Role of seasonal influenza in the aetiology of hospitalised acute lower respiratory infections in young children
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Background Respiratory viruses are a leading cause of acute lower respiratory infections (ALRI) in young children. The role of seasonal influenza virus in childhood ALRI is generally underappreciated. This is because the global burden of disease due to ALRI attributable to seasonal influenza virus in children is unknown. This thesis aims to estimate the global and regional hospital admissions for seasonal influenzaassociated ALRI and the possible boundaries for influenza-associated ALRI mortality in children younger than five years. The WHO has developed guidelines for influenza surveillance using severe acute respiratory infections (SARI) sentinel surveillance network. However, data from sentinel surveillance are not routinely used in estimating disease burden in a population. This thesis also aims to provide tools for estimating influenza disease burden using data from SARI sentinel surveillance in developing country settings. Methods Incidence data for influenza-associated ALRI (from passive, hospital-based studies) were collected using a systematic review of studies published between January 1, 1995 and October 31, 2010. These data were supplemented by unpublished data from 15 population-based studies that were obtained by forming a consortium of researchers (Influenza Study Group) working in developing countries. The incidence meta-estimates were applied to global and regional population estimates for 2008 to calculate the estimated number of hospitalised influenza-associated ALRI cases that year. The possible bounds for influenza-associated mortality were estimated by combining incidence estimates with in-hospital case fatality ratios and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. The data to estimate the incidence of all-cause hospitalised ALRI were collected using a systematic literature review that was supplemented with unpublished data from 24 population-based studies that were obtained by collaborating with research sites in developing countries (Severe ALRI Working Group). The hospitalised ALRI incidence meta-estimates were applied to global and regional population estimates for 2008 to calculate the estimated number of all-cause hospitalised ALRI cases that year. Data on the proportion of hospitalised ALRI cases that were positive for influenza were collected using a systematic review of the studies published between January 1, 1995 and December 31, 2011. The meta-estimates of the proportion of hospitalised ALRI cases positive for influenza were applied to the estimated number of hospitalised ALRI cases in the year 2008 to estimate the number of hospitalised influenza-associated ALRI cases globally and for the six WHO regions using this alternative method. The tools for estimating influenza disease burden using surveillance data were developed after a literature review and a survey of 27 end-users (influenza epidemiologists) in 24 countries. Results Thirty nine studies (21 from developing and 18 from industrialised regions) satisfying the eligibility criteria, provided data on the incidence of influenza-associated hospitalised ALRI. The incidence is highest in infants in the first six months of life, both in developing as well as industrialised countries. It is estimated that the incidence of hospitalised influenza-associated ALRI in children under the age of five years was about 1.5 (95% CI 1.0 to 2.3) and 1.2 (95% CI 0.9 to 1.6) per 1000 children in developing and industrialised countries respectively. This translates to about 911,000 (95% CI 617,000 to 1.4 million) hospitalisations worldwide due to influenza-associated ALRI in children younger than five years in 2008, 93% of the cases occurring in developing countries (where 90% of the global under-5 population reside). An estimated 21,500 (based on 20 studies) to 115,000 deaths (based on only 1 study) in under-five children were attributable to influenza-associated ALRI in 2008. Incidence and mortality varied substantially from year to year in any one setting. Eighty five studies (61 from developing and 24 from industrialised) reported incidence of hospitalised ALRI in children aged 0 to 4 years. It is estimated that about 11.3 (95% CI 9.5 to 13.5) million episodes of ALRI resulting in hospitalisation occurred worldwide in children aged 0 to 4 years in 2008, 92% of these occurring in developing countries. Twenty three studies (19 from developing and 4 from industrialised) reported data on proportion of hospitalised ALRI cases testing positive for influenza using laboratory tests. The estimated proportion of influenza-positive hospitalised ALRI cases was about 5.0 (95% CI 3.6 to 7) percent and 8.4 (95% CI 4.2 to 16.7) percent in developing and industrialised countries respectively. This translates to about 772,000 (95% CI 343,000 to 1.8 million) cases of influenza-associated hospitalised ALRI in children younger than five years worldwide in the year 2008. A manual (targeted at developing countries) describing the methods to estimate the disease burden associated with seasonal influenza using the various surveillance data was developed after considering the results of the preliminary survey. An electronic tool (based on a spread sheet model) to help the end-users (epidemiologists at sentinel surveillance sites and Ministries of Health) to estimate the disease burden at local and national levels was developed as an adjunct to the manual. The manual along with the electronic tool were piloted at three different sites in two developing countries (India and Ghana) and feedback from the end-users was obtained to make the version more user-friendly. The final draft of the manual along with the tool has been submitted to the WHO for final clearance. The member states and the WHO Eastern Mediterranean Regional Office decided to adopt the manual and in the first instance estimate the influenza disease burden in 8 member states having the requisite data for undertaking disease burden estimation. Conclusions Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on hospital inpatient services worldwide. There are significant gaps in published data from developing countries (especially the African and Eastern Mediterranean regions of the WHO). Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not presently available. Effective use of sentinel surveillance data for disease burden estimation would greatly improve the quality and precision of disease burden estimates (especially those resulting in hospitalisation). Improved disease burden estimates (particularly at the national level) would inform policy makers and national governments in formulating immunization policies for vaccinating high-risk groups, and planning annual requirements for vaccines and anti-viral drugs against seasonal influenza.