RESEARCH

Comparative impact assessment of child pneumonia interventions

Evaluation comparative des impacts des interventions contre la pneumonie chez l'enfant

Evaluación comparativa del impacto de las intervenciones contra la neumonía en la niñez

Louis Niessen^{I, *}; Anne ten Hove^II; Henk Hilderink^III; Martin Weber^IV; Kim Mulholland^V; Majid Ezzati^VI

^IDepartment of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD, 21205, United States of America (USA)
^IIDepartment for Health Policy and Management, Erasmus University, Rotterdam, the Netherlands
^IIINetherlands Environmental Assessment Agency, Bilthoven, the Netherlands
^IVWorld Health Organization Country Office, Jakarta, Indonesia
^VInfectious Disease Epidemiology Unit, London School of Hygiene, London, England
^VIDepartment of Population and International Health and Department of Environmental Health, Harvard School of Public Health, Cambridge, MA, USA

ABSTRACT

OBJECTIVE: To compare the cost-effectiveness of interventions to reduce pneumonia mortality through risk reduction, immunization and case management.
METHODS: Country-specific pneumonia burden estimates and intervention costs from WHO were used to review estimates of pneumonia risk in children under 5 years of age and the efficacy of interventions (case management, pneumonia-related vaccines, improved nutrition and reduced indoor air pollution from household solid fuels). We calculated health benefits (disability-adjusted life years, DALYs, averted) and intervention costs over a period of 10 years for 40 countries, accounting for 90% of pneumonia child deaths.
FINDINGS: Solid fuel use contributes 30% (90% confidence interval: 18–44) to the burden of childhood pneumonia. Efficacious community-based treatment, promotion of exclusive breastfeeding, zinc supplementation and Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae immunization through existing programmes showed cost-effectiveness ratios of 10–60 International dollars (I$) per DALY in low-income countries and less than I$ 120 per DALY in middle-income countries. Low-emission biomass stoves and cleaner fuels may be cost-effective in low-income regions. Facility-based treatment is potentially cost-effective, with ratios of I$ 60–120 per DALY. The cost-effectiveness of community case management depends on home visit cost.
CONCLUSION: Vaccines against Hib and S. pneumoniae, efficacious case management, breastfeeding promotion and zinc supplementation are cost-effective in reducing pneumonia mortality. Environmental and nutritional interventions reduce pneumonia and provide other benefits. These strategies combined may reduce total child mortality by 17%.

RÉSUMÉ

OBJECTIF: Comparer les rapports coût/efficacité d'interventions pour diminuer la mortalité par pneumonie à travers la réduction des risques, la vaccination et la prise en charge des cas.
MÉTHODS: Nous avons utilisé des estimations établies par l'OMS pour la charge de pneumonies par pays et les coûts des interventions afin d'analyser les estimations du risque de pneumonie chez les enfants de moins de 5 ans et l'efficacité d'un certain nombre d'interventions (prise en charge des cas, vaccinations en rapport avec la pneumonie, amélioration de la nutrition et réduction de la pollution de l'air intérieur due aux combustibles solides ménagers). Nous avons calculé les bénéfices pour la santé [années de vie corrigées de l'incapacité (DALY) évitées] et les coûts des interventions sur une période de 10 ans pour 40 pays totalisant 90 % des décès d'enfants par pneumonie.
RÉSULTATS: L'utilisation de combustibles fossiles contribue pour 30 % (intervalle de confiance à 95 % : 18-44) à la charge de pneumonie infantile. Le traitement efficace au niveau communautaire, la promotion de l'allaitement exclusif, la supplémentation en zinc et les vaccinations contre Haemophilus influenzae type B (Hib) et Streptocccus pneumoniae par le biais des programmes existants ont présenté des rapports coût/efficacité de $ int. 10 à $ int. 60 par DALY dans les pays à faible revenu et inférieurs à $ int. 120 par DALY dans les pays à revenu moyen. L'utilisation de fourneaux à biomasse à faible émission et de combustibles plus propres pourrait offrir un rapport coût/efficacité satisfaisant dans les régions à faible revenu. Le traitement en établissement de soins pourrait également fournir un bon rapport coût/efficacité, situé entre $ int. 60 et 120 par DALY. Le rapport coût/efficacité de la prise en charge des cas au niveau communautaire dépend du coût des visites à domicile.
CONCLUSION: La vaccination contre Hib et S. pneumoniae, la prise en charge efficace des cas, la promotion de l'allaitement maternel et la supplémentation en zinc sont des interventions présentant un bon rapport coût/efficacité dans la réduction de la mortalité par pneumonie. Les interventions d'ordre environnemental et nutritionnel font régresser la pneumonie et procurent d'autres bénéfices. La combinaison de ces stratégies peut permettre une réduction globale de la mortalité infantile de 17 %.

RESUMEN

OBJETIVO: Comparar la costoeficacia de las intervenciones tendentes a reducir la mortalidad por neumonía mediante la reducción del riesgo, la inmunización y el manejo de casos.
MÉTODOS: Partiendo de estimaciones de la carga de neumonía por países y del costo de las intervenciones según la OMS, se analizaron las estimaciones del riesgo de neumonía entre los menores de 5 años y la eficacia de las intervenciones (manejo de casos, vacunas relacionadas con la neumonía, mejoras de la nutrición y reducción de la contaminación del aire en locales cerrados por combustibles sólidos domésticos). Calculamos los beneficios para la salud (años de vida ajustados en función de la discapacidad -AVAD- evitados) y el costo de las intervenciones a lo largo de 10 años para 40 países, abarcando el 90% de las defunciones por neumonía en la niñez.
RESULTADOS: El uso de combustibles sólidos contribuye en un 30% (intervalo de confianza del 90%: 18–44) a la carga de neumonía en la niñez. Un tratamiento comunitario eficaz, la promoción de la lactancia natural como alimentación exclusiva, la administración de suplementos de zinc y la inmunización contra Haemophilus influenzae tipo b (Hib) y Streptococcus pneumoniae a través de los programas existentes mostraron unas relaciones costo-eficacia de 10–60 dólares internacionales (I$) por AVAD en los países de ingresos bajos, y de menos de I$ 120 por AVAD en los países de ingresos medios. Las estufas de biomasa de baja emisión y unos combustibles más limpios pueden ser costoeficaces en las regiones de ingresos bajos. La administración de tratamiento en servicios de salud es una opción potencialmente costoeficaz, pues supone I$ 60–120 por AVAD. La relación costo-eficacia del manejo de casos comunitario depende del costo de las visitas domiciliarias.
CONCLUSIÓN: La vacunación contra Hib y S. pneumoniae, el manejo eficaz de los casos, la promoción de la lactancia natural y la administración de suplementos de zinc son medidas costoeficaces contra la mortalidad en la niñez. Las intervenciones ambientales y nutricionales reducen la neumonía y reportan también otros beneficios. La combinación de estas estrategias puede reducir en total la mortalidad en la niñez en un 17%.

Introduction

Progress in reducing mortality from pneumonia in children under 5 years of age has been relatively slow in many parts of the developing world, where about 155 million clinical pneumonia episodes and 2 million deaths occur annually.^1,2 Risk factors for pneumonia include stunting and underweight,^1,3,4 suboptimal breastfeeding,^5,6 lack of immunization^7,8 and indoor air pollution from household use of solid fuels.^9–12 There is evidence that effective and appropriate management of clinical cases is possible^13,14 at health-care facilities¹⁵ and in the community,¹⁶ but this level of management is often lacking.

Efforts to control pneumonia are needed to meet Millennium Development Goal 4 (MDG 4), to reduce child mortality in the world by two-thirds by 2015.¹⁷ Often, a package of priority interventions is developed to address MDG targets and reduce child mortality.^4,6,18–20 Cost-effectiveness analysis has become vital in deciding what interventions to implement and scale up.²¹ Single-candidate interventions to reduce pneumonia have been evaluated in general economic terms,^{6,11,18,22–24} but no comprehensive analysis has focused on pneumonia control.

Different interventions can affect incidence or case fatality, with differences noted across age groups. Population risk interventions can target specific subpopulations, while immunization is intended for all infants. Preventive interventions of this kind may reduce the incidence of pneumonia, whereas case management influences case fatality after falling ill. Both types of interventions can reduce pneumonia mortality.

The aim of this study was to compare the impact of eight preventive and curative interventions at the population level^6,25–27 and to identify the intervention mixes that generate the highest possible level of child health at the lowest cost.

Methods

To estimate the population health effects and total costs of pneumonia interventions from a health-care perspective, we applied demographic life tables for the 40 countries with the highest mortality (list available at: http://oldwww.bmg.eur.nl/personal/niessen/Webtable%20Countries%20by%20Region.doc The tables were used to estimate the health effect of risk factors, as well as the reductions in incidence and case fatality in population cohorts, simultaneously and consistently.^6,25–27 Detailed descriptions of concepts, methods, background papers, regional studies and data are available at: WHO-CHOICE (CHOosing Interventions that are Cost Effective) at: www.who.int/choice/en. Box 1 provides an overview of the approach.

We considered the epidemiological characteristics and level of health care of each of the 40 countries, as well as the coverage levels of the expanded programme on immunization (EPI) and of facility-based case management. Due to the large uncertainties involved in the epidemiologic, effectiveness and cost estimates, we included a high and a low cost-effectiveness scenario for each mix of interventions.

Each country's life table provides summary estimates of how pneumonia affects mortality and morbidity, expressed in terms of disability-adjusted life years (DALYs) lost. The tables also provide estimates of the effect and cost of mixed health interventions, in United States dollars (US$) for the year 2000, with a 3% discount rate according to health economics guidelines. We combined estimated health gains and costs per intervention to identify the sets of health interventions that maximized child health at different budget levels by providing the greatest health yield per dollar spent. The life tables were implemented in C++ (a general programming language) using M language (a language for working with data and building domain models). The script with M-equations is available at: http://oldwww.bmg.eur.nl/persona/niessen/GAPP_LOW.MPdf.pdf

Epidemiologic and demographic data

The life tables used in the model were based on the recently published WHO country data, which draw on reviews of incidence and mortality for childhood and neonatal pneumonia. Incidence estimates were taken from the epidemiological review.¹ Consistent applied case-fatality rates were calculated by dividing annual incidence figures by annual mortality rates from the global burden of disease data set.^2,7

Risk factor prevalence data were derived from the WHO Statistical Information System (WHOSIS), available at: http://www.who.int/whosis/en/index.html They included nonexclusive breastfeeding, undernutrition (defined as underweight for age, z < -2), measles immunization coverage and exposure to indoor air pollution in the population under 5 years of age. Relative risks of indoor air pollution by type of biomass fuel for pneumonia incidence were derived from the Global Action Plan for Pneumonia (GAPP).^9,10,28 Other relative risks for pneumonia incidence were obtained from the same review.¹

National statistics on neonatal, infant and child mortality for 2005 were obtained from the online database of the Institute for Health Metrics and Evaluation.⁷ The fractions of neonatal mortality attributable to pneumonia and sepsis were obtained from the The Lancet nutrition series.²⁰ Case-fatality ratios for children are specified by three age groups: neonatal period until 1 month of age, remainder of the first year (2-12 months of age) and 1–5 years.

The disability weight used to compute pneumonia morbidity for a disease episode lasting 2 weeks was 0.279.²⁹ DALYs were calculated by applying the region-specific disability weights for the general population by age and sex.³⁰ Country-level demographic data on population structure, birth rates and general mortality rates were obtained from official 2005 estimates by the Population Reference Bureau (available at: http://www.prb.org/Publications/Datasheets/2008/2008wpds.aspx).

Interventions, effectiveness and costs

In all scenarios we assumed a programme effectiveness time horizon of 10 years for all interventions, starting in 2005. After that, the new population cohorts resumed pre-intervention status, in line with the standardized cost-effectiveness approach of WHO-CHOICE project.⁶ The calculations included the extra life-years lived by additional surviving children beyond the 10-year period, as well as the pneumonia incidence reduction from immunization until the last immunized age group reaches the age of 5 years (in 2020). We estimated total health effects over a period of 100 years to include all life-years gained beyond the 10-year time horizon, among all survivors. We calculated intervention costs in International dollars (I$) to allow comparisons.

Table 1 shows the selected interventions and related input data for various scenarios. The subsections below describe the scenario assumptions by intervention category.

Reduction of indoor air pollution

The 90% confidence interval (CI) of the relative risk (RR) of pneumonia due to exposure to indoor air pollution was estimated to be 1.42 to 2.53.²⁸ Two interventions for indoor air pollution were selected.^9,28 The first was a switch at the household level to cleaner gaseous or liquid fuels (liquefied petroleum gas, kerosene or ethanol); the second was better combustion ventilation through high-quality and well-maintained biomass stoves. The health effect of intervening against this risk factor derives primarily from observational studies (including one unpublished randomized study of high-quality stoves). The GAPP reviews assumed that introducing cleaner fuel reduces pneumonia risk.^9,28 Based on this assumption, changing to full-scale cleaner household fuel could lower pneumonia incidence by 50% (the attributable burden for indoor air pollution). However, high-quality, well-maintained stoves are not expected to prevent all exposure to indoor air pollution. In an earlier review and cost-effectiveness study, a 75% reduction in exposure was assumed in a scenario of full coverage with good stoves.¹¹ Given the high and low RRs linked to indoor air pollution under this scenario (equations in Table 1), the pneumonia incidence reduction would be 22.2% to 45.8%.²⁸ The cost methodology and actual cost estimates are based on WHO reports^11,23 with a two- or four-year stove lifetime.

Nutritional interventions

Selected nutritional interventions to reduce pneumonia were exclusive breastfeeding promotion up to 6 months of age^6,18 and food supplementation with zinc.^3,33 Region-specific cost estimates were based on those from the WHO-CHOICE programme.

Immunizations

The scenarios included two vaccines as potential interventions to reduce pneumonia risk. The measles vaccine was not included, since its already high coverage in most of the 40 countries studied would have made its effect on pneumonia mortality difficult to quantify. The population effectiveness of immunization depends on the level of protection against the bacteria (Hib and pneumococcus), but even more on the actual attributable contribution of these bacteria to the pneumonia burden. Hib and pneumococcus may account for more than half of pneumonia mortality in children.¹⁷ The relative importance of these bacteria as causes of pneumonia in different settings is unknown, but the similarity of the trial results suggests that major differences between populations do not exist. The effectiveness range given by the high and low country scenarios takes into account the variety of agents (Table 1). The joint effect of the two vaccination programmes targeting two different microorganisms was assumed to be additive. The cost estimates were based on earlier economic evaluations.^22,24 Implementation was assumed to occur within existing immunization programmes and infrastructure.

Pneumonia case management

Two delivery strategies were chosen to treat children with pneumonia: a facility-based approach,¹⁵ and a community-level approach in which children were diagnosed and treated by community health workers.¹⁶ The estimated reduction of pneumonia mortality through pneumonia case management was based on two reviews.^13,16 These reported an efficacious (i.e. under ideal circumstances) reduction of 42% (90% CI: 22–57) in neonatal pneumonia mortality and of 36% (90% CI: 20–49) in child pneumonia mortality, confirmed by a review of management by community health workers.³¹ We subtracted these expected reductions from the country-specific, age-specific case fatality rates, while we included the uncertainty range based on the CI. In severe cases (8.6% of all incident cases), we assumed a case fatality reduction of 51%.³² The cost data of case-management strategies at the facility level are from the WHO-CHOICE programme and updates by WHO's Child and Adolescent Health Department.^21,32 The community-based cost estimates are from the Disease Control Priorities in Developing Countries (DCP2) project.¹⁴ We varied the number of budgeted visits by a village agent to children treated for pneumonia by one (low-cost scenario) to two times (high- cost scenario).^14,31

Results

Table 2 shows the regional aggregate results on the effect of using solid fuels on pneumonia mortality in children. Table 3 shows the potential impact of pneumonia interventions on total mortality among children under 5, and Table 4 lists the cost-effectiveness ratios. In each table, all eight intervention options are grouped into the four intervention areas described above (indoor air pollution, undernutrition, immunization and case management). In the country profiles, further expansion of pneumonia programmes is considered, alongside existing vaccination programmes and curative services.

The attributable pneumonia burden due to indoor air pollution by WHO region was based on the country-specific exposure estimates from the WHOSIS database. The two countries with the largest populations – China and India – showed a high level ( > 70%) of solid fuel use. The attributable burden for indoor air pollution in world regions varied from 10% to 38%, with a limited uncertainty range. The contribution of indoor air pollution to the global burden of childhood pneumonia is large (30%; CI: 18–44). Table 3 provides the aggregated results by WHO region of health gains for two intervention packages in the high-burden countries.

Table 5, which illustrates the possibilities for country-level policy-making, presents two country profiles with combinations of eight intervention scenarios. Both single (Table 4) and combined interventions (Table 5) show low-cost outcomes between I$ 10 and I$ 60 per DALY averted for interventions in the WHO Africa D and E subregions, and in the WHO Eastern Mediterranean D subregion. In other regions, effective options were immunization, nutritional interventions and community-based case management. A listing of WHO epidemiological subregions is available at: http://www.who.int/choice/demography/regions Many mixes of interventions fell in the cost range of I$ 60 to I$ 120 per DALY averted; others were less cost-effective in light of the general country income level. In some poorer regions, the two indoor air pollution interventions showed the same cost-effective levels as other interventions. In general, the indoor air pollution interventions appear to be less cost-effective than other interventions for reducing pneumonia mortality. The maximum potential reduction in child mortality, given existing infrastructures and including indoor air pollution interventions, appears to be about 13–17%. Thus, most of the child pneumonia mortality could be avoided if all interventions were implemented.

Discussion

Population-based preventive measures and expanding community-based case management appear to be the most effective options for reducing pneumonia mortality. Adding these measures to existing facility-based case management would increase the efficiency of health system as a whole. When outreach expansion is limited and infrastructure is lacking, immunization is costly. Where measles vaccination coverage is already high, both types of pneumonia vaccine are attractive options. The estimates on immunization depend strongly on the price per dose. Expanded case management, combined with expanded use of new vaccines, would increase system efficiency further. Adding new vaccines and expanding immunization coverage, nutritional interventions and community case management lead to relatively cost-effective pneumonia packages, as compared with facility-based management alone, because the latter was more costly in all scenarios.

Additionally, we found that health risk reduction through nutritional and immunization intervention programmes increases the cost-effectiveness of programmes for case management of childhood illnesses. The region and country league tables present the additional cost-effective options of expanded community case management and improved neonatal management.

The cost-effectiveness results showed the efficiency of implementing interventions alongside an existing health care structure, in comparison with a baseline situation. Presenting the results in this way provides policy-makers with a general impression of the impact of an intervention; it also makes it possible to compare the efficiency of existing and new packages and possible ways to improve the allocation of funds. For example, in a country such as Guatemala, the most attractive additional options would be zinc supplementation combined with community case management. If these interventions were introduced simultaneously with the available environmental interventions, the additional cost of the package per DALY would increase. When environmental interventions are introduced wherever other interventions are already in place, the extra health benefits are limited and the additional cost per DALY (i.e. marginal cost-effectiveness) can be high. For example, in a country such as Nigeria, which has some infrastructure but no proven options to reduce indoor air pollution, including up-scaling community case management, along with preventive programmes, would increase the cost-effectiveness of implementing a pneumonia control package.

Data are limited in almost all countries. Detailed data on pneumonia deaths are lacking, and community-based data on clinical episodes are sparse.1 Research is needed to better diagnose pneumonia and identify it as the cause of death. Our results are therefore difficult to validate beyond the recent reviews presented, whose quality determines the results of the economic impact evaluation. We were unable to distinguish between studies that reported intervention efficacy and those that reported community effectiveness. We attempted to consider this issue and other sources of uncertainty in our high and low effectiveness and cost scenarios; however, better data on community effectiveness and associated costs are needed. New preventive interventions may lead to net cost savings by preventing costly disease. However, we did not take into account potential savings due to cost offsets, lower use of health services and averted loss of workdays due to fewer illness episodes. Our results are thus conservative.

A point of debate is the cost of investing in cleaner fuels, whose cost per DALY averted is higher than that of other options. The results are not directly comparable, however, because the cost of cleaner fuels is offset by other societal benefits, such as time saved looking for firewood or other biomass fuels. If only the additional implementation efforts in an already existing health sector setting are considered and the extra costs of clean fuels are ignored, the cost-effectiveness ratio is lower. Uncertainty also surrounds the effectiveness and cost of community case management programmes. These are likely to be directly correlated with the quality improvements and the additional cost per village of visits by a village agent. These variables make it difficult to draw definite conclusions from the economic evaluation of these interventions. Still, our studies have identified three potentially valuable interventions to improve child survival: nutritional interventions, immunization and low-cost, effective case management. Innovative use of vaccines, focusing on the highest at-risk groups, could amplify the impact.

National priorities

Donors and national agencies involved in child survival programmes need to select those that maximize child health after considering existing mortality levels, infrastructure and funds available.³⁴ The present study, focused on children, offers policy-makers a range of potential pneumonia interventions and estimates of the money they require.³⁵

Internationally, there is agreement on using disease-burden estimates and data on the cost-effectiveness of interventions to select priority areas. New insights should be applied in real-life country settings to find local solutions and implement appropriate options. Country programme managers need more specific information on the effects and costs of child programmes so they can weigh them against other criteria, such as equity and other societal benefits.^35–37

We included in our scenarios only interventions for which effectiveness data were available. Due to a lack of data we could not examine the management of severe malnutrition through improved complementary feeding or strong community programmes. Malnutrition is a major risk factor for severe pneumonia,¹ yet no adequate study of the preventive effectiveness of such programmes has been performed.

The links between evidence and policy tend to be weak because national policies are the outcome of complicated processes among parties with different interests.^36,37 Impact analysis strengthens the selection of optimum child packages, and this paper shows how policy in this area can be more evidence based.

Acknowledgements

We thank the two anonymous reviewers for their detailed comments, and the members of the Global Action Plan for Pneumonia review groups for their scientific contributions. We also thank Shamim Qazi for his coordinating efforts and support.

Funding: The research is supported by a grant from the Netherlands Environmental Assessment Agency on integrated modelling, while two expert workshops were funded by WHO and the United Nations Children's Fund.

Competing interests: None declared.

References

1. Rudan I, Boschi-Pinto C, Wardlaw T, Johansson E, Biloglav Z, Mulholland K, et al. The epidemiology and etiology of childhood pneumonia. Bull World Health Organ 2008;86:408-16. doi:10.2471/BLT.07.048769 PMID:18545744        

2. Lopez AD, Mathews CD, Ezzati M, Jamison DT, Murray CJL. Global burden of disease and risk factors. Washington, DC: The World Bank; 2006.         

3. Roth DE, Caulfield LE, Ezzati M, Black RE. Acute lower respiratory infections in childhood: opportunities for reducing the global burden through nutritional interventions. Bull World Health Organ 2008;86:356-64. doi:10.2471/BLT.07.049114 PMID:18545738        

4. Gakidou E, Oza S, Vidal Fuertes C, Li AY, Lee DK, Sousa A, et al. Improving child survival through environmental and nutritional interventions: the importance of targeting interventions toward the poor. JAMA 2007;298:1876-87. doi:10.1001/jama.298.16.1876 PMID:17954539        

5. Victora CG, Kirkwood BR, Ashworth A, Black RE, Rogers S, Sazawal S, et al. Potential interventions for the prevention of childhood pneumonia in developing countries: improving nutrition. Am J Clin Nutr 1999;70:309-20. PMID:10479192        

6. Edejer TT, Aikins M, Black RE, Wolfson L, Hutubessy R, Evans DB. Cost effectiveness analysis of strategies for child health in developing countries. BMJ 2005;331:1177. doi:10.1136/bmj.38652.550278.7C PMID:16282378        

7. Murray CJ, Laakso T, Shibuya K, Hill K, Lopez AD. Can we achieve Millennium Development Goal 4? New analysis of country trends and forecasts of under-5 mortality to 2015. Lancet 2007;370:1040-54. doi:10.1016/S0140-6736(07)61478-0 PMID:17889243        

8. Madhi SA, Levine OS, Hajjeh R, Mansoor OD, Cherian T. Vaccines to prevent pneumonia and improve child survival. Bull World Health Organ 2008;86:365-72. doi:10.2471/BLT.07.044503 PMID:18545739        

9. Bruce N, Rehfuess E, Mehta S, Hutton S, Smith K. Indoor air pollution. In: Jamison DT, Breman GJ, Measham AR (eds). Disease control priorities in developing countries. 2nd ed. Washington, DC: The World Bank and Oxford University Press; 2006. pp. 793-815.         

10. Smith KR, Mehta S, Maeusezahl-Fuez M. Indoor air pollution from household use of solid fuels. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL, eds. Comparative quantification of health risks: global and regional burden of disease attributable to selected major risk factors. Geneva: World Health Organization; 2004. pp. 1436-93.         

11. Mehta S, Shahpar C. The health benefits of interventions to reduce indoor air pollution from solid fuel use: a cost-effectiveness analysis. Energy Sustain Develop 2004;8:353-9.         

12. Bailis R, Ezzati M, Kammen DM. Mortality and greenhouse gas impacts of biomass and petroleum energy futures in Africa. Science 2005;308:98-103. doi:10.1126/science.1106881 PMID:15802601        

13. Sazawal S, Black RE. Pneumonia Case Management Trials Group. Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials. Lancet Infect Dis 2003;3:547-56. doi:10.1016/S1473-3099(03)00737-0 PMID:12954560        

14. Simoes EAF, Cherian T, Chow J, Shahid–Salles SA, Laxminarayan R, Jacob John T. Acute respiratory infections in children. In: Jamison DT, Breman GJ, Measham AR (eds). Disease control priorities in developing countries. 2nd ed. Washington, DC: The World Bank; 2006.         

15. Graham SM, English M, Hazir T, Enarson P, Duke T. Challenges to improving case management of childhood pneumonia at health facilities in resource-limited settings. Bull World Health Organ 2008;86:349-55. doi:10.2471/BLT.07.048512 PMID:18545737        

16. Marsh DR, Gilroy KE, Weerdt van de R, Wansi E, Qazi S. Community-based treatment of pneumonia – at a tipping point? Bull World Health Organ 2008;86:381-9. doi:10.2471/BLT.07.048462 PMID:18545741        

17. Mulholland K. Childhood pneumonia mortality – a permanent global emergency. Lancet 2007;370:285-9. doi:10.1016/S0140-6736(07)61130-1 PMID:17658399        

18. Adam T, Lim SS, Mehta S, Bhutta ZA, Fogstad H, Mathai M, et al. Cost effectiveness analysis of strategies for maternal and neonatal health in developing countries. BMJ 2005;331:1107. doi:10.1136/bmj.331.7525.1107 PMID:16282407        

19. Bryce J, Victora CG, Habicht JP, Black RE, Scherpbier RW. Programmatic pathways to child survival: results of a multi-country evaluation of Integrated Management of Childhood Illness. Health Policy Plan 2005;20:15-17. doi:10.1093/heapol/czi055        

20. Bryce J, Black RE, Walker N, Bhutta ZA, Lawn JE, Steketee RW. Can the world afford to save the lives of 6 million children each year? Lancet 2005;365:2193-200. doi:10.1016/S0140-6736(05)66777-3 PMID:15978927        

21. Johns B, Sigurbjörnsdóttir K, Fogstad H, Zupan J, Mathai M, Tan-Torres Edejer T. Estimated global resources needed to attain universal coverage of maternal and newborn health services. Bull World Health Organ 2007;85:256-63. doi:10.2471/BLT.06.032037 PMID:17546306        

22. Akumu AO, English M, Scott JA, Griffiths UK. Economic evaluation of delivering Haemophilus influenzae type b vaccine in routine immunization services in Kenya. Bull World Health Organ 2007;85:511-8. doi:10.2471/BLT.06.034686 PMID:17768499        

23. Hutton G, Rehfuess E, Tediosi F, Weiss S. Evaluation of the costs and benefits of household energy and health interventions. Geneva: World Health Organization; 2006.         

24. Sinha A, Levine O, Knoll MD, Muhib F, Lieu TA. Cost-effectiveness of pneumococcal conjugate vaccination in the prevention of child mortality: an international economic analysis. Lancet 2007;369:389-96. doi:10.1016/S0140-6736(07)60195-0 PMID:17276779        

25. Weinstein MC, Stason WB. Foundations of cost-effectiveness analysis for health and medical practices. N Engl J Med 1977;296:716-21. PMID:402576        

26. Niessen LW. Roads to health – multi-state modelling of population health and resource use. Amsterdam: Dutch University Press and Barnes and Noble; 2002.         

27. Baltussen R, Brouwer W, Niessen L. Cost-effectiveness analysis for priority setting in health: penny-wise but pound-foolish. Int J Technol Assess Health Care 2005;21:532-4. doi:10.1017/S0266462305050750 PMID:16262980        

28. Dherani M, Pope D, Mascarenhas M, Smith KR, Weber M, Bruce N. Indoor air pollution from unprocessed solid fuel use and pneumonia risk in children aged under five years: a systematic review and meta-analysis. Bull World Health Organ 2008;86:390-8. doi:10.2471/BLT.07.044529 PMID:18545742        

29. Murray CJL, Lopez AD. The global burden of disease. Cambridge, MA: Harvard University Press; 1996 (Global Burden of Disease and Injury Series).         

30. Ustün TB, Rehm J, Chatterji S, Saxena S, Trotter R, Room R, et al. WHO/NIH Joint Project CAR Study Group. Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. Lancet 1999;354:111-5. doi:10.1016/S0140-6736(98)07507-2 PMID:10408486        

31. Lehmann U, Sanders D. The state of the evidence on programmes, activities, costs and impact on health outcomes of using community health workers. Geneva: World Health Organization; 2007.         

32. Qazi SA, Rehman GN, Khan MA. Standard management of acute respiratory infections in a children's hospital in Pakistan: impact on antibiotic use and case fatality. Bull World Health Organ 1996;74:501-7. PMID:9002330        

33. Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, et al., Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008;371:243-60. doi:10.1016/S0140-6736(07)61690-0 PMID:18207566        

34. Stenberg K, Johns B, Scherpbier RW, Edejer TT. A financial road map to scaling up essential child health interventions in 75 countries. Bull World Health Organ 2007;85:305-14. doi:10.2471/BLT.06.032052 PMID:17546312        

35. Laterveer L, Niessen LW, Yadcek A. Progress in poverty reduction strategies. Health Policy Plan 2003;18:138-45. doi:10.1093/heapol/czg018 PMID:12740318        

36. Baltussen R, ten Asbroek AH, Koolman X, Shrestha N, Bhattarai P, Niessen LW. Priority setting using multiple criteria: should a lung health programme be implemented in Nepal? Health Policy Plan 2007;22:178-85. doi:10.1093/heapol/czm010 PMID:17412742        

37. Niessen LW, Grijseels EWM, Rutten FFH. The evidence-based approach in health policy and health care delivery. Soc Sci Med 2000;51:859-69. doi:10.1016/S0277-9536(00)00066-6 PMID:10972430        

(Submitted: 24 January 2008 – Revised version received: 1 October 2008 – Accepted: 2 October 2008 – Published online: 16 April 2009)

* Correspondence to LW Niessen (e-mail: lniessen@jhsph.edu).