Estimation of Burden of Influenza among under-Five Children in India: A Meta-Analysis

Estimation of Burden of Influenza among under-Five Children in India: A Meta-Analysis Abstract Background We estimated the burden of influenza-related acute respiratory tract infection (ARI) among under-fives in India through meta-analysis. Methodology We estimated pooled incidence and proportional positivity of laboratory-diagnosed influenza among under-fives using data from observational studies published from 1 January 1961 to 31 December 2016. Death due to influenza was estimated using a multiplier model. Results Influenza-associated ARI incidence was estimated as 132 per 1000 child-years (115–149). The patients positive for influenza among ARI in outpatients and inpatients were estimated to be 11.2% (8.8–13.6) and 7.1% (5.5–8.8), respectively. We estimated total influenza cases during 2016 as 16 009 207 (13 942 916–18 082 769) in India. Influenza accounted for 10 913 476 (9 504 666–12 362 310) outpatient visits and 109 431 (83 882–134 980) hospitalizations. A total of 27 825 (21 382–34 408) influenza-associated under-five deaths were estimated in India in 2016. Conclusion Influenza imposes a substantial burden among under-fives in India. Public health approach for its prevention and control needs to be explored. influenza, death, hospitalization, outpatients, review, meta-analysis INTRODUCTION Evidence of burden of a disease [1, 2] is of utmost importance for advocacy, development of policy and guidelines regarding wider use of the related vaccine for any section of population. Many countries across the world have established guidelines for influenza immunization, and few have already introduced the vaccine in routine immunization schedule among priority groups [3–8]. Indian Government and Indian Academy of Paediatrics (IAP) recommend the vaccine among risk groups [1, 9]. According to IAP, lack of sufficient data to support the disease burden of influenza in India hinders the decision of inclusion of influenza vaccine in National Immunization Schedule (NIS) [1]. Worldwide, 90 million cases and 28 000–111 500 influenza deaths were estimated in under-five age groups in 2008 [10]. Influenza contributes to 1–25% of outpatient acute respiratory tract infection (ARI) visits among all age groups and 0.6–15.6% of ARI-associated hospitalization among under-fives [11]. In India, few studies reported influenza burden in community [12–14] and most of the data exist in the form of hospital-based studies [15–23]. Previous reviews undertaken to identify burden of influenza indicated gaps in research [11, 24–28]. Limited regional data and their considerable heterogeneity make any estimates for India questionable. We attempted a meta-analysis in the context of Indian scenario with available literature to measure the burden of seasonal influenza in community, outpatient and inpatient settings. METHODOLOGY Search strategy and selection criteria Systematic literature review was done with the following key words: influenza, seasonal influenza, children, outpatient, surveillance, community, hospital visit, inpatient, India, southeast Asia. Limits used are 'infant, new-born, child, preschool'. Reference lists of included articles were also checked for eligible articles. Search was restricted to English language articles in PubMed, IndMed, Google Scholar and World Health Organisation (WHO) database. National influenza experts were contacted to identify more studies. All articles available from 1 January 1961 to 31 December 2016 were reviewed. Inclusion criteria Community cohorts, control arm of randomized controlled trial and cross-sectional studies set in hospitals were considered. Any of these studies that reported laboratory-diagnosed seasonal influenza among under-five, segregated by settings were included in the review. All studies were organized according to geographical regions. A minimum of 10 studies were considered essential to have a robust estimate for each of the three settings, namely, community, outpatient and inpatient. The studies set in India were screened first and if the required number of articles (10) were not found, search extended to next geographical areas in the following order: South-Asia, other Asian countries, non-Asian developing countries and then non-Asian developed countries. All the eligible studies of an included area were considered even if the total number of studies exceeded 10. Statistical Analysis Eligible studies were appraised using STrengthening the Reporting of OBservational (STROBE) check list [29] for observational studies. Extracted qualitative and quantitative data (Panel 1) were compiled using a spread sheet. The outcomes are listed in Panel 1. The burden of influenza was estimated for each setting. Pooled estimates and 95% confidence intervals of the key indicators were calculated in Stata 13.1 (Stata Corp). Owing to wide variation in methodology, random effects models were used for all three analyses. Subgroup analysis was done across age groups [(i) 0–2 years, (ii) 0–3 years and (iii) 0–5 years], case definitions and diagnostic techniques. Estimates for India Morbidity burden The annual influenza morbidity among under-fives in India was estimated by extrapolating the findings of meta-analysis on Indian population. Following assumptions were made: (i) same health care seeking of influenza and ARI, (ii) the first contact of seeking care was an outpatient setting. We took the census population of 2011 [30] and built up the population for 2016 using annual natural growth rate of population from yearly Sample Registration System data [31–35]. The proportion of under-fives in census population is applied on population of 2016 to find the total under-fives. The incidence rate of influenza was applied on under-five population to estimate total influenza cases. Applying the health care seeking rate of ARI (National Family Health Survey (NFHS-3)) [36], annual outpatient visits due to influenza was calculated. Hospitalization rate of respiratory disease among under-fives [37] was used to estimate the annual respiratory-disease-related hospitalization. Annual influenza hospitalization was obtained by multiplying the total hospitalization with proportional influenza positivity among inpatient. Mortality burden We used multiplier model to estimate influenza-associated mortality among under-fives in India. The total number of deaths due to influenza in under-fives = number of live births (L) × under-five pneumonia mortality rate (M) × proportional influenza positivity among hospitalized children (P). Total number of annual live births (L) for India was estimated from data on total population and birth rate [30, 35] for the year 2016. Mortality rate (M) due to pneumonia among Indian children aged 1 month to <5 years was extracted from nationally representative study on causes of death [38]. Product of L and M gives the total number of under-five deaths due to pneumonia. Proportional positivity of influenza (P) among inpatient admitted with pneumonia or other respiratory tract infection estimated by the meta-analysis was used as proxy for the proportion of death due to influenza among all under-five pneumonia deaths. This assumes that case fatality rate among influenza-associated respiratory infection is same as that of other etiologies. Uncertainty analysis was done to generate the upper and lower bounds of number of deaths due to influenza by considering all possible values of the rates within their confidence interval of the point estimates (birth rate, mortality rate, positivity rate) by using a simulation model in Stata 13.1. In all, 10 000 random sets of values for each of the parameters were generated. The 2.5th and the 97.5th percentile were taken to show the range of total influenza deaths. Based on the equation (L* M* P), 10 000 estimates for total number of deaths in under-five were generated. Panel 1: Data extraction points and outcome indicators Data extraction points (1) country, (2) author, (3) study period, (4) publication year, (5) study setting: Out Patient Department (OPD), In Patient Department (IPD), Community, (6) sample size, (7) sampling methods, (8) case definitions, (9) inclusion and exclusion criteria, (10) details of data collection, (11) duration or seasonality of the study, (12) specimen collected for influenza testing, (13) diagnostic procedure for definition of influenza, (14) statistical analysis, (15) number of under-five subjects in three settings, inpatient or outpatient or community, (16) number of children in under-five found positive for seasonal influenza by setting. Outcome indicators in different settings Community settings Outcome: Incidence of influenza: estimated as cases/1000 child years Outpatient setting: Outcome: Influenza positivity among those seeking OPD care for respiratory symptoms: estimated as influenza positive cases/100 eligible OPD attendee Inpatient settings: Outcome: Influenza positivity among those hospitalized for respiratory symptoms: estimated as influenza positive cases/100 eligible IPD attendee RESULTS In all, 3121 articles were obtained using the search terms. Excluding non-relevant articles using screening criteria detailed in Fig. 1, a total of 40 studies were finalized and included both in the systematic review and meta-analysis (Supplementary Tables S1–S4). Fig. 1. View largeDownload slide Flow diagram for selection of studies for review and meta-analysis. Fig. 1. View largeDownload slide Flow diagram for selection of studies for review and meta-analysis. Data for community component were extracted from 10 studies [12, 39–47] (Figs 2 and 3, Supplementary Tables S1 and S2). Among these, only six studies used the definition of ARI/Influenza Like Illness (ILI). We grouped studies reporting ARI/ILI and Acute Lower Respiratory Infection (ALRI) separately. The pooled incidence of influenza varied with case definition and age stratification (Table 1). Table 1 Summary estimates (95% CI and I2) of the meta-analysis in different settings Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 a Treating Nasreen et al. [41] as an outlier (1.3 per 1000 child years) pooled estimate of other 5 studies in the ALRI group were found out to be 25.7 (95% CI: 14.7–36.6; I2 = 73.7) in under-five children b Treating Ruutu et al. [48] as an outlier [25.9 (95% CI: 19.6–32.3)] pooled proportional positivity from 10 studies is found to be to 10.2% in under-five children. Includes two studies [49, 50] reporting incidence among under six years. Table 1 Summary estimates (95% CI and I2) of the meta-analysis in different settings Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 a Treating Nasreen et al. [41] as an outlier (1.3 per 1000 child years) pooled estimate of other 5 studies in the ALRI group were found out to be 25.7 (95% CI: 14.7–36.6; I2 = 73.7) in under-five children b Treating Ruutu et al. [48] as an outlier [25.9 (95% CI: 19.6–32.3)] pooled proportional positivity from 10 studies is found to be to 10.2% in under-five children. Includes two studies [49, 50] reporting incidence among under six years. Fig. 2. View largeDownload slide Pooled estimate of incidence of influenza-related ARI among under-five children—cases/1000 child-year. Fig. 2. View largeDownload slide Pooled estimate of incidence of influenza-related ARI among under-five children—cases/1000 child-year. Fig. 3. View largeDownload slide Pooled estimate of incidence of influenza-related ALRI among under-five children: cases/1000 child-years. Fig. 3. View largeDownload slide Pooled estimate of incidence of influenza-related ALRI among under-five children: cases/1000 child-years. Eleven studies [21, 48–57] (Fig. 4, Supplementary Table S3) contributed to the estimation of influenza positivity among patients attending outpatient department with respiratory symptoms. Fig. 4. View largeDownload slide Summary estimate of studies on influenza positivity among under-five children seeking care for respiratory symptoms in outpatient setting. Fig. 4. View largeDownload slide Summary estimate of studies on influenza positivity among under-five children seeking care for respiratory symptoms in outpatient setting. The pooled estimate of influenza positivity among outpatient attendees varied with age and case definitions (Table 1). Twenty-five studies [48, 50, 51, 54, 56, 58–77] (Fig. 5, Supplementary Table S4) contributed to influenza positivity among hospitalized children. Data from 68% of these studies were available for under-fives, whereas others reported hospitalization in younger age groups. Summary estimates of proportional positivity varied by age, region and case definitions (Table 1, Table 2). Heterogeneity of pooled estimate of influenza positivity varied with age, geographical region, case definition and influenza diagnosis technique of the studies (Table 2) Table 2 Summary estimates (95% CI, I2) of the meta-analysis of influenza positivity in under-five children hospitalized with respiratory symptoms stratified by different scenarios Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 a Four studies used more than one method of influenza diagnosis, hence not included in the subgroup analysis. Similarly, 2 studies that did not use either of the techniques mentioned above were not included in the subgroup analysis. Table 2 Summary estimates (95% CI, I2) of the meta-analysis of influenza positivity in under-five children hospitalized with respiratory symptoms stratified by different scenarios Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 a Four studies used more than one method of influenza diagnosis, hence not included in the subgroup analysis. Similarly, 2 studies that did not use either of the techniques mentioned above were not included in the subgroup analysis. Fig. 5. View largeDownload slide Summary estimates of studies of influenza positivity among under-five children hospitalized with respiratory symptom. Fig. 5. View largeDownload slide Summary estimates of studies of influenza positivity among under-five children hospitalized with respiratory symptom. Estimates for India Estimates of influenza burden in India is summarized in Panel 2 and Fig. 6. Fig. 6. View largeDownload slide Estimated burden of influenza in under-fives in India in the year 2016. Fig. 6. View largeDownload slide Estimated burden of influenza in under-fives in India in the year 2016. Panel 2: Estimation of annual influenza burden among under-fives in India. Morbidity burden of influenza ○ The incidence rate: 132.1/1000 child year (95% CI: 115.1–149.2). ○ Under-five population: 121 million. ○ Health care seeking rate of ARI: 68.17 (95% CI: 59.4–77.2). ○ Hospitalization rate of respiratory disease among under-five: 12.71 per 1000 children (95% CI: 9.5–16.6). ○ Proportional influenza positivity among inpatient: 7.1% (95% CI: 5.5–8.8). ○ Total influenza cases: 16 009 207 (95% CI: 13 942 916–18 082 769). ○ Total outpatient visits: 10 913 476 (95% CI: 9 504 666–12 362 310). ○ Total influenza hospitalization: 109 431 (95% CI: 83 882–134 980). Mortality burden of influenza ○ Population: 1 300 840 155. ○ Birth rate: 20.8 (95% CI: 20.6, 21.0) per 1000 midyear population. ○ Pneumonia mortality: 14.5 (95% CI: 14·1, 15·0) per 1000 live births. ○ Influenza positivity: 7.1 (95% CI: 5.5, 8.8) per 100 cases. ○ Influenza deaths: 27 895 (95% CI: 21 382–34 408). From the uncertainty analysis performed by the simulation, the mean death estimated as 28 124 (95% CI: 28 050–28 199). The median estimate was 28 061 and the 2.5th and 97.5th percentile level were 21 921 and 34 533, respectively. This would be equivalent to 1 death per 1000 live births per year or 2.1 per 100 000 of total population. DISCUSSION This review highlighted the dearth of literature on influenza from India and Indian subcontinent and wide methodological differences in estimation of the influenza burden. There was a sudden rise of influenza reports in 2009–2010 but these were mostly of pandemic influenza. Articles containing only p (Hemagglutinin Type 1 and Neuraminidase Type 1 (H1N1)) were excluded until WHO announced it as an endemic strain. Community-clinic based or passive surveillance studies that reported the total population of the catchment area were included in community setting of meta-analyses owing to lack of reports of active community-based influenza surveillance. The issue of completeness of coverage and representativeness would be an important concern for these studies. The proportional positivity of influenza among under-fives found by the present study was comparable with previous reviews and meta-analysis done by Simmerman et al. [24], Nair et al. [10], Rudan et al. [28] and Global Respiratory Hospitalizations–Influenza Proportion Positive study group [78]. A systematic review from sub-Saharan Africa by Gessner et al. [11] reported wide range of positivity among inpatients, whereas Luksik et al. [26] reported much lower positivity. In India, diagnostic tests for influenza are not done routinely. Consequently, influenza could not be ascertained as a cause of death. We used influenza positivity among severely ill children, admitted to a hospital as proxy for positivity among dead children. Homaira et al. [79] used a similar multiplier method to estimate influenza deaths. Nair et al. [10] estimated the mean influenza-associated ALRI deaths in under-five by combining the verbal autopsy and influenza circulation data of Ballabgarh, India. The mean annual death for 2006–08 was close to the estimate of present study (25 556 vs. 28 124). However, they estimated a much smaller number of deaths (5998) using an alternative approach. Comparable data achieved by different methodologies support the robustness of the assumptions. The total estimated influenza-related deaths expressed as a proportion of influenza-related hospitalization gives a case fatality rate of 18.9%, which was much higher than that reported in literature (4–12%) [80–82]. The estimate was probably higher, as the present study considered all deaths related to influenza irrespective of the hospitalization status of the child. Nair et al. [27] reported that 81% of severe ALRI deaths occurred outside hospitals. This review and meta-analysis compiled the estimates of published literature of influenza burden for the past three decades in the lower and lower-middle income countries of South Asia in all the settings and the pooled estimate represents the overall prevailing burden of influenza throughout this period. As data on temporal trends are not available, it is difficult to say how the inclusion of old studies would affect our estimate. A high level of heterogeneity among studies was found in all settings. This heterogeneity was perhaps owing to variations in case definitions (supplementary file), duration of data collection, qualification of data collectors and influenza diagnostics. Previous authors [25, 28] also experienced similar issues. However, subgroup analysis showed reduction of heterogeneity. Therefore, the estimate derived from this meta-analysis should be used with caution. However, the effort to restrict the studies as much as possible closer to Indian situation makes it more relevant to India. In case of mortality too, despite the limitations of the validity of the assumptions used, our estimates appear reasonable and are supported by results of previous estimation procedures. Evidence of burden of any disease plays a crucial role in introducing the vaccine in NIS. Published studies reporting burden of Haemophilus influenzae type B, Streptococcus pneumoniae and Rotavirus infection influenced the decision of Indian Government to include the related vaccines in NIS [83–89]. This study would add to the burden estimates of influenza in India and could help the policy makers to take decision on influenza vaccine. The methodology of obtaining influenza burden could be used for other diseases too for resource constraint settings. However, to obtain a robust estimate, country-specific multisite studies are required. SUPPLEMENTARY DATA Supplementary data are available at Journal of Tropical Pediatrics online. ACKNOWLEDGEMENTS We gratefully acknowledge the contribution of Dr Siddhartha Saha for his suggestions that greatly improved the manuscript. We are also thankful to our colleagues for their input from time to time during finalization of the manuscript. REFERENCES 1 Advisory Committee on Vaccines and Immunisation Practices (ACVIP) . Indian Academy of peadiatrics. IAP Guidebook on Immunisation 2013-2014 [Internet]. National Publication House, Indian Academy of Peadiatrics. http://www.iapindia.org/files/IAP Guidelines/IAP Guidebook on Immunization 2013-14. 2 Vashishtha VM , Kalra A , Choudhury P. Influenza vaccination in India: position paper of Indian Academy of Pediatrics, 2013 . Indian Pediatr 2013 ; 50 : 867 – 74 . Google Scholar CrossRef Search ADS PubMed 3 Ropero-Álvarez A , Kurtis HJ , Danovaro-Holliday MC , et al. Expansion of seasonal influenza vaccination in the Americas . BMC Public Health 2009 ; 9 : 361 . Google Scholar CrossRef Search ADS PubMed 4 National Influenza Specialist Group . Everything you need to know about FLU [Internet]. Immunisation Advisory Centre, The University of Auckland. [cited 2015 Jun 21]. http://www.influenza.org.nz/sites/default/files/2015 Flu Kit (21 June 2015 , date last accessed). 5 Department of Health, Government of Western Australia . Childhood immunisation schedule [Internet]. Healthy WA, Health information for Western Australians. http://ww2.health.wa.gov.au/Healthy-WA/Articles/A_E/Childhood-immunisation-schedule (21 June 2015 , date last accessed). 6 Australian Government Department of Health . National Immunisation Program Schedule (From 20 April 2015 ) [Internet]. Australian Government Department of Health. http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/national-immunisation-program-schedule (21 June 2015, date last accessed). 7 Gupta V , Dawood FS , Muangchana C , et al. Influenza vaccination guidelines and vaccine sales in Southeast Asia: 2008–2011 . Boni MF, editor. PLoS One 2012 ; 7 : e52842 . Google Scholar CrossRef Search ADS PubMed 8 Infectious Disease Surveillance Center . Immunisation Schedule, Japan 2014 [Internet]. National Institute of Infectious Diseases. idsc.nih.go.jp/vaccine/dschedule (4 November 2014 , date last accessed). 9 Ministry of Health & Family Welfare . Technical Guidelines, Swine flu-H1N1 (seasonal influenza) [Internet]. Government of India, Ministry of Health & Family Welfare. http://mohfw.gov.in/index1.php?lang=1&level=1&sublinkid=4987&lid=3070 (13 December 2016 , date last accessed). 10 Nair H , Brooks WA , Katz M , et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis . Lancet 2011 ; 378 : 1917 – 30 . Google Scholar CrossRef Search ADS PubMed 11 Gessner BD , Shindo N , Briand S. Seasonal influenza epidemiology in sub-Saharan Africa: a systematic review . Lancet Infect Dis 2011 ; 11 : 223 – 35 . Google Scholar CrossRef Search ADS PubMed 12 Broor S , Parveen S , Bharaj P , et al. A Prospective Three-Year Cohort Study of the epidemiology and virology of acute respiratory infections of children in Rural India . PLoS One 2 : e491 . CrossRef Search ADS PubMed 13 Purakayastha DR , Gupta V , Broor S , et al. Clinical differences between influenza A (H1N1) pdm09 & influenza B infections identified through active community surveillance in north India . Indian J Med Res 2013 ; 138 : 962 – 8 . Google Scholar PubMed 14 Fowler KB , Gupta V , Sullender W , et al. Incidence of symptomatic A (H1N1) pdm09 influenza during the pandemic and post-pandemic periods in a rural Indian community . Int J Infect Dis 2013 ; 17 : e1182 – 5 . Google Scholar CrossRef Search ADS PubMed 15 Misra PK , Chaudhary RS , Jain A , et al. Viral aetiology of acute respiratory infections in children in North India . J Trop Pediatr 1990 ; 36 : 24 – 7 . Google Scholar CrossRef Search ADS PubMed 16 Jain A , Pande A , Misra PK , et al. An Indian hospital study of viral causes of acute respiratory infection in children . J Med Microbiol 1991 ; 35 : 219 – 23 . Google Scholar CrossRef Search ADS PubMed 17 Rao BL , Banerjee K. Influenza surveillance in Pune, India, 1978-90 . Bull World Health Organ 1993 ; 71 : 177 – 81 . Google Scholar PubMed 18 Rao BL , Kadam SS , Pawar MS. Isolation of recent variant influenza types A(H3N2), A (H1N1) & B strains in Pune, India . Indian J Med Res 2001 ; 114 : 157 – 9 . Google Scholar PubMed 19 Rao BL , Yeolekar LR , Kadam SS , et al. Influenza surveillance in Pune, India, 2003 . Southeast Asian J Trop Med Public Health 2005 ; 36 : 906 – 9 . Google Scholar PubMed 20 Ramamurty N , Pillai LC , Gunasekaran P , et al. Influenza activity among the paediatric age group in Chennai . Indian J Med Res 2005 ; 121 : 776 – 9 . Google Scholar PubMed 21 Broor S , Krishnan A , Roy DS , et al. Dynamic patterns of circulating seasonal and pandemic A(H1N1)pdm09 Influenza viruses from 2007–2010 in and around Delhi, India . PLoS One 2012 ; 7 : e29129 . Google Scholar CrossRef Search ADS PubMed 22 Chadha MS , Hirve S , Dawood FS , et al. Burden of seasonal and pandemic influenza-associated hospitalization during and after 2009 A(H1N1) pdm09 pandemic in a rural community in India . PLoS One 2013 ; 8 : e55918. Google Scholar CrossRef Search ADS PubMed 23 Hirve S , Krishnan A , Dawood FS , et al. Incidence of influenza-associated hospitalization in rural communities in western and northern India, 2010-2012: a multi-site population-based study . J Infect 2015 ; 70 : 160 – 70 . Google Scholar CrossRef Search ADS PubMed 24 Simmerman JM , Uyeki TM. The burden of influenza in East and South-East Asia: a review of the English language literature . Influenza Other Respir Viruses 2008 ; 2 : 81 – 92 . Google Scholar CrossRef Search ADS PubMed 25 Bueving HJ , van der Wouden JC , Berger MY , et al. Incidence of influenza and associated illness in children aged 0–19 years: a systematic review . Rev Med Virol 2005 ; 15 : 383 – 91 . Google Scholar CrossRef Search ADS PubMed 26 Lukšić I , Kearns PK , Scott F , et al. Viral etiology of hospitalized acute lower respiratory infections in children under 5 years of age – a systematic review and meta-analysis . Croat Med J 2013 ; 54 : 122 – 34 . Google Scholar CrossRef Search ADS PubMed 27 Nair H , Simões EA , Rudan I , et al. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis . Lancet 2013 ; 381 : 1380 – 90 . Google Scholar CrossRef Search ADS PubMed 28 Rudan I , O’brien KL , Nair H , et al. Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries . J Glob Health 2013 ; 3 : 010401 . Google Scholar CrossRef Search ADS PubMed 29 STROBE statement: strengthening the reporting of observational studies in epidemiology [Internet] . http://www.strobe-statement.org/index.php?id=strobe-home (28 August 2016 , date last accessed). 30 Office of the Registrar General and Census Commissioner, Ministry of Home affairs, Government of India . Population Ennumeration Data (Final Population), 2011 Census data [Internet]. http://www.censusindia.gov.in/2011census/population_enumeration.html. 31 Registrar General, India . SRS Bulletin 2011 , Sample registration System [Internet]. Report No.: Volume 47 No.2. 2012. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletins/SRS_Bulletin-October_2012.pdf. 32 Registrar General, India . SRS Bulletin 2012 , Sample Registration System [Internet]. Report No.: Vol 48 No.2. 2013. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletins/SRS_Bulletin-September_2013.pdf. 33 Registrar General, India . SRS Bulletin 2013 , Sample registration System [Internet]. Report No.: Vol 49 No1. 2014. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletins/SRS%20Bulletin%20-Sepetember%202014.pdf. 34 Registrar General, India . SRS Bulletin 2014 , Sample Registration System [Internet]. Report No.: Vol 50 No.1. 2016. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletin_2014.pdf. 35 Registrar General, India . SRS Bulletin 2015 , Sample registration System [Internet]. Report No.: Vol.50 No.2. 2016. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletin_2015.pdf. 36 International Institute for Population Sciences, Deonar, Mumbai . National Family Health Survey-3(2005-2006), India [Internet]. http://rchiips.org/nfhs/chapters.shtml (18 May 2016 , date last accessed). 37 Ministry of Statistics and Programme Implementation . India - Social Consumption : Health, NSS 71st Round : Jan - June 2014 - Overview [Internet]. Report No.: 574. 2015 . (DDI-IND-NSSO-71Rnd-Sch25pt0-Jan-June-2014). http://mail.mospi.gov.in/index.php/catalog/161 (26 September 2016, date last accessed). 38 Government of India . Causes of death in India 2010-13, Census of India : Sample Registration System [Internet]. http://www.censusindia.gov.in/2011-Common/Sample_Registration_System.html (23 June 2016 , date last accessed). 39 Homaira N , Luby SP , Petri WA , et al. Incidence of respiratory virus-associated pneumonia in urban poor young children of Dhaka, Bangladesh, 2009–2011 . Madhi SA, editor. PLoS One 2012 ; 7 : e32056 . Google Scholar CrossRef Search ADS PubMed 40 Vathanophas K , Sangchai R , Raktham S , et al. A Community-Based Study of acute respiratory tract infection in Thai children . Clin Infect Dis 1990 ; 12(Suppl. 8) : S957 – 65 . Google Scholar CrossRef Search ADS 41 Nasreen S , Luby SP , Brooks WA , et al. Population-based incidence of severe acute respiratory virus infections among children aged <5 years in Rural Bangladesh, June–October 2010 . Schulz TF, editor. PLoS One 2014 ; 9 : e89978 . Google Scholar CrossRef Search ADS PubMed 42 Brooks WA , Goswami D , Rahman M , et al. Influenza is a major contributor to childhood pneumonia in a tropical developing country . Pediatr Infect Dis J 2010 ; 29 : 216 – 21 . Google Scholar CrossRef Search ADS PubMed 43 Kimura Y , Saito R , Tsujimoto Y , et al. Geodemographics profiling of influenza A and B virus infections in community neighborhoods in Japan . BMC Infect Dis 2011 ; 11 : 36 . Google Scholar CrossRef Search ADS PubMed 44 Heikkinen T , Silvennoinen H , Peltola V , et al. Burden of Influenza in children in the community . J Infect Dis 2004 ; 190 : 1369 – 73 . Google Scholar CrossRef Search ADS PubMed 45 Forgie IM , Campbell H , Lloyd-Evans N , et al. Etiology of acute lower respiratory tract infections in children in a rural community in The Gambia . Pediatr Infect Dis J 1992 ; 11 : 466 – 73 . Google Scholar CrossRef Search ADS PubMed 46 Borrero HI , Fajardo RL , Bedoya MA , et al. Acute respiratory tract infections among a birth cohort of children from Cali, Colombia, who were studied through 17 months of age . Clin Infect Dis 1990 ; 12(Suppl. 8) : S950 – 6 . Google Scholar CrossRef Search ADS 47 Tupasi TE , de Leon LE , Lupisan S , et al. Patterns of acute respiratory tract infection in children: a longitudinal study in a depressed community in Metro Manila . Rev Infect Dis 1990 ; 12(Suppl. 8) : S940 – 9 . Google Scholar CrossRef Search ADS PubMed 48 Ruutu P , Halonen P , Meurman O , et al. Viral lower respiratory tract infections in Filipino children . J Infect Dis 1990 ; 161 : 175 – 9 . Google Scholar CrossRef Search ADS PubMed 49 Agrawal AS , Sarkar M , Chakrabarti S , et al. Comparative evaluation of real-time PCR and conventional RT-PCR during a 2 year surveillance for influenza and respiratory syncytial virus among children with acute respiratory infections in Kolkata, India, reveals a distinct seasonality of infection . J Med Microbiol 2009 ; 58 : 1616 – 22 . Google Scholar CrossRef Search ADS PubMed 50 Dilantika C , Sedyaningsih ER , Kasper MR , et al. Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness . BMC Infect Dis 2010 ; 10 : 3 . Google Scholar CrossRef Search ADS PubMed 51 Yeolekar LR , Damle RG , Kamat AN , et al. Respiratory virus in acute respiratory tract infections in Western India . Indian J Pediatr 2008 ; 75 : 341 – 5 . Google Scholar CrossRef Search ADS PubMed 52 Mathisen M , Strand TA , Sharma BN , et al. RNA viruses in community-acquired childhood pneumonia in semi-urban Nepal; a cross-sectional study . BMC Med 2009 ; 7 : 35 . Google Scholar CrossRef Search ADS PubMed 53 Nguyen HT , Dharan NJ , Le MTQ , et al. National influenza surveillance in Vietnam, 2006–2007 . Vaccine 2009 ; 28 : 398 – 402 . Google Scholar CrossRef Search ADS PubMed 54 Chittaganpitch M , Supawat K , Olsen SJ , et al. Influenza viruses in Thailand: 7 years of sentinel surveillance data, 2004-2010: Influenza in Thailand . Influenza Other Respir Viruses 2012 ; 6 : 276 – 83 . Google Scholar CrossRef Search ADS PubMed 55 Khamphaphongphane B , Ketmayoon P , Lewis HC , et al. Epidemiological and virological characteristics of seasonal and pandemic influenza in Lao PDR, 2008-2010: seasonal and pandemic influenza in Lao PDR 2008-2010 . Influenza Other Respir Viruses 2013 ; 7 : 304 – 11 . Google Scholar CrossRef Search ADS PubMed 56 Tallo VL , Kamigaki T , Tan AG , et al. Estimating influenza outpatients’ and inpatients’ incidences from 2009 to 2011 in a tropical urban setting in the Philippines . Influenza Other Respir Viruses 2014 ; 8 : 159 – 68 . Google Scholar CrossRef Search ADS PubMed 57 Otomaru H , Kamigaki T , Tamaki R , et al. Influenza and Other Respiratory Viruses detected by Influenza-like illness surveillance in Leyte Island, the Philippines, 2010–2013 . Chuang JH, editor. PLoS One 2015 ; 10 : e0123755 . Google Scholar CrossRef Search ADS PubMed 58 Huq F , Rahman M , Nahar N , et al. Acute lower respiratory thact infection due to virus among hospitalized children in Dhaka, Bangladesh . Clin Infect Dis 1990 ; 12(Suppl. 8) : S982 – 7 . Google Scholar CrossRef Search ADS 59 Sung RYT , Chan PKS , Tsen T , et al. Identification of viral and atypical bacterial pathogens in children hospitalized with acute respiratory infections in Hong Kong by multiplex PCR assays: Multiplex PCR for Respiratory viruses . J Med Virol 2009 ; 81 : 153 – 9 . Google Scholar CrossRef Search ADS PubMed 60 Maitreyi RS , Broor S , Kabra SK , et al. Rapid detection of respiratory viruses by centrifugation enhanced cultures from children with acute lower respiratory tract infections . J Clin Virol 2000 ; 16 : 41 – 7 . Google Scholar CrossRef Search ADS PubMed 61 Hasan K , Jolly P , Marquis G , et al. Viral etiology of pneumonia in a cohort of newborns till 24 months of age in Rural Mirzapur, Bangladesh . Scand J Infect Dis 2006 ; 38 : 690 – 5 . Google Scholar CrossRef Search ADS PubMed 62 Simmerman JM , Chittaganpitch M , Levy J , et al. Incidence, seasonality and mortality associated with Influenza pneumonia in Thailand: 2005–2008 . Myer L, editor. PLoS One 2009 ; 4 : e7776 . Google Scholar CrossRef Search ADS PubMed 63 Olsen SJ , Thamthitiwat S , Chantra S , et al. Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand . Epidemiol Infect 2010 ; 138 : 1811 – 22 . Google Scholar CrossRef Search ADS PubMed 64 Samransamruajkit R , Hiranrat T , Chieochansin T , et al. Prevalence, clinical presentations and complications among hospitalized children with influenza pneumonia . Jpn J Infect Dis 2008 ; 61 : 446 – 9 . Google Scholar PubMed 65 Singh AK , Jain A , Jain B , et al. Viral aetiology of acute lower respiratory tract illness in hospitalised paediatric patients of a tertiary hospital: one year prospective study . Indian J Med Microbiol 2014 ; 32 : 13 . Google Scholar CrossRef Search ADS PubMed 66 Hirve S , Chadha M , Lele P , et al. Performance of case definitions used for Influenza surveillance among hospitalized patients in a rural area of India . Bull World Health Organ 2012 ; 90 : 804 – 12 . Google Scholar CrossRef Search ADS PubMed 67 Kaur C , Chohan S , Khare S , et al. Respiratory viruses in acute bronchiolitis in Delhi . Indian Pediatr 2010 ; 47 : 342 – 4 . Google Scholar CrossRef Search ADS PubMed 68 Do AHL , van Doorn HR , Nghiem MN , et al. Viral etiologies of acute respiratory infections among hospitalized Vietnamese children in Ho Chi Minh City, 2004-2008 . PLoS One 2011 ; 6 : e18176. Google Scholar CrossRef Search ADS PubMed 69 Suntarattiwong P , Sian-nork C , Thongtipa P , et al. Influenza-associated hospitalization in urban Thai children . Influenza Other Respir Viruses 2007 ; 1 : 177 – 82 . Google Scholar CrossRef Search ADS PubMed 70 Suntarattiwong P , Sojisirikul K , Sitaposa P , et al. Clinical and epidemiological characteristics of respiratory syncytial virus and influenza virus associated hospitalization in Urban Thai infants . J Med Assoc Thai 2011 ; 94 : S164 – 71 . Google Scholar PubMed 71 Yoshida LM , Suzuki M , Yamamoto T , et al. Viral pathogens associated with acute respiratory infections in central vietnamese children . Pediatr Infect Dis J 2010 ; 29 : 75 – 7 . Google Scholar CrossRef Search ADS PubMed 72 Yoshida LM , Suzuki M , Nguyen HA , et al. Respiratory syncytial virus: co-infection and paediatric lower respiratory tract infections . Eur Respir J 2013 ; 42 : 461 – 9 . Google Scholar CrossRef Search ADS PubMed 73 Mathisen M , Basnet S , Sharma A , et al. RNA viruses in young Nepalese children hospitalized with severe pneumonia . Pediatr Infect Dis J 2011 ; 30 : 1032 – 6 . Google Scholar CrossRef Search ADS PubMed 74 Sunakorn P , Chunchit L , Niltawat S , et al. Epidemiology of acute respiratory infections in young children from Thailand . Pediatr Infect Dis J 1990 ; 9 : 873 – 7 . Google Scholar CrossRef Search ADS PubMed 75 Rahman M , Huq F , Sack DA , et al. Acute lower respiratory tract infections in hospitalized patients with Diarrhea in Dhaka, Bangladesh . Clin Infect Dis 1990 ; 12(Suppl. 8) : S899 – 906 . Google Scholar CrossRef Search ADS 76 Hasan R , Rhodes J , Thamthitiwat S , et al. Incidence and etiology of acute lower respiratory tract infections in hospitalized children younger than 5 years in Rural Thailand . Pediatr Infect Dis J 2014 ; 33 : e45 – 52 . Google Scholar CrossRef Search ADS PubMed 77 Tupasi TE , Lucero MG , Magdangal DM , et al. Etiology of acute lower respiratory tract infection in children from Alabang, Metro Manila . Rev Infect Dis 1990 ; 12(Suppl. 8) : S929 – 39 . Google Scholar CrossRef Search ADS PubMed 78 Lafond KE , Nair H , Rasooly MH , et al. Global role and burden of influenza in pediatric respiratory hospitalizations, 1982-2012: a systematic analysis . PLoS Med 2016 ; 13 : e1001977 . Google Scholar CrossRef Search ADS PubMed 79 Homaira N , Luby SP , Alamgir A , et al. Influenza-associated mortality in 2009 in four sentinel sites in Bangladesh . Bull World Health Organ 2012 ; 90 : 272 – 8 . Google Scholar CrossRef Search ADS PubMed 80 Djelantik IGG , Gessner BD , Sutanto A , et al. Case fatality proportions and predictive factors for mortality among children hospitalized with severe pneumonia in a rural developing country setting . J Trop Pediatr 2003 ; 49 : 327 – 32 . Google Scholar CrossRef Search ADS PubMed 81 Naheed A , Saha SK , Breiman RF , et al. Multihospital surveillance of pneumonia burden among children aged <5 years hospitalized for pneumonia in Bangladesh . Clin Infect Dis 2009 ; 48(Suppl. 2) : S82 – 9 . Google Scholar CrossRef Search ADS PubMed 82 Ramachandran P , Nedunchelian K , Vengatesan A , et al. Risk factors for mortality in community-acquired pneumonia among children aged 1–59 months admitted in a referral hospital . Indian Pediatr 2012 ; 49 : 889 – 95 . Google Scholar CrossRef Search ADS PubMed 83 Kant L. NTAGI subcommittee recommendations on haemophilus influenzae type b (Hib) vaccine introduction in India . Indian Pediatr 2009 ; 46 : 945 – 54 . Google Scholar PubMed 84 Johnson H , Bassani D , Perin J , et al. Burden of childhood mortality caused by Streptococcus pneumoniae in India. The 8th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD). Abstract # A-428-0023- 00743. Iguaçu Falls, Brazil, 2012 . 85 Thomas K. Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India . Lancet 1999 ; 353 : 1216 – 21 . Google Scholar CrossRef Search ADS PubMed 86 Levine O , Cherian T. Pneumococcal vaccination for Indian children . Indian Pediatr 2007 ; 44 : 491 – 6 . Google Scholar PubMed 87 Gavi, the vaccine alliance. India to introduce four new vaccines [Internet]. http://www.gavi.org/library/news/statements/2014/india-to-introduce-four-new-vaccines/ (29 September 2016 , date last accessed). 88 Press Information Bureau, Government of India, Prime Minister’s Office . Three new vaccines including rotavirus vaccine to be provided to all Indian children [Internet]. http://pib.nic.in/newsite/PrintRelease.aspx?relid=106055 (3 July 2014 , date last accessed). 89 Kang G , Arora R , Chitambar SD , et al. Multicenter, hospital-based surveillance of rotavirus disease and strains among Indian children aged <5 years . J Infect Dis 2009 ; 200(Suppl. 1) : S147 – 53 . Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. 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Estimation of Burden of Influenza among under-Five Children in India: A Meta-Analysis

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Oxford University Press
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© The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0142-6338
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10.1093/tropej/fmx087
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Abstract

Abstract Background We estimated the burden of influenza-related acute respiratory tract infection (ARI) among under-fives in India through meta-analysis. Methodology We estimated pooled incidence and proportional positivity of laboratory-diagnosed influenza among under-fives using data from observational studies published from 1 January 1961 to 31 December 2016. Death due to influenza was estimated using a multiplier model. Results Influenza-associated ARI incidence was estimated as 132 per 1000 child-years (115–149). The patients positive for influenza among ARI in outpatients and inpatients were estimated to be 11.2% (8.8–13.6) and 7.1% (5.5–8.8), respectively. We estimated total influenza cases during 2016 as 16 009 207 (13 942 916–18 082 769) in India. Influenza accounted for 10 913 476 (9 504 666–12 362 310) outpatient visits and 109 431 (83 882–134 980) hospitalizations. A total of 27 825 (21 382–34 408) influenza-associated under-five deaths were estimated in India in 2016. Conclusion Influenza imposes a substantial burden among under-fives in India. Public health approach for its prevention and control needs to be explored. influenza, death, hospitalization, outpatients, review, meta-analysis INTRODUCTION Evidence of burden of a disease [1, 2] is of utmost importance for advocacy, development of policy and guidelines regarding wider use of the related vaccine for any section of population. Many countries across the world have established guidelines for influenza immunization, and few have already introduced the vaccine in routine immunization schedule among priority groups [3–8]. Indian Government and Indian Academy of Paediatrics (IAP) recommend the vaccine among risk groups [1, 9]. According to IAP, lack of sufficient data to support the disease burden of influenza in India hinders the decision of inclusion of influenza vaccine in National Immunization Schedule (NIS) [1]. Worldwide, 90 million cases and 28 000–111 500 influenza deaths were estimated in under-five age groups in 2008 [10]. Influenza contributes to 1–25% of outpatient acute respiratory tract infection (ARI) visits among all age groups and 0.6–15.6% of ARI-associated hospitalization among under-fives [11]. In India, few studies reported influenza burden in community [12–14] and most of the data exist in the form of hospital-based studies [15–23]. Previous reviews undertaken to identify burden of influenza indicated gaps in research [11, 24–28]. Limited regional data and their considerable heterogeneity make any estimates for India questionable. We attempted a meta-analysis in the context of Indian scenario with available literature to measure the burden of seasonal influenza in community, outpatient and inpatient settings. METHODOLOGY Search strategy and selection criteria Systematic literature review was done with the following key words: influenza, seasonal influenza, children, outpatient, surveillance, community, hospital visit, inpatient, India, southeast Asia. Limits used are 'infant, new-born, child, preschool'. Reference lists of included articles were also checked for eligible articles. Search was restricted to English language articles in PubMed, IndMed, Google Scholar and World Health Organisation (WHO) database. National influenza experts were contacted to identify more studies. All articles available from 1 January 1961 to 31 December 2016 were reviewed. Inclusion criteria Community cohorts, control arm of randomized controlled trial and cross-sectional studies set in hospitals were considered. Any of these studies that reported laboratory-diagnosed seasonal influenza among under-five, segregated by settings were included in the review. All studies were organized according to geographical regions. A minimum of 10 studies were considered essential to have a robust estimate for each of the three settings, namely, community, outpatient and inpatient. The studies set in India were screened first and if the required number of articles (10) were not found, search extended to next geographical areas in the following order: South-Asia, other Asian countries, non-Asian developing countries and then non-Asian developed countries. All the eligible studies of an included area were considered even if the total number of studies exceeded 10. Statistical Analysis Eligible studies were appraised using STrengthening the Reporting of OBservational (STROBE) check list [29] for observational studies. Extracted qualitative and quantitative data (Panel 1) were compiled using a spread sheet. The outcomes are listed in Panel 1. The burden of influenza was estimated for each setting. Pooled estimates and 95% confidence intervals of the key indicators were calculated in Stata 13.1 (Stata Corp). Owing to wide variation in methodology, random effects models were used for all three analyses. Subgroup analysis was done across age groups [(i) 0–2 years, (ii) 0–3 years and (iii) 0–5 years], case definitions and diagnostic techniques. Estimates for India Morbidity burden The annual influenza morbidity among under-fives in India was estimated by extrapolating the findings of meta-analysis on Indian population. Following assumptions were made: (i) same health care seeking of influenza and ARI, (ii) the first contact of seeking care was an outpatient setting. We took the census population of 2011 [30] and built up the population for 2016 using annual natural growth rate of population from yearly Sample Registration System data [31–35]. The proportion of under-fives in census population is applied on population of 2016 to find the total under-fives. The incidence rate of influenza was applied on under-five population to estimate total influenza cases. Applying the health care seeking rate of ARI (National Family Health Survey (NFHS-3)) [36], annual outpatient visits due to influenza was calculated. Hospitalization rate of respiratory disease among under-fives [37] was used to estimate the annual respiratory-disease-related hospitalization. Annual influenza hospitalization was obtained by multiplying the total hospitalization with proportional influenza positivity among inpatient. Mortality burden We used multiplier model to estimate influenza-associated mortality among under-fives in India. The total number of deaths due to influenza in under-fives = number of live births (L) × under-five pneumonia mortality rate (M) × proportional influenza positivity among hospitalized children (P). Total number of annual live births (L) for India was estimated from data on total population and birth rate [30, 35] for the year 2016. Mortality rate (M) due to pneumonia among Indian children aged 1 month to <5 years was extracted from nationally representative study on causes of death [38]. Product of L and M gives the total number of under-five deaths due to pneumonia. Proportional positivity of influenza (P) among inpatient admitted with pneumonia or other respiratory tract infection estimated by the meta-analysis was used as proxy for the proportion of death due to influenza among all under-five pneumonia deaths. This assumes that case fatality rate among influenza-associated respiratory infection is same as that of other etiologies. Uncertainty analysis was done to generate the upper and lower bounds of number of deaths due to influenza by considering all possible values of the rates within their confidence interval of the point estimates (birth rate, mortality rate, positivity rate) by using a simulation model in Stata 13.1. In all, 10 000 random sets of values for each of the parameters were generated. The 2.5th and the 97.5th percentile were taken to show the range of total influenza deaths. Based on the equation (L* M* P), 10 000 estimates for total number of deaths in under-five were generated. Panel 1: Data extraction points and outcome indicators Data extraction points (1) country, (2) author, (3) study period, (4) publication year, (5) study setting: Out Patient Department (OPD), In Patient Department (IPD), Community, (6) sample size, (7) sampling methods, (8) case definitions, (9) inclusion and exclusion criteria, (10) details of data collection, (11) duration or seasonality of the study, (12) specimen collected for influenza testing, (13) diagnostic procedure for definition of influenza, (14) statistical analysis, (15) number of under-five subjects in three settings, inpatient or outpatient or community, (16) number of children in under-five found positive for seasonal influenza by setting. Outcome indicators in different settings Community settings Outcome: Incidence of influenza: estimated as cases/1000 child years Outpatient setting: Outcome: Influenza positivity among those seeking OPD care for respiratory symptoms: estimated as influenza positive cases/100 eligible OPD attendee Inpatient settings: Outcome: Influenza positivity among those hospitalized for respiratory symptoms: estimated as influenza positive cases/100 eligible IPD attendee RESULTS In all, 3121 articles were obtained using the search terms. Excluding non-relevant articles using screening criteria detailed in Fig. 1, a total of 40 studies were finalized and included both in the systematic review and meta-analysis (Supplementary Tables S1–S4). Fig. 1. View largeDownload slide Flow diagram for selection of studies for review and meta-analysis. Fig. 1. View largeDownload slide Flow diagram for selection of studies for review and meta-analysis. Data for community component were extracted from 10 studies [12, 39–47] (Figs 2 and 3, Supplementary Tables S1 and S2). Among these, only six studies used the definition of ARI/Influenza Like Illness (ILI). We grouped studies reporting ARI/ILI and Acute Lower Respiratory Infection (ALRI) separately. The pooled incidence of influenza varied with case definition and age stratification (Table 1). Table 1 Summary estimates (95% CI and I2) of the meta-analysis in different settings Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 a Treating Nasreen et al. [41] as an outlier (1.3 per 1000 child years) pooled estimate of other 5 studies in the ALRI group were found out to be 25.7 (95% CI: 14.7–36.6; I2 = 73.7) in under-five children b Treating Ruutu et al. [48] as an outlier [25.9 (95% CI: 19.6–32.3)] pooled proportional positivity from 10 studies is found to be to 10.2% in under-five children. Includes two studies [49, 50] reporting incidence among under six years. Table 1 Summary estimates (95% CI and I2) of the meta-analysis in different settings Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 Setting Influenza-associated ARI/ILI incidence/1000 child years  <2 years <3 years <5 years Community 120.1 152.3 132.1 (98.2, 141.9) (111.2, 193.3) (115.1–149.2) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 84.3 I2 = 93.6 Influenza-associated ALRI incidence/1000 child years 28.1 30.5 21.1a (18.2–38.0) (21.8–39.3) (9.4–32.8) 2 studies 3 studies 6 studies I2 = 0.0 I2 = 0.0 I2 = 92.7 Outpatient Influenza positivity among those seeking health care with respiratory Symptoms—Cases/100 children 5.0 5.7 11.2b (2.9–7.2) (3.9, 7.5) (8.8–13.6). 3 studies 5 studies 11 studies I2 = 65.9 I2 = 88.3 I2 = 96.6 Inpatient Influenza positivity among those hospitalized with respiratory symptoms—Cases/100 children 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) (9 studies) (10 studies) (25 studies) I2 = 94 I2 = 94.3 I2 = 96.2 a Treating Nasreen et al. [41] as an outlier (1.3 per 1000 child years) pooled estimate of other 5 studies in the ALRI group were found out to be 25.7 (95% CI: 14.7–36.6; I2 = 73.7) in under-five children b Treating Ruutu et al. [48] as an outlier [25.9 (95% CI: 19.6–32.3)] pooled proportional positivity from 10 studies is found to be to 10.2% in under-five children. Includes two studies [49, 50] reporting incidence among under six years. Fig. 2. View largeDownload slide Pooled estimate of incidence of influenza-related ARI among under-five children—cases/1000 child-year. Fig. 2. View largeDownload slide Pooled estimate of incidence of influenza-related ARI among under-five children—cases/1000 child-year. Fig. 3. View largeDownload slide Pooled estimate of incidence of influenza-related ALRI among under-five children: cases/1000 child-years. Fig. 3. View largeDownload slide Pooled estimate of incidence of influenza-related ALRI among under-five children: cases/1000 child-years. Eleven studies [21, 48–57] (Fig. 4, Supplementary Table S3) contributed to the estimation of influenza positivity among patients attending outpatient department with respiratory symptoms. Fig. 4. View largeDownload slide Summary estimate of studies on influenza positivity among under-five children seeking care for respiratory symptoms in outpatient setting. Fig. 4. View largeDownload slide Summary estimate of studies on influenza positivity among under-five children seeking care for respiratory symptoms in outpatient setting. The pooled estimate of influenza positivity among outpatient attendees varied with age and case definitions (Table 1). Twenty-five studies [48, 50, 51, 54, 56, 58–77] (Fig. 5, Supplementary Table S4) contributed to influenza positivity among hospitalized children. Data from 68% of these studies were available for under-fives, whereas others reported hospitalization in younger age groups. Summary estimates of proportional positivity varied by age, region and case definitions (Table 1, Table 2). Heterogeneity of pooled estimate of influenza positivity varied with age, geographical region, case definition and influenza diagnosis technique of the studies (Table 2) Table 2 Summary estimates (95% CI, I2) of the meta-analysis of influenza positivity in under-five children hospitalized with respiratory symptoms stratified by different scenarios Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 a Four studies used more than one method of influenza diagnosis, hence not included in the subgroup analysis. Similarly, 2 studies that did not use either of the techniques mentioned above were not included in the subgroup analysis. Table 2 Summary estimates (95% CI, I2) of the meta-analysis of influenza positivity in under-five children hospitalized with respiratory symptoms stratified by different scenarios Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 Stratified by age-group <2 years <3 years <5 years 4.9 5.1 7.1 (2.5–7.2) (2.9–7.4) (5.5–8.8) 9 studies 10 studies 25 studies I2 = 94 I2 = 94.3 Stratified by geographic region Indian Indian subcontinent Other Asian countries 5.63 4.67 8.53 (2.12–9.14) (2.77–6.57) (6.08–0.97) 5 studies 9 studies 16 studies I2 = 89.6 I2 = 85.1 I2 = 97.3 Stratified by case definition ALRI Pneumonia Severe acute respiratory infection ARI/ILI 6.6 6.9 6.2 8.7 (4.0–9.3) (3.4–10.5) (−0.2–12.6) (3.8–13.5) 10 studies 6 studies 2 studies 7 studies I2 = 96 I2 = 96 I2 = 82 I2 = 96.4 Stratified by influenza diagnosis methoda RT-PCR Culture 9.0 2.1 (7.2–10.9) (−3.7–7.9) 12 studies 7 studies I2 = 92.8 I2 = 90.4 a Four studies used more than one method of influenza diagnosis, hence not included in the subgroup analysis. Similarly, 2 studies that did not use either of the techniques mentioned above were not included in the subgroup analysis. Fig. 5. View largeDownload slide Summary estimates of studies of influenza positivity among under-five children hospitalized with respiratory symptom. Fig. 5. View largeDownload slide Summary estimates of studies of influenza positivity among under-five children hospitalized with respiratory symptom. Estimates for India Estimates of influenza burden in India is summarized in Panel 2 and Fig. 6. Fig. 6. View largeDownload slide Estimated burden of influenza in under-fives in India in the year 2016. Fig. 6. View largeDownload slide Estimated burden of influenza in under-fives in India in the year 2016. Panel 2: Estimation of annual influenza burden among under-fives in India. Morbidity burden of influenza ○ The incidence rate: 132.1/1000 child year (95% CI: 115.1–149.2). ○ Under-five population: 121 million. ○ Health care seeking rate of ARI: 68.17 (95% CI: 59.4–77.2). ○ Hospitalization rate of respiratory disease among under-five: 12.71 per 1000 children (95% CI: 9.5–16.6). ○ Proportional influenza positivity among inpatient: 7.1% (95% CI: 5.5–8.8). ○ Total influenza cases: 16 009 207 (95% CI: 13 942 916–18 082 769). ○ Total outpatient visits: 10 913 476 (95% CI: 9 504 666–12 362 310). ○ Total influenza hospitalization: 109 431 (95% CI: 83 882–134 980). Mortality burden of influenza ○ Population: 1 300 840 155. ○ Birth rate: 20.8 (95% CI: 20.6, 21.0) per 1000 midyear population. ○ Pneumonia mortality: 14.5 (95% CI: 14·1, 15·0) per 1000 live births. ○ Influenza positivity: 7.1 (95% CI: 5.5, 8.8) per 100 cases. ○ Influenza deaths: 27 895 (95% CI: 21 382–34 408). From the uncertainty analysis performed by the simulation, the mean death estimated as 28 124 (95% CI: 28 050–28 199). The median estimate was 28 061 and the 2.5th and 97.5th percentile level were 21 921 and 34 533, respectively. This would be equivalent to 1 death per 1000 live births per year or 2.1 per 100 000 of total population. DISCUSSION This review highlighted the dearth of literature on influenza from India and Indian subcontinent and wide methodological differences in estimation of the influenza burden. There was a sudden rise of influenza reports in 2009–2010 but these were mostly of pandemic influenza. Articles containing only p (Hemagglutinin Type 1 and Neuraminidase Type 1 (H1N1)) were excluded until WHO announced it as an endemic strain. Community-clinic based or passive surveillance studies that reported the total population of the catchment area were included in community setting of meta-analyses owing to lack of reports of active community-based influenza surveillance. The issue of completeness of coverage and representativeness would be an important concern for these studies. The proportional positivity of influenza among under-fives found by the present study was comparable with previous reviews and meta-analysis done by Simmerman et al. [24], Nair et al. [10], Rudan et al. [28] and Global Respiratory Hospitalizations–Influenza Proportion Positive study group [78]. A systematic review from sub-Saharan Africa by Gessner et al. [11] reported wide range of positivity among inpatients, whereas Luksik et al. [26] reported much lower positivity. In India, diagnostic tests for influenza are not done routinely. Consequently, influenza could not be ascertained as a cause of death. We used influenza positivity among severely ill children, admitted to a hospital as proxy for positivity among dead children. Homaira et al. [79] used a similar multiplier method to estimate influenza deaths. Nair et al. [10] estimated the mean influenza-associated ALRI deaths in under-five by combining the verbal autopsy and influenza circulation data of Ballabgarh, India. The mean annual death for 2006–08 was close to the estimate of present study (25 556 vs. 28 124). However, they estimated a much smaller number of deaths (5998) using an alternative approach. Comparable data achieved by different methodologies support the robustness of the assumptions. The total estimated influenza-related deaths expressed as a proportion of influenza-related hospitalization gives a case fatality rate of 18.9%, which was much higher than that reported in literature (4–12%) [80–82]. The estimate was probably higher, as the present study considered all deaths related to influenza irrespective of the hospitalization status of the child. Nair et al. [27] reported that 81% of severe ALRI deaths occurred outside hospitals. This review and meta-analysis compiled the estimates of published literature of influenza burden for the past three decades in the lower and lower-middle income countries of South Asia in all the settings and the pooled estimate represents the overall prevailing burden of influenza throughout this period. As data on temporal trends are not available, it is difficult to say how the inclusion of old studies would affect our estimate. A high level of heterogeneity among studies was found in all settings. This heterogeneity was perhaps owing to variations in case definitions (supplementary file), duration of data collection, qualification of data collectors and influenza diagnostics. Previous authors [25, 28] also experienced similar issues. However, subgroup analysis showed reduction of heterogeneity. Therefore, the estimate derived from this meta-analysis should be used with caution. However, the effort to restrict the studies as much as possible closer to Indian situation makes it more relevant to India. In case of mortality too, despite the limitations of the validity of the assumptions used, our estimates appear reasonable and are supported by results of previous estimation procedures. Evidence of burden of any disease plays a crucial role in introducing the vaccine in NIS. Published studies reporting burden of Haemophilus influenzae type B, Streptococcus pneumoniae and Rotavirus infection influenced the decision of Indian Government to include the related vaccines in NIS [83–89]. This study would add to the burden estimates of influenza in India and could help the policy makers to take decision on influenza vaccine. The methodology of obtaining influenza burden could be used for other diseases too for resource constraint settings. However, to obtain a robust estimate, country-specific multisite studies are required. SUPPLEMENTARY DATA Supplementary data are available at Journal of Tropical Pediatrics online. ACKNOWLEDGEMENTS We gratefully acknowledge the contribution of Dr Siddhartha Saha for his suggestions that greatly improved the manuscript. We are also thankful to our colleagues for their input from time to time during finalization of the manuscript. REFERENCES 1 Advisory Committee on Vaccines and Immunisation Practices (ACVIP) . Indian Academy of peadiatrics. IAP Guidebook on Immunisation 2013-2014 [Internet]. National Publication House, Indian Academy of Peadiatrics. http://www.iapindia.org/files/IAP Guidelines/IAP Guidebook on Immunization 2013-14. 2 Vashishtha VM , Kalra A , Choudhury P. Influenza vaccination in India: position paper of Indian Academy of Pediatrics, 2013 . Indian Pediatr 2013 ; 50 : 867 – 74 . Google Scholar CrossRef Search ADS PubMed 3 Ropero-Álvarez A , Kurtis HJ , Danovaro-Holliday MC , et al. Expansion of seasonal influenza vaccination in the Americas . BMC Public Health 2009 ; 9 : 361 . Google Scholar CrossRef Search ADS PubMed 4 National Influenza Specialist Group . Everything you need to know about FLU [Internet]. Immunisation Advisory Centre, The University of Auckland. [cited 2015 Jun 21]. http://www.influenza.org.nz/sites/default/files/2015 Flu Kit (21 June 2015 , date last accessed). 5 Department of Health, Government of Western Australia . Childhood immunisation schedule [Internet]. Healthy WA, Health information for Western Australians. http://ww2.health.wa.gov.au/Healthy-WA/Articles/A_E/Childhood-immunisation-schedule (21 June 2015 , date last accessed). 6 Australian Government Department of Health . National Immunisation Program Schedule (From 20 April 2015 ) [Internet]. Australian Government Department of Health. http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/national-immunisation-program-schedule (21 June 2015, date last accessed). 7 Gupta V , Dawood FS , Muangchana C , et al. Influenza vaccination guidelines and vaccine sales in Southeast Asia: 2008–2011 . Boni MF, editor. PLoS One 2012 ; 7 : e52842 . Google Scholar CrossRef Search ADS PubMed 8 Infectious Disease Surveillance Center . Immunisation Schedule, Japan 2014 [Internet]. National Institute of Infectious Diseases. idsc.nih.go.jp/vaccine/dschedule (4 November 2014 , date last accessed). 9 Ministry of Health & Family Welfare . Technical Guidelines, Swine flu-H1N1 (seasonal influenza) [Internet]. Government of India, Ministry of Health & Family Welfare. http://mohfw.gov.in/index1.php?lang=1&level=1&sublinkid=4987&lid=3070 (13 December 2016 , date last accessed). 10 Nair H , Brooks WA , Katz M , et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis . Lancet 2011 ; 378 : 1917 – 30 . Google Scholar CrossRef Search ADS PubMed 11 Gessner BD , Shindo N , Briand S. Seasonal influenza epidemiology in sub-Saharan Africa: a systematic review . Lancet Infect Dis 2011 ; 11 : 223 – 35 . Google Scholar CrossRef Search ADS PubMed 12 Broor S , Parveen S , Bharaj P , et al. A Prospective Three-Year Cohort Study of the epidemiology and virology of acute respiratory infections of children in Rural India . PLoS One 2 : e491 . CrossRef Search ADS PubMed 13 Purakayastha DR , Gupta V , Broor S , et al. Clinical differences between influenza A (H1N1) pdm09 & influenza B infections identified through active community surveillance in north India . Indian J Med Res 2013 ; 138 : 962 – 8 . Google Scholar PubMed 14 Fowler KB , Gupta V , Sullender W , et al. Incidence of symptomatic A (H1N1) pdm09 influenza during the pandemic and post-pandemic periods in a rural Indian community . Int J Infect Dis 2013 ; 17 : e1182 – 5 . Google Scholar CrossRef Search ADS PubMed 15 Misra PK , Chaudhary RS , Jain A , et al. Viral aetiology of acute respiratory infections in children in North India . J Trop Pediatr 1990 ; 36 : 24 – 7 . Google Scholar CrossRef Search ADS PubMed 16 Jain A , Pande A , Misra PK , et al. An Indian hospital study of viral causes of acute respiratory infection in children . J Med Microbiol 1991 ; 35 : 219 – 23 . Google Scholar CrossRef Search ADS PubMed 17 Rao BL , Banerjee K. Influenza surveillance in Pune, India, 1978-90 . Bull World Health Organ 1993 ; 71 : 177 – 81 . Google Scholar PubMed 18 Rao BL , Kadam SS , Pawar MS. Isolation of recent variant influenza types A(H3N2), A (H1N1) & B strains in Pune, India . Indian J Med Res 2001 ; 114 : 157 – 9 . Google Scholar PubMed 19 Rao BL , Yeolekar LR , Kadam SS , et al. Influenza surveillance in Pune, India, 2003 . Southeast Asian J Trop Med Public Health 2005 ; 36 : 906 – 9 . Google Scholar PubMed 20 Ramamurty N , Pillai LC , Gunasekaran P , et al. Influenza activity among the paediatric age group in Chennai . Indian J Med Res 2005 ; 121 : 776 – 9 . Google Scholar PubMed 21 Broor S , Krishnan A , Roy DS , et al. Dynamic patterns of circulating seasonal and pandemic A(H1N1)pdm09 Influenza viruses from 2007–2010 in and around Delhi, India . PLoS One 2012 ; 7 : e29129 . Google Scholar CrossRef Search ADS PubMed 22 Chadha MS , Hirve S , Dawood FS , et al. Burden of seasonal and pandemic influenza-associated hospitalization during and after 2009 A(H1N1) pdm09 pandemic in a rural community in India . PLoS One 2013 ; 8 : e55918. Google Scholar CrossRef Search ADS PubMed 23 Hirve S , Krishnan A , Dawood FS , et al. Incidence of influenza-associated hospitalization in rural communities in western and northern India, 2010-2012: a multi-site population-based study . J Infect 2015 ; 70 : 160 – 70 . Google Scholar CrossRef Search ADS PubMed 24 Simmerman JM , Uyeki TM. The burden of influenza in East and South-East Asia: a review of the English language literature . Influenza Other Respir Viruses 2008 ; 2 : 81 – 92 . Google Scholar CrossRef Search ADS PubMed 25 Bueving HJ , van der Wouden JC , Berger MY , et al. Incidence of influenza and associated illness in children aged 0–19 years: a systematic review . Rev Med Virol 2005 ; 15 : 383 – 91 . Google Scholar CrossRef Search ADS PubMed 26 Lukšić I , Kearns PK , Scott F , et al. Viral etiology of hospitalized acute lower respiratory infections in children under 5 years of age – a systematic review and meta-analysis . Croat Med J 2013 ; 54 : 122 – 34 . Google Scholar CrossRef Search ADS PubMed 27 Nair H , Simões EA , Rudan I , et al. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis . Lancet 2013 ; 381 : 1380 – 90 . Google Scholar CrossRef Search ADS PubMed 28 Rudan I , O’brien KL , Nair H , et al. Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries . J Glob Health 2013 ; 3 : 010401 . Google Scholar CrossRef Search ADS PubMed 29 STROBE statement: strengthening the reporting of observational studies in epidemiology [Internet] . http://www.strobe-statement.org/index.php?id=strobe-home (28 August 2016 , date last accessed). 30 Office of the Registrar General and Census Commissioner, Ministry of Home affairs, Government of India . Population Ennumeration Data (Final Population), 2011 Census data [Internet]. http://www.censusindia.gov.in/2011census/population_enumeration.html. 31 Registrar General, India . SRS Bulletin 2011 , Sample registration System [Internet]. Report No.: Volume 47 No.2. 2012. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletins/SRS_Bulletin-October_2012.pdf. 32 Registrar General, India . SRS Bulletin 2012 , Sample Registration System [Internet]. Report No.: Vol 48 No.2. 2013. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletins/SRS_Bulletin-September_2013.pdf. 33 Registrar General, India . SRS Bulletin 2013 , Sample registration System [Internet]. Report No.: Vol 49 No1. 2014. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletins/SRS%20Bulletin%20-Sepetember%202014.pdf. 34 Registrar General, India . SRS Bulletin 2014 , Sample Registration System [Internet]. Report No.: Vol 50 No.1. 2016. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletin_2014.pdf. 35 Registrar General, India . SRS Bulletin 2015 , Sample registration System [Internet]. Report No.: Vol.50 No.2. 2016. http://www.censusindia.gov.in/vital_statistics/SRS_Bulletin_2015.pdf. 36 International Institute for Population Sciences, Deonar, Mumbai . National Family Health Survey-3(2005-2006), India [Internet]. http://rchiips.org/nfhs/chapters.shtml (18 May 2016 , date last accessed). 37 Ministry of Statistics and Programme Implementation . India - Social Consumption : Health, NSS 71st Round : Jan - June 2014 - Overview [Internet]. Report No.: 574. 2015 . (DDI-IND-NSSO-71Rnd-Sch25pt0-Jan-June-2014). http://mail.mospi.gov.in/index.php/catalog/161 (26 September 2016, date last accessed). 38 Government of India . Causes of death in India 2010-13, Census of India : Sample Registration System [Internet]. http://www.censusindia.gov.in/2011-Common/Sample_Registration_System.html (23 June 2016 , date last accessed). 39 Homaira N , Luby SP , Petri WA , et al. Incidence of respiratory virus-associated pneumonia in urban poor young children of Dhaka, Bangladesh, 2009–2011 . Madhi SA, editor. PLoS One 2012 ; 7 : e32056 . Google Scholar CrossRef Search ADS PubMed 40 Vathanophas K , Sangchai R , Raktham S , et al. A Community-Based Study of acute respiratory tract infection in Thai children . Clin Infect Dis 1990 ; 12(Suppl. 8) : S957 – 65 . Google Scholar CrossRef Search ADS 41 Nasreen S , Luby SP , Brooks WA , et al. Population-based incidence of severe acute respiratory virus infections among children aged <5 years in Rural Bangladesh, June–October 2010 . Schulz TF, editor. PLoS One 2014 ; 9 : e89978 . Google Scholar CrossRef Search ADS PubMed 42 Brooks WA , Goswami D , Rahman M , et al. Influenza is a major contributor to childhood pneumonia in a tropical developing country . Pediatr Infect Dis J 2010 ; 29 : 216 – 21 . Google Scholar CrossRef Search ADS PubMed 43 Kimura Y , Saito R , Tsujimoto Y , et al. Geodemographics profiling of influenza A and B virus infections in community neighborhoods in Japan . BMC Infect Dis 2011 ; 11 : 36 . Google Scholar CrossRef Search ADS PubMed 44 Heikkinen T , Silvennoinen H , Peltola V , et al. Burden of Influenza in children in the community . J Infect Dis 2004 ; 190 : 1369 – 73 . Google Scholar CrossRef Search ADS PubMed 45 Forgie IM , Campbell H , Lloyd-Evans N , et al. Etiology of acute lower respiratory tract infections in children in a rural community in The Gambia . Pediatr Infect Dis J 1992 ; 11 : 466 – 73 . Google Scholar CrossRef Search ADS PubMed 46 Borrero HI , Fajardo RL , Bedoya MA , et al. Acute respiratory tract infections among a birth cohort of children from Cali, Colombia, who were studied through 17 months of age . Clin Infect Dis 1990 ; 12(Suppl. 8) : S950 – 6 . Google Scholar CrossRef Search ADS 47 Tupasi TE , de Leon LE , Lupisan S , et al. Patterns of acute respiratory tract infection in children: a longitudinal study in a depressed community in Metro Manila . Rev Infect Dis 1990 ; 12(Suppl. 8) : S940 – 9 . Google Scholar CrossRef Search ADS PubMed 48 Ruutu P , Halonen P , Meurman O , et al. Viral lower respiratory tract infections in Filipino children . J Infect Dis 1990 ; 161 : 175 – 9 . Google Scholar CrossRef Search ADS PubMed 49 Agrawal AS , Sarkar M , Chakrabarti S , et al. Comparative evaluation of real-time PCR and conventional RT-PCR during a 2 year surveillance for influenza and respiratory syncytial virus among children with acute respiratory infections in Kolkata, India, reveals a distinct seasonality of infection . J Med Microbiol 2009 ; 58 : 1616 – 22 . Google Scholar CrossRef Search ADS PubMed 50 Dilantika C , Sedyaningsih ER , Kasper MR , et al. Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness . BMC Infect Dis 2010 ; 10 : 3 . Google Scholar CrossRef Search ADS PubMed 51 Yeolekar LR , Damle RG , Kamat AN , et al. Respiratory virus in acute respiratory tract infections in Western India . Indian J Pediatr 2008 ; 75 : 341 – 5 . Google Scholar CrossRef Search ADS PubMed 52 Mathisen M , Strand TA , Sharma BN , et al. RNA viruses in community-acquired childhood pneumonia in semi-urban Nepal; a cross-sectional study . BMC Med 2009 ; 7 : 35 . Google Scholar CrossRef Search ADS PubMed 53 Nguyen HT , Dharan NJ , Le MTQ , et al. National influenza surveillance in Vietnam, 2006–2007 . Vaccine 2009 ; 28 : 398 – 402 . Google Scholar CrossRef Search ADS PubMed 54 Chittaganpitch M , Supawat K , Olsen SJ , et al. Influenza viruses in Thailand: 7 years of sentinel surveillance data, 2004-2010: Influenza in Thailand . Influenza Other Respir Viruses 2012 ; 6 : 276 – 83 . Google Scholar CrossRef Search ADS PubMed 55 Khamphaphongphane B , Ketmayoon P , Lewis HC , et al. Epidemiological and virological characteristics of seasonal and pandemic influenza in Lao PDR, 2008-2010: seasonal and pandemic influenza in Lao PDR 2008-2010 . Influenza Other Respir Viruses 2013 ; 7 : 304 – 11 . Google Scholar CrossRef Search ADS PubMed 56 Tallo VL , Kamigaki T , Tan AG , et al. Estimating influenza outpatients’ and inpatients’ incidences from 2009 to 2011 in a tropical urban setting in the Philippines . Influenza Other Respir Viruses 2014 ; 8 : 159 – 68 . Google Scholar CrossRef Search ADS PubMed 57 Otomaru H , Kamigaki T , Tamaki R , et al. Influenza and Other Respiratory Viruses detected by Influenza-like illness surveillance in Leyte Island, the Philippines, 2010–2013 . Chuang JH, editor. PLoS One 2015 ; 10 : e0123755 . Google Scholar CrossRef Search ADS PubMed 58 Huq F , Rahman M , Nahar N , et al. Acute lower respiratory thact infection due to virus among hospitalized children in Dhaka, Bangladesh . Clin Infect Dis 1990 ; 12(Suppl. 8) : S982 – 7 . Google Scholar CrossRef Search ADS 59 Sung RYT , Chan PKS , Tsen T , et al. Identification of viral and atypical bacterial pathogens in children hospitalized with acute respiratory infections in Hong Kong by multiplex PCR assays: Multiplex PCR for Respiratory viruses . J Med Virol 2009 ; 81 : 153 – 9 . Google Scholar CrossRef Search ADS PubMed 60 Maitreyi RS , Broor S , Kabra SK , et al. Rapid detection of respiratory viruses by centrifugation enhanced cultures from children with acute lower respiratory tract infections . J Clin Virol 2000 ; 16 : 41 – 7 . Google Scholar CrossRef Search ADS PubMed 61 Hasan K , Jolly P , Marquis G , et al. Viral etiology of pneumonia in a cohort of newborns till 24 months of age in Rural Mirzapur, Bangladesh . Scand J Infect Dis 2006 ; 38 : 690 – 5 . Google Scholar CrossRef Search ADS PubMed 62 Simmerman JM , Chittaganpitch M , Levy J , et al. Incidence, seasonality and mortality associated with Influenza pneumonia in Thailand: 2005–2008 . Myer L, editor. PLoS One 2009 ; 4 : e7776 . Google Scholar CrossRef Search ADS PubMed 63 Olsen SJ , Thamthitiwat S , Chantra S , et al. Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand . Epidemiol Infect 2010 ; 138 : 1811 – 22 . Google Scholar CrossRef Search ADS PubMed 64 Samransamruajkit R , Hiranrat T , Chieochansin T , et al. Prevalence, clinical presentations and complications among hospitalized children with influenza pneumonia . Jpn J Infect Dis 2008 ; 61 : 446 – 9 . Google Scholar PubMed 65 Singh AK , Jain A , Jain B , et al. Viral aetiology of acute lower respiratory tract illness in hospitalised paediatric patients of a tertiary hospital: one year prospective study . Indian J Med Microbiol 2014 ; 32 : 13 . Google Scholar CrossRef Search ADS PubMed 66 Hirve S , Chadha M , Lele P , et al. Performance of case definitions used for Influenza surveillance among hospitalized patients in a rural area of India . Bull World Health Organ 2012 ; 90 : 804 – 12 . Google Scholar CrossRef Search ADS PubMed 67 Kaur C , Chohan S , Khare S , et al. Respiratory viruses in acute bronchiolitis in Delhi . Indian Pediatr 2010 ; 47 : 342 – 4 . Google Scholar CrossRef Search ADS PubMed 68 Do AHL , van Doorn HR , Nghiem MN , et al. Viral etiologies of acute respiratory infections among hospitalized Vietnamese children in Ho Chi Minh City, 2004-2008 . PLoS One 2011 ; 6 : e18176. Google Scholar CrossRef Search ADS PubMed 69 Suntarattiwong P , Sian-nork C , Thongtipa P , et al. Influenza-associated hospitalization in urban Thai children . Influenza Other Respir Viruses 2007 ; 1 : 177 – 82 . Google Scholar CrossRef Search ADS PubMed 70 Suntarattiwong P , Sojisirikul K , Sitaposa P , et al. Clinical and epidemiological characteristics of respiratory syncytial virus and influenza virus associated hospitalization in Urban Thai infants . J Med Assoc Thai 2011 ; 94 : S164 – 71 . Google Scholar PubMed 71 Yoshida LM , Suzuki M , Yamamoto T , et al. Viral pathogens associated with acute respiratory infections in central vietnamese children . Pediatr Infect Dis J 2010 ; 29 : 75 – 7 . Google Scholar CrossRef Search ADS PubMed 72 Yoshida LM , Suzuki M , Nguyen HA , et al. Respiratory syncytial virus: co-infection and paediatric lower respiratory tract infections . Eur Respir J 2013 ; 42 : 461 – 9 . Google Scholar CrossRef Search ADS PubMed 73 Mathisen M , Basnet S , Sharma A , et al. RNA viruses in young Nepalese children hospitalized with severe pneumonia . Pediatr Infect Dis J 2011 ; 30 : 1032 – 6 . Google Scholar CrossRef Search ADS PubMed 74 Sunakorn P , Chunchit L , Niltawat S , et al. Epidemiology of acute respiratory infections in young children from Thailand . Pediatr Infect Dis J 1990 ; 9 : 873 – 7 . Google Scholar CrossRef Search ADS PubMed 75 Rahman M , Huq F , Sack DA , et al. Acute lower respiratory tract infections in hospitalized patients with Diarrhea in Dhaka, Bangladesh . Clin Infect Dis 1990 ; 12(Suppl. 8) : S899 – 906 . Google Scholar CrossRef Search ADS 76 Hasan R , Rhodes J , Thamthitiwat S , et al. Incidence and etiology of acute lower respiratory tract infections in hospitalized children younger than 5 years in Rural Thailand . Pediatr Infect Dis J 2014 ; 33 : e45 – 52 . Google Scholar CrossRef Search ADS PubMed 77 Tupasi TE , Lucero MG , Magdangal DM , et al. Etiology of acute lower respiratory tract infection in children from Alabang, Metro Manila . Rev Infect Dis 1990 ; 12(Suppl. 8) : S929 – 39 . Google Scholar CrossRef Search ADS PubMed 78 Lafond KE , Nair H , Rasooly MH , et al. Global role and burden of influenza in pediatric respiratory hospitalizations, 1982-2012: a systematic analysis . PLoS Med 2016 ; 13 : e1001977 . Google Scholar CrossRef Search ADS PubMed 79 Homaira N , Luby SP , Alamgir A , et al. Influenza-associated mortality in 2009 in four sentinel sites in Bangladesh . Bull World Health Organ 2012 ; 90 : 272 – 8 . Google Scholar CrossRef Search ADS PubMed 80 Djelantik IGG , Gessner BD , Sutanto A , et al. Case fatality proportions and predictive factors for mortality among children hospitalized with severe pneumonia in a rural developing country setting . J Trop Pediatr 2003 ; 49 : 327 – 32 . Google Scholar CrossRef Search ADS PubMed 81 Naheed A , Saha SK , Breiman RF , et al. Multihospital surveillance of pneumonia burden among children aged <5 years hospitalized for pneumonia in Bangladesh . Clin Infect Dis 2009 ; 48(Suppl. 2) : S82 – 9 . Google Scholar CrossRef Search ADS PubMed 82 Ramachandran P , Nedunchelian K , Vengatesan A , et al. Risk factors for mortality in community-acquired pneumonia among children aged 1–59 months admitted in a referral hospital . Indian Pediatr 2012 ; 49 : 889 – 95 . Google Scholar CrossRef Search ADS PubMed 83 Kant L. NTAGI subcommittee recommendations on haemophilus influenzae type b (Hib) vaccine introduction in India . Indian Pediatr 2009 ; 46 : 945 – 54 . Google Scholar PubMed 84 Johnson H , Bassani D , Perin J , et al. Burden of childhood mortality caused by Streptococcus pneumoniae in India. The 8th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD). Abstract # A-428-0023- 00743. Iguaçu Falls, Brazil, 2012 . 85 Thomas K. Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India . Lancet 1999 ; 353 : 1216 – 21 . Google Scholar CrossRef Search ADS PubMed 86 Levine O , Cherian T. Pneumococcal vaccination for Indian children . Indian Pediatr 2007 ; 44 : 491 – 6 . Google Scholar PubMed 87 Gavi, the vaccine alliance. India to introduce four new vaccines [Internet]. http://www.gavi.org/library/news/statements/2014/india-to-introduce-four-new-vaccines/ (29 September 2016 , date last accessed). 88 Press Information Bureau, Government of India, Prime Minister’s Office . Three new vaccines including rotavirus vaccine to be provided to all Indian children [Internet]. http://pib.nic.in/newsite/PrintRelease.aspx?relid=106055 (3 July 2014 , date last accessed). 89 Kang G , Arora R , Chitambar SD , et al. Multicenter, hospital-based surveillance of rotavirus disease and strains among Indian children aged <5 years . J Infect Dis 2009 ; 200(Suppl. 1) : S147 – 53 . Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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Journal of Tropical PediatricsOxford University Press

Published: Nov 3, 2017

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