods before and during PCV7; reductions were greatest among children <2 years old. The reductions beyond the PCV7 period support the effectiveness of the vaccine’s 6 additional serotypes in preventing OM.

Key words: PCV13, Otitis Media, NAMCS, NHAMCS, S. pneumoniae

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1. Introduction In the United States (US), otitis media (OM) is among the most common reasons for sick visits in

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children under 5 years of age, with a peak incidence between 6 and 18 months of age [1-3]. Before the US introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in February 2000, OM accounted for approximately 24.5 million office visits and up to $5.3 billion in treatment costs each year [4-8]. OM

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is also the most common reason for antibiotic prescriptions among US children, accounting for 15 million prescriptions annually, despite the fact that a large proportion of clinical OM does not have a bacterial

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etiology [4, 5]. Historically, about 30% to 55% of OM episodes in children <5 years old were caused by Streptococcus pneumoniae [9-11]. A Finnish study demonstrated that among children with OM episodes due to pneumococcus, approximately 60% had serotypes included in PCV7 (i.e. 4, 6B, 9V, 14, 18C, 19F, and 23F) [12]. The 13-valent pneumococcal conjugate vaccine (PCV13), approved in February 2010 in the US, includes an additional 6 serotypes (1, 3, 5, 6A, 7F, and 19A). PCV13 is approved in the US for

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use in children from 6 weeks through 5 years of age for active immunization for prevention of invasive disease caused by 13 S. pneumoniae serotypes and OM caused by the 7 S. pneumoniae serotypes in PCV7 [13]. The recommended immunization schedule is a 4-dose series at 2, 4, 6, and 12-15 months of age.

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Randomized clinical trials and observational post-licensure studies support the effectiveness of PCV7 against OM and/or acute OM (AOM) [3, 11, 14, 15]. Pre-licensure trials demonstrated vaccine efficacy

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(VE) of 57% against AOM caused by the serotypes included in the vaccine as well as significant efficacy against recurrent OM (VE ~9%) and tympanostomy tube placement (VE ~20%) in addition to OM overall (VE ~6%-8%), regardless of etiology [3, 11]. Most post-marketing observational studies have suggested that routine use of the vaccine had greater impact on the frequency of overall OM visits than found in the pre-licensure trials, [1, 3, 5, 11, 16-19] with reductions of approximately 20% to over 40% among US children <2 years old [1, 5, 16]. More recent observational studies of PCV13 have shown further declines of 7% to over 50% in OM or AOM incidence or related hospitalizations, and ambulatory care visits in

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children <2 years or older after introduction of PCV13 national immunization programs (NIP) in the US and elsewhere [ 20-24]. Published studies that evaluate the national impact of PCV13 on OM visits among young children in the US beyond the 1st year after the introduction of PCV13 are limited.

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The primary objective of this study was to assess the impact of PCV13 on OM by evaluating changes in US ambulatory care visit rates between the PCV7 period (2001-2009) and after the introduction of PCV13 (2011-2013) among US children <5 years old. We further evaluated the impact of PCV13

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compared to pre-PCV7 (1997-1999) and PCV7 periods, as well as the impact of PCV7 compared to pre-

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PCV periods.

2. Methods 2.1 Study design and setting:

This study was a non-interventional, ecological database study using 2 publicly available data sources

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from ongoing national surveillance of US ambulatory care utilization. Data include visits by children under age 5 to office-based physicians and hospital emergency rooms. Three distinct periods representing the pre-PCV7 (1997-1999), PCV7 (2001-2009), and PCV13 (2011-2013) periods were analyzed. The years 2000 and 2010 (introduction and implementation of PCV7 and PCV13, respectively) were

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considered transition years and were not included in the analysis. The primary endpoint was OM visits.

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Skin rash and trauma visits were selected as control endpoints, as ambulatory care visit rates for these diagnoses are unlikely to be related to vaccination. Up to 3 medical diagnoses per patient visit in both national surveys are recorded using the International Classification of Diseases, Clinical Modification, Ninth Revision (ICD-9-CM). The detailed ICD-CM diagnosis codes of ambulatory care visits for OM [1], skin rash, and trauma are listed in Supplementary Table 1 and remain the same across all analysis periods. 2.2 Data source:

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Data sources were the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS). NAMCS is a national survey that provides objective, reliable information about the provision and use of office based ambulatory medical care services in the

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US [25]. NHAMCS collects data on the utilization and provision of ambulatory care services in hospital emergency and outpatient departments and in ambulatory surgery centers located in the 50 States and the District of Columbia [26]. Both surveys are based on a national sample of medical visits, not people. The

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diagnoses of OM and the two control endpoints are the physician’s diagnosis in the medical record. If the patient only saw a physician assistant or nurse practitioner at the sampled visit then his/her diagnosis was

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recorded. More details of the data sources are described elsewhere [1]. Due to unavailability of outpatient department (OPD) data in 2012 and 2013 NHAMCS at the time of this study, and the removal of Community Health Center (CHC) data in 2012 and 2013 NAMCS due to an adjustment by the National Center for Health Statistics (NCHS) to its survey method, both OPD and CHC data were not included to maintain comparable data across calendar years. Thus, we reported ambulatory visits from physician

2.3 Analysis:

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offices (excepting community health center data) (NAMCS) and emergency departments (NHAMCS).

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Age stratification: Analyses were stratified on age categories <2 years and 2-<5 years, as children under 2 are the primary target of immunization with PCV13. Visit rates among children <5 years were also pooled

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to show the overall rates in this age group. Calculation of visit rates: Annual OM visit rates during the three periods in children <2 years, 2-<5 years and <5 years, respectively, were derived by dividing the total number of OM visits (the projected national estimate) by the corresponding age-specific, civilian, non-institutional population estimates from the US Census Bureau [25-27]. Only estimates based on >30 unweighted observations and relative standard errors (RSE) <30 were reported, as recommended by NCHS [ 28-29]. In addition to yearly visit rates, individual yearly data were combined in pairs to provide robust estimates when possible [28].

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Stable baseline period: A stable baseline, defined as a period without a statistically significant trend in the data, was used to serve as the baseline for the comparison of period visit rates and to account for temporal variability. Trend analysis was performed for the periods 2001-2009 and 1997-1999 to identify the

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baseline periods for comparison with PCV13 and PCV7, respectively. If a statistically significant trend in annual visit rates during these two periods was found, a stepwise procedure was employed to determine the baseline period as follows: 1) data for the earliest calendar year were removed from analysis, and the

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test for trend was repeated; 2) if a statistically significant trend persisted, data for the earliest calendar year in the subsequent period were removed and the test for trend was repeated. This process was

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repeated until the test for trend indicated no statistically significant trend in the data. This period was then selected as the baseline period for the comparison.

Statistical analysis: The weighted mean visit rate over each of the 3 analysis periods were calculated with weights equal to using the inverse of the variance. Mean visit rate ratios (RR), rate differences (RD),

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and percentage changes ((1-RR)*100) between the PCV13 period and the PCV7 baseline period were compared respectively for OM, skin rash, and trauma among children <2 years, 2-<5 years, and <5 years (Primary Analysis). These analyses were also conducted between the PCV13 period and pre-PCV7

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baseline period and between the PCV7 period and pre-PCV7 baseline period (Secondary Analysis). Weighted least-squares regression of visit rates was performed to identify baseline periods and examine

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trends in visit rates for OM, skin rash, and trauma during PCV7 and PCV13 periods. The trend in OM visits was further examined by extending the period to include pre-PCV7 period. Statistical significance was at α=0.05 (2 sided). All analyses were performed using SAS version 9.4 (SAS Institute Inc. Cary, NC).

3. Results 3.1 Comparison of PCV13 with PCV7 period (primary analysis)

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A baseline period for PCV7 (2002-2009) was identified for comparison with PCV13 (2011-2013) (Supplementary Table 2). In general, boys had more OM visits than girls over time among children <2 and 2-<5 years during both the PCV13 and PCV7 periods (Supplementary Figure 1). The majority of

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OM visits were among white children, then black and “other” across each age group (Supplementary Figure 2). During 2002-2013, annual OM visit rates declined from 101 to 58, 54 to 33, and 74 to 43 visits per 100 children <2, 2-<5, and <5 years, respectively; each of these downward trends was

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statistically significant (p<0.0001, p=0.03, p<0.0001, Figure 1).

Mean OM visit rates declined from 84 to 64 visits per 100 children aged <2 years, 41 to 34 per 100

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children aged 2-<5 years, and 59 to 46 per 100 children aged <5 years during the PCV7 (2002-2009) and PCV13 (2011-2013) periods, respectively (Figure 2). The observed reductions in OM visit rates after introduction of PCV13 were most marked among children <2 years (Figure 2). Comparing PCV13 to PCV7 periods, the mean rate ratios of OM visits were 0.76, 0.84, and 0.78, representing significant reductions of 24% (95% CI: 13%, 35%), 16% (95% CI: 2%, 29%), and 22% (95% CI: 12%, 32%) among

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children <2, 2-<5, and <5 years respectively (Figure 3). Comparison of mean visit rate differences between PCV13 and PCV7 periods demonstrated significant reductions in OM visits per 100 children among those <2, 2-<5, and <5 years (-21 visits (95% CI: -31.04, -9.98), -6 visits (95% CI: -12.36, -0.57),

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and -13 visits (95% CI: -19.69, -6.26)) respectively (Figure 4). Visit rates for skin rash and trauma remained stable during PCV13 and PCV7 periods among children <2, 2-<5, and <5 years (p>0.05), as

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well as in the comparison of percentage change between the 2 periods (Figure 5).

3.2 Comparison of PCV13 and PCV 7 with Pre-PCV7 period (secondary analysis) The stable baseline for pre-PCV7 (1997-1998) was identified for comparison with PCV13 (2011- 2013) and PCV7 (2002-2009) periods (Supplementary Table 3). Between 1997 and 2013, annual OM visit rates declined from 133 to 58, 49 to 33, and 82 to 43 per 100 children <2, 2-<5, and <5 years respectively. At a population level, the total number of OM visits dropped from 10.5 to 4.6 million, 5.8 to 4.0 million, and

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16.3 to 8.6 million in each of the age groups. A statistically significant downward trend in OM visit rates over time was observed in these age groups (p<0.0001, p=0.002, p<0.0001; Figure 6). In addition, a significant downward trend in OM visit rates during 1997-2009 among children<2 and <5 years was also

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observed. Among children <2 years, 2-<5 years, and <5 years, a greater decline in mean OM visit rates per 100 children was observed between the pre-PCV7 (1997-98) to the PCV13 (2011-13) periods (122 to 64, 48

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to 34, and 78 to 46) than between pre-PCV7 to PCV7 (2002-09) periods (122 to 84, 48 to 41, and 78 to 59) (Figure 2). The observed reduction in OM visit rates after introduction of PCV13 and PCV7 was

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most marked among children <2 years. Comparing the percentage change from PCV13 to pre-PCV7 periods, statistically significant reductions in mean OM visits rates among children <2, 2-<5, and <5 years were 48% (95% CI: 37%, 59%), 29% (95% CI: 13%, 45%), and 41% (95% CI: 30%, 52%) respectively (Figure 3). The mean visit rate differences between these two periods showed statistically significant reductions in OM visits per 100 children among those <2, 2-<5, and <5 years: -59 visits (95% CI: -80.60,

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-36.86), -14 visits (95% CI: -24.25, -3.88), and -32 visits (95% CI: -45.35, -19.19) respectively (Figure 4). Comparing PCV7 vs. pre-PCV7 periods, we found a statistically significant reduction in mean OM visit RR and RD for children <2 and <5 years, but not for the subset of children 2-<5 years (Figure 3 and

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Figure 4).

4. Discussion

We evaluated the national impact of PCV13 and PCV7 vaccination programs by combining data from two national surveys to provide national estimates of OM visit rates in the US. Using nationally representative data, this ecological study demonstrated a significant decline in ambulatory OM visit rates among US children <5 years after introduction of PCV13. Our findings were most pronounced in children <2 years of age (those with highest OM incidence and those most likely receive PCV13), with

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24% reduction compared to the PCV7 period and 48% reduction compared to the period before introduction of the PCV7. We also observed a significant reduction in OM visit rates during the years associated with the PCV7 vaccination program compared to pre-vaccination period among children <5

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years of age with a marked protective effect among children <2 years. Stability of visit rates for two control endpoints suggested that the observed reductions in visit rates for OM were not likely due to overall changes in healthcare visit rates. Our choice of an ecological design is ideal to examine the impact

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of national policies and programs that involve the entire population under study and help reduce selection bias. A declining trend could indicate changes associated with a vaccine’s introduction into the population

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and provides indirect evidence of its effectiveness. Such ecologic studies including those using the same data sources were used successfully to evaluate the impact of national vaccination programs including PCV [1, 20, 23, 30]. Our results in this study, while not providing direct evidence of causality, nonetheless suggest a significant and positive impact of the PCV13 vaccination program on otitis media for children <5 years of age in the US, with further reductions in OM visits observed in PCV13 period

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following a decade of PCV7 use.

The observed reductions in OM visit rates associated with PCV13 compared with those of PCV7 are consistent with other observational studies demonstrating further significant declines in overall OM/AOM

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visit rates or incidence in PCV13 ranging from 7% to more than 50% among children <2 years or older in various study settings[ 20-24], including a recent study reporting an additional reduction in OM office

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visit rates of 31% (95% CI: 19%-41%) in PCV13 using the same data source [20]. A US study using data from 8 children’s hospitals demonstrated that the proportion of S pneumoniae isolates included in PCV13 (plus a related serotype) decreased from 50% to 29% (p=0.0006) among middle ear and/or mastoid isolates over the 3-year period following the introduction of PCV13 (2011-2013) [31]. Prospective tympanocentesis studies in young children are more challenging to conduct, but provide the best evidence for the impact of these vaccines on OM. A prospective population-based active surveillance study evaluating pathogen-specific incidence of OM episodes in children aged <2 years in southern Israel

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before and after PCV7 and PCV13 introduction to the Israeli NIP reported up to 91% (95% CI: 80%96%) reduction in OM incidence caused by the additional 6 serotypes in PCV13, and 52% (95% CI: 46%58%) reductions of all-cause OM incidence in PCV13 vs. PCV7 period [24]. A smaller prospective

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tympanocentesis study in the US of the impact of PCV13 on AOM found similar reductions in middle ear disease caused by the 6 additional serotypes [32], especially that caused by serotypes 19A and 6A.

Because nasopharyngeal carriage (NPC) is a necessary precursor of otitis media, evaluation of NPC has

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been proposed as an appropriate surrogate for assessing the impact of PCV on OM [33-34]. Studies of nasopharyngeal carriage (NPC) in children vaccinated with PCV13 showed significant reductions in NPC

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by vaccine serotypes of S. pneumoniae [32, 35-37]. The overall patterns in annual OM visit rates from 2002-2009 among children <2 years in our study were also consistent with those described in the published literature using the same data source with a shorter PCV7 period [1]. Taken together, these data suggest that the reductions observed in our ecologic study are likely associated with the introduction and widespread use of first PCV7 and then PCV13. Nevertheless, we would remind readers that the cause of

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acute OM would not necessarily be due to S. pneumoniae as other pathogens, including bacteria and viruses, can cause otitis media. In our study, the etiology was not defined and is beyond the scope of this study.

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Several limitations are worth noting. First, by using an ecologic study design, it is not possible to provide direct evidence of the field effectiveness of PCV13, neither its effect on individual children nor individual

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serotypes. Second, the identification of OM relies on the healthcare provider’s clinical diagnosis which may or may not be made following specific diagnostic criteria, and gives no additional information regarding causative agent, thus likely leading to some degree of misclassification. Secular trends due to the use of more stringent diagnostic criteria for AOM introduced by the American Academy of Pediatrics (AAP) cannot be ruled out completely. However, we have incorporated the temporary decrease in OM visits in 2004 into the PCV7 baseline by using mean visit rates and observed that there was a substantial (or the largest) decrease in OM visit rates in 2012, prior to the 2013 guidelines. Therefore, the combined

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effect of the AAP guidelines in 2004 and 2013 on the observed reduction would likely be small or negligible and is unlikely to affect the overall trends over time. Third, the survey data used in this study do not distinguish between initial and follow-up visits for OM; however, including all visits of interest for

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all the years under study provides a reasonable assessment of ambulatory care both before and after introduction of the vaccine. Finally, OPD and CHC data were not included in the final analysis due to data unavailability and changes to survey methods. The assessment of the impact before and after

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removal of OPD and CHC data indicated that the study’s overall conclusions are unchanged.

5. Conclusion

Significant reductions in ambulatory visit rates for otitis media were observed among US children aged <5 years after introduction of PCV13 compared to before and during PCV7 periods, suggesting a significant and positive impact of the PCV13 vaccination program, which includes 3 primary doses in

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infancy followed by a booster dose in the second year of life. The observed reductions were most marked among children <2 years. The additional reductions after PCV7 are likely due to the 6 additional serotypes in PCV13. Given the high healthcare burden and incidence of OM, and the association of

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organisms causing OM with antibiotic resistance, the significant and continuous decline in OM visits after

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the introduction of PCV13 suggests important added benefits to the public health of young children in the

Acknowledgements:

Scott Vuocolo, PhD (Pfizer, Inc.) provided editorial assistance for this manuscript, and Rongjun Shen, MS (Pfizer, Inc) provided assistance with data analysis.

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[28] Hsiao C.J, Understanding and using NAMCS and NHAMCS data, National Conference on Health Statistics, 2010, Washington D.C. [29] Centers for Disease Control and Prevention. National Center for Health Statistics. Ambulatory healthcare data. www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm. Last accessed August 6th, 2018. [30] Brotherton J.M., Fridman M., May C.L., Chappell G., Saville A.M., Gertig D.M., Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study, Lancet. 377 (2011) 2085-2092. doi: 10.1016/S0140-6736(11)60551-5. [31] Kaplan S.L., Center K.J., Barson W.J., Ling-Lin P., Romero J.R., Bradley J.S., et al., Multicenter surveillance of Streptococcus pneumoniae isolates from middle ear and mastoid cultures in the 13-valent pneumococcal conjugate vaccine era, Clin. Infect. Dis. 60 (2015) 1339-1345. doi: 10.1093/cid/civ067. [32] Pichichero M., Kaur R., Scott D.A., Gruber W.C., Trammel J., Almudevar A., et al., Effectiveness of 13-valent pneumococcal conjugate vaccination for protection against acute otitis media caused by

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Streptococcus pneumoniae in healthy young children: a prospective observational study, Lancet Ch. Adol. Health. 2 (2018) 561-568. doi: 10.1016/S2352-4642(18)30168-8. [33] Simell B., Auranen K., Kayhty H., Goldblatt D., Dagan R., O'Brien K.L., et al., The fundamental link between pneumococcal carriage and disease, Exp. Rev. Vacc. 11 (2012) 841-855. doi: 10.1586/erv.12.53.

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34] Goldblatt D., Ramakrishnan M., O'Brien K., Using the impact of pneumococcal vaccines on nasopharyngeal carriage to aid licensing and vaccine implementation; a PneumoCarr meeting report, Vaccine. 32 (2013) 146-152. doi: 10.1016/j.vaccine.2013.06.040.

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[35] Dagan R., Patterson S., Juergens C., Greenberg D., Givon-Lavi N., Porat N., et al., Comparative immunogenicity and efficacy of 13-valent and 7-valent pneumococcal conjugate vaccines in reducing nasopharyngeal colonization: a randomized double-blind trial, Clin. Infect. Dis. 57 (2013) 952-962. doi: 10.1093/cid/cit428. [36] Cohen R., Levy C., Bingen E., Koskas M., Nave I., Varon E., Impact of 13-valent Pneumococcal conjugate vaccine on pneumococcal nasopharyngeal carriage in children with acute otitis media, Ped. Infec. Dis. J. 31 (2012) 297-301. doi: 10.1097/INF.0b013e318247ef84.

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[37] Allemann A., Frey P.M., Brugger S.D., Hilty M., Pneumococcal carriage and serotype variation before and after introduction of pneumococcal conjugate vaccines in patients with acute otitis media in Switzerland, Vaccine. 35 (2017) 1946-1953. doi: 10.1016/j.vaccine.2017.02.010.

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Individual yearly data were combined in pair. Transition year (2010) is included to construct the year pair.

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Figure 1. Average Annual Visit Rates (Per 100 Children) of OM (2002-2013)1

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Figure 2. Mean OM Visit Rates (Per 100 Children) During the Pre-PCV7, PCV7, and PCV13 Periods

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Figure 3. Percentage Changes in OM Visit Rates: Comparing PCV13 to PCV7 Period, PCV13 to Pre-PCV7 Period, and PCV7 to Pre-PCV7 Period*

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* PCV13 (2011-2013), PCV7 (2002-2009), and Pre-PCV7 (1997-1998)

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Figure 4. Differences in OM Visit Rates Per 100 Children: Comparing PCV13 to PCV7 Period, PCV13 to Pre-PCV7 Period, and PCV7 to Pre-PCV7 Period*

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* PCV13 (2011-2013), PCV7 (2002-2009), and Pre-PCV7 (1997-1998)

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Figure 5. Percentage Changes in Visit Rates for Skin Rash and Trauma: Comparing PCV13 to PCV7 Period*

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* PCV13 (2011-2013) and PCV7 (2002-2009)

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Figure 6. Average Annual Visit Rates (Per 100 Children) of OM (1997-2013)1

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Individual yearly data were combined in pair. Transition year (2010) is included to construct the year pair. Year 1999 was not included in the analysis due to an unstable estimate resulted from unusually small number of pediatricians sampled in the 1999 NAMCS and large number of those sampled that were out-of-scope for the survey