High pneumonia lifetime-ever incidence in Beijing children compared with locations in other countries, and implications for national PCV and Hib vaccination

Objectives To compare the proportion of Beijing children who have ever had pneumonia (%Pneumonia) to those in other locations, and to estimate by how much national vaccine coverage with Pneumococcal Conjugate Vaccine (PCV) and Haemophilus Influenzae Type b (Hib) could reduce Beijing %Pneumonia. Methods %Pneumonia was obtained for each age group from 1 to 8 years inclusive from 5,876 responses to a cross-sectional questionnaire. Literature searches were conducted for world-wide reports of %Pneumonia. Previous vaccine trials conducted worldwide were used to estimate the pneumococcal (S. pneumoniae) and Hib (H. influenzae) burdens and %Pneumonia as well as the potential for PCV and Hib vaccines to reduce Beijing children’s %Pneumonia. Findings The majority of pneumonia cases occurred by the age of three. The cumulative %Pneumonia for 3–8 year-old Beijing children, 26.9%, was only slightly higher than the 25.4% for the discrete 3 year-old age group, similar to trends for Tianjin (China) and Texas (USA). Beijing’s %Pneumonia is disproportionally high relative to its Gross National Income (GNI) per capita, and markedly higher than %Pneumonia in the US and other high GNI per capita countries. Chinese diagnostic guidelines recommend chest X-ray confirmation while most other countries discourage it in favor of clinical diagnosis. Literature review shows that chest X-ray confirmation returns far fewer pneumonia diagnoses than clinical diagnosis. Accordingly, Beijing’s %Pneumonia is likely higher than indicated by raw numbers. Vaccine trials suggest that national PCV and Hib vaccination could reduce Beijing’s %Pneumonia from 26.9% to 19.7% and 24.9% respectively. Conclusion National PCV and Hib vaccination programs would substantially reduce Beijing children’s pneumonia incidence.

of different diagnostic criteria, national vaccination status and GNI per capita and (2) to estimate by how much Beijing children's %Pneumonia could be reduced by national coverage with PCV and Hib.

Acquisition of Beijing, Tianjin and Texas data
The Beijing CCHH cross-sectional survey was conducted in 2010-2011. Its methods are described in Qu et al. 2013 [17] and the full CCHH questionnaire is published in Zhang et al. 2013 [8]. The Texas and Tianjin studies used the same methods. The question for pneumonia is: Has your child been diagnosed with pneumonia by a doctor? (Yes/No). We will use %Pneumonia to represent the proportion of children, at a given age, who have ever had pneumonia.

Worldwide lifetime-ever pneumonia incidence (%Pneumonia)
We conducted a literature search for %Pneumonia in other regions and countries. Inclusion criteria required (1) age-specific %Pneumonia and (2) total doctor-diagnosed %Pneumonia, regardless of whether hospitalization was required and (3) data for any group of children 3 years old and older. Nine studies, with data for 23 different locations, met these criteria ( Table 1, Results and Discussion).

Age groups
For a specific age group, %Pneumonia is given by: where n lifetime is the number of children in that age group who have ever had pneumonia, that is, the number of children who have had at least one episode of pneumonia, and N is the total number of children in that age group. Because a child can have more than one case of pneumonia, the total number of pneumonia cases for a population is greater than %Pneumonia. Pneumonia incidence, defined as the number of cases in a population of children, is highest in the first 2-3 years (S1 Table). We hypothesized that %Pneumonia, defined as the proportion of children who have ever had pneumonia, increases from 0 to 3 years-old and then plateaus. If so, %Pneumonia can be compared among any samples of children between 3 and 8 yearsold, with the understanding that that there are slight %Pneumonia increases for successive ages. For samples of children <3 years-old, %Pneumonia can be compared only among identical age groups. That is, for age i where 3 i 8, %Pneumonia can be approximated as: We test this hypothesis in the Results and Discussion section (%Pneumonia related to age).

Diagnostic criteria
Pneumonia is diagnosed predominantly by chest X-ray confirmation of clinically suspected pneumonia, or by clinical signs and symptoms alone. We used the country's national diagnostic guidelines as default if a study did not report diagnostic criteria.

Relative GNI
Every year, the World Bank sets GNI per capita index numbers for low, lower middle, upper middle and high income [10]. A country whose GNI is equal to or more than the high income index is classified as "developed." Accordingly, we calculated a relative GNI as the ratio of a country's average GNI per capita for the children's birth years to the average high income index for those years [10], so that a country's whose relative GNI per capita !1.0 can be considered as "developed" [10]. GNIs were not directly available for the province-level municipalities Beijing, Tianjin, Chongqing and Shanghai, so we estimated these GNIs from their GDPs [12] multiplied by China's GNI/GDP ratio [10,12]: where the subscript "m" denotes municipalities and the subscript "C" denotes China. These estimates assume that the municipality's GNI/GDP ratio scales linearly with that of China.

Results and discussion
The Beijing cross-sectional survey yielded 5,876 completed questionnaires, a 65% response rate. The 5,440 Beijing children aged 3 to 8 had an average %Pneumonia of 26.9%, with diagnoses most likely confirmed by chest X-ray, as per China's national guidelines [7,19]. Table 1 shows that the %Pneumonia for the Chinese cities in recent years is the highest, followed by those of Central European countries (Bulgaria, Czechoslovakia, Hungary, Poland, Romania and Slovakia), whose %Pneumonia in the 1980s were only slightly lower than for China cities. The lowest %Pneumonias are for locations in the US, Germany, Australia and Spain in various years.

%Pneumonia related to age
Is it valid to compare %Pneumonia for any age group !3 as we have done in Table 1? We plotted %Pneumonia for age groups 1-8 years from Beijing, Tianjin and Texas in Fig 1, the data for which are shown in S2 and Changsha [20] also show %Pneumonia increasing until age three, and then plateauing. These data are, to the best of our knowledge, the total of available %Pneumonia data for each age group. For incidence, abundant data are available (S1 Table), and an example of incidence versus age for half-year age groups is shown in S1 Fig. In this scatterplot, the incidence of Lower Respiratory Tract Infection rises steeply until 3 years old and then plateaus, similarly to that of %Pneumonia. We conclude that %Pneumonia can be compared for any two years between 3 and 8 inclusive, recognizing that each subsequent year (or added year) will increase %Pneumonia slightly. %Pneumonia comparisons between groups younger than 3 years-old can only be made between same-age groups.
No diagnostic "gold standard" Table 1 specifies whether %Pneumonia was obtained using clinical judgment of signs and symptoms or chest X-ray confirmation of clinical suspicion. The national guidelines for pneumonia diagnosis in China require chest X-ray confirmation and at least one of four clinical signs or laboratory findings [5,19]. By contrast, most countries represented in Table 1 There is no diagnostic "gold standard" for pneumonia [4,32,33]. We surveyed literature studies in which each subject was diagnosed separately by clinical signs/symptoms and chest X-ray ( Table 2). The ratios for clinical to chest X-ray diagnoses range from 1.1 to 7.7, clustering between 2 and 3. In other words, just 1/3 to 1/2 those diagnosed with pneumonia using clinical signs had their pneumonia confirmed by chest X-ray. Accordingly, differences between % Pneumonia in Chinese cities (diagnosis by X-ray) and locations where diagnosis was by clinical signs are even greater than those indicated by the raw numbers of Table 1. S1 Text (Pneumonia diagnosis) further explores the difficulties associated with diagnosing pneumonia. %Pneumonia using chest X-ray: Beijing, Tianjin and Tucson (USA) Table 3 shows %Pneumonia generated by chest X-ray (CXR) diagnoses for Beijing, Tianjin, and Tucson AZ, USA [25]. We compared 3 year-olds only so as to minimize uncertainty inherent in comparing different age groups. The %Pneumonias for the Chinese cities are substantially higher than that for the USA city. Table 3 does not include the 11.2%Pneumonia from a study in northeast Texas USA of 384 three-year-olds born in 2004 [57], because diagnosis was primarily by clinical criteria. Since %Pneumonia by clinical diagnosis is reliably higher than by chest X-ray confirmation, the Texas %Pneumonia is consistent with the Tucson data.
where I u is the incidence in the unvaccinated "control" sample and I v is the incidence in the vaccinated "test" sample [58,59]. Re-arranging yields the incidence in a vaccinated population: While Vaccine Probe studies of PCV and Hib have not yet been conducted in China, they have been conducted in countries that differ from each other demographically and climatically, and have yielded remarkably tight ranges for both S. Pneumoniae and H. Influenzae etiological fractions, with chest X-ray confirmed pneumonia as the endpoint. Table 4 shows VEs calculated via meta-analysis of PCV and Hib studies. Information on the individual studies used for these meta-analyses is given in S3 Table (S3A and S3B Table). These VEs are Table 3

Location
Children Of great interest is the impact of introducing both PCV and Hib. There are no studies to guide a prediction of this impact. However, we can propose a Confidence Interval (CI): the lower limit of %Pneumonia reduction is equal to or slightly greater than that of PCV alone and the upper limit is the sum of PCV and Hib reductions. Table 5 shows that for a population with no vaccination, the maximum reduction by PCV + Hib in %Pneumonia would be to 14.8% from 26.9%. For Beijing's 122,747 children born in 2012, 14,900 fewer children would get pneumonia. For a population that had 1.2% PCV and 41% Hib vaccination rates, the maximum reduction in %Pneumonia would be to 16.9% from 26.9%. For Beijing's 122,747 children born in 2012, 12,300 fewer children would get pneumonia. %Pneumonia related to GNI per capita  Table 6. Consistent with smaller pneumonia incidence in developed than developing countries [3,4], the trend is of % Pneumonia decreasing with increasing GNI per capita. However, Beijing, Tianjin and Shanghai, with relative GNIs at 0.98, 0.85 and 1.02 respectively, depart markedly from this trend as shown in Fig 2. These cities have %Pneumonia as high as or higher than countries with relative GNIs only half as great.
Beijing has developed towards being a high GNI per capita city with unprecedented speed [64]. Although increasing GNI per capita is accompanied by changes that ameliorate risk factors for infectious diseases [65], it is possible that Beijing's modernization and development has been so rapid that the positive effects have not yet had enough time to take root. Moreover, when a certain proportion of a population has been vaccinated, the reduced density of pathogens results in decreased incidence in the unvaccinated, or a "herd effect," which further decreases the overall incidence [66].

Limitations
This study is subject to the limitations of survey questionnaires, including recall bias and memory errors. In addition, reported "incidences" are an underestimate if medical attention was not sought for a sick child with pneumonia, but an overestimate if there was incentive, as there has been in China, for physicians to prescribe antibiotics [67]. The literature estimates of VE are for children 2 years old and not for older children; however, we have shown that for children aged 1 to 8, most pneumonia happens before age 3 (Fig 1 and S1 Fig). Literature VEs were derived from incidence rather than %Pneumonia data, and it is not known whether they can be applied to %Pneumonia. Our data do not include mortality statistics. However, we can estimate from the U5MR mortality rate of 0.25‰ in 2012 [1] that the pneumonia deaths in this sample of approximately 6,000 would have been 1.5, a mathematically negligible quantity. We also do not know the severity of pneumonia cases (whether the pneumonia required hospitalization or was invasive) or the number of cases per child. Finally, fluctuations in the severity of yearly influenza, a risk factor for pneumonia [68] and likely to increase pneumonia incidence especially in children 0-3 years-old, have been neglected.

Conclusions
The proportion of Beijing children who have had pneumonia at least once by age 8, 26.9%, is similar to that of Tianjin. Because the Beijing %Pneumonia is mostly chest X-ray derived, it likely represents true pneumonia cases, but also may underestimate %Pneumonia for Beijing children. Beijing, Tianjin and Shanghai all have higher %Pneumonia than those of other comparably high GNI regions and countries. There is potential for reducing Beijing's %Pneumonia. China, unlike other country locations with lower %Pneumonia, lacks both PCV and Hib national vaccination programs. Based on vaccine efficacies, it is estimated that national PCV and Hib vaccination would reduce Beijing's %Pneumonia from 26.9% to 19.7% and 24.9% respectively. However, Beijing would still have greater %Pneumonia than consistent with high GNI per capita. It is likely that Beijing's severe air pollution [64], a known risk factor for pneumonia [69][70][71] must be addressed to achieve further reduction.