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- - - INTERVENTIONS TO ADDRESS DEATHS FROM CHILDHOOD PNEUMONIA AND DIARRHOEA EQUITABLY: WHAT WORKS AND AT WHAT COST?

Saturday, 13th of April 2013

• INTERVENTIONS TO ADDRESS DEATHS FROM CHILDHOOD PNEUMONIA AND DIARRHOEA EQUITABLY: WHAT WORKS AND AT WHAT COST?

 

The Lancet Early Online Publication, 12 April 2013

 

Original Text

Prof Zulfiqar A Bhutta PhD a b , Jai K Das MBA a, Neff Walker MPH b, Arjumand Rizvi MSc a, Prof Harry Campbell MD c, Prof Igor Rudan PhD c, Prof Robert E Black MD b, for The Lancet Diarrhoea and Pneumonia Interventions Study Group†

Global mortality in children younger than 5 years has fallen substantially in the past two decades from more than 12 million in 1990, to 6·9 million in 2011, but progress is inconsistent between countries. Pneumonia and diarrhoea are the two leading causes of death in this age group and have overlapping risk factors. Several interventions can effectively address these problems, but are not available to those in need. We systematically reviewed evidence showing the effectiveness of various potential preventive and therapeutic interventions against childhood diarrhoea and pneumonia, and relevant delivery strategies. We used the Lives Saved Tool model to assess the effect on mortality when these interventions are applied. We estimate that if implemented at present annual rates of increase in each of the 75 Countdown countries, these interventions and packages of care could save 54% of diarrhoea and 51% of pneumonia deaths by 2025 at a cost of US$3·8 billion. However, if coverage of these key evidence-based interventions were scaled up to at least 80%, and that for immunisations to at least 90%, 95% of diarrhoea and 67% of pneumonia deaths in children younger than 5 years could be eliminated by 2025 at a cost of $6·715 billion. New delivery platforms could promote equitable access and community platforms are important catalysts in this respect. Furthermore, several of these interventions could reduce morbidity and overall burden of disease, with possible benefits for developmental outcomes.

This is the second in a Series of four papers about childhood pneumonia and diarrhoea

Although global mortality in children younger than 5 years has substantially reduced in the past two decades from more than 12 million deaths in 1990, to 6·9 million in 2011,1 improvements have been inconsistent worldwide. Whereas some countries and regions have reduced child mortality by more than half,2 progress in others has been much slower. Half of all deaths worldwide in children younger than 5 years are concentrated in only five countries: India, Nigeria, the Democratic Republic of the Congo, Pakistan, and China.1 In the past decade, the number of child deaths decreased by 2 million worldwide, with reductions in deaths due to pneumonia and diarrhoea contributing to 40% of the overall reduction.3 Notwithstanding this success, pneumonia diseases still account for 1·3 million deaths and diarrhoeal diseases for 0·7 million deaths, and both are major causes of post-neonatal child deaths.2, 3 Pneumonia is the largest cause of child deaths worldwide. Corresponding reductions in burden of disease and morbidity have been much slower than those for global child mortality. Incidence of diarrhoea has fallen from 3·4 episodes to 2·9 episodes per child-year, and that of pneumonia from 0·29 episodes to 0·23 episodes per child-year between 1990 and 2010.4 Despite such decreases, these disorders are two of the most common reasons for health service attendance and hospital admission, with an estimated 1731 (uncertainty range 1376—2033) million episodes of childhood diarrhoea (uncertainty range 26·6—42·4 million severe episodes) and 120 (60·83—277·03) million episodes of pneumonia (10·03—40·04 million severe episodes) in 2011.5, 6

Pneumonia and diarrhoea deaths are closely associated, with overlapping risk factors such as those related to poverty, undernutrition, poor hygiene, and deprived home environments making children more likely to develop these diseases. Improvements in socioeconomic development with corresponding increases in maternal education, falling fertility rates, and improved living conditions (with reduced crowding) are important contributors to reductions in child mortality.7 However, to reduce childhood pneumonia and diarrhoea, interventions are needed that directly lower disease transmission and severity, and promote access to life-saving treatment once a child becomes sick. Previous reviews8—11 have shown that increases in coverage with present evidence-based interventions could greatly reduce child mortality and deaths from diarrhoea and pneumonia. However, little consensus exists about approaches to scale up coverage and about delivery strategies to reduce disparities and provide equitable access to marginalised populations.12

Key messages

• Worldwide, pneumonia and diarrhoeal diseases are the two major killers of children younger than 5 years
• Each year, 1·3 million children die from pneumonia and 700 000 from diarrhoea
• Preventive and therapeutic interventions exist that could have a role in reducing the morbidity and mortality burden due to diarrhoea and pneumonia, especially in children younger than 5 years
• Few interventions with wide range of outcomes have been assessed at a sufficient scale
• Interventions with maximum effect include breastfeeding, oral rehydration solution, and community case management
• Despite persistent burden, childhood diarrhoea and pneumonia deaths are avoidable and 15 interventions delivered at scale can prevent most of these avoidable deaths
• Estimates modelled with the Lives Saved Tool show that if the interventions are scaled up by 80% in the 75 Countdown countries, they could save 95% of diarrhoeal and 67% of pneumonia deaths in children younger than 5 years by 2025
• Scaling up of diarrhoea and pneumonia interventions would cost US$6·715 billion, only $2·9 billion more than present levels of spending; costs needed for lives saved calculated on the basis of estimates of projected spending based on historic trend
• Scaling up of these interventions could also ensure equitable delivery of care
• The cost-effectiveness of these interventions in national health systems needs urgent assessment
• With an increasing number of countries deploying community health-worker programmes to reach unreached populations, real opportunities exist to scale-up community advocacy and education programmes and early case detection and management strategies

In this Series paper, we systematically review evidence for the effectiveness of various potential health interventions on morbidity and mortality due to diarrhoea and pneumonia in line with guidelines from the Child Health Epidemiology Reference Group.13 We used a standardised method with criteria from the Child Health and Nutrition Research Initiative (CHNRI) to identify priority areas for research and future interventions. We modelled the potential effect of delivery of these interventions to the 75 high-burden countries that are part of the Countdown to 2015 initiative and assessed the result of scaling-up of interventions on diarrhoea and pneumonia mortality across poverty quintiles in three countries (Bangladesh, Pakistan, and Ethiopia).

We used a conceptual framework to assess preventive and case management interventions for diarrhoea and pneumonia, including preventive and therapeutic interventions common to both disorders (figure 1). We selected these interventions from several previous reports that identified their benefits and effects.9,14—26 We specifically reviewed the interventions to identify data for their effectiveness on diarrhoea or pneumonia, or both; incidence; and morbidity or mortality. Systematic reviews of potential interventions were undertaken by teams of researchers in Karachi, Pakistan; Baltimore, USA; and Toronto, Canada, and were done with standard methodologies. Reviews were done in line with Lives Saved Tool (LiST) methods,13 employing Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria (appendix). Researchers did 26 reviews for various interventions, consisting of 15 new reviews done to generate estimates of effect, and assessment of 11 existing reviews for possible updates.

 

Figure 1 Full-size image (72K) Download to PowerPoint

Conceptual framework of the effect of interventions for diarrhoea and pneumonia

WASH=water, sanitation, and hygiene. IMCI=Integrated Management of Childhood Illness. *Interventions common to both diarrhoea and pneumonia.

Strategies to promote breastfeeding

Table 1 summarises the available evidence and effect estimates for interventions to prevent and manage diarrhoea and pneumonia. Breast milk provides various immunological, psychological, social, economic, and environmental benefits, and is therefore recommended as the best feeding option for newborn babies and young infants in developing countries, even in HIV-infected populations.31 Lamberti and colleagues27 reviewed 18 studies from developing countries reporting the effect of breastfeeding on diarrhoea morbidity and mortality. The investigators estimated that not breastfeeding was associated with a 165% increase in diarrhoea incidence in 0—5-month-olds and a 32% increase in 6—11-month-olds. Not breastfeeding was also associated with a 47% increase in diarrhoea-related mortality in 6—11-month-olds and a 157% increase in 12—23-month-olds. Overall, not breast feeding was associated with a 566% increase in all-cause mortality in children aged 6—11 months, and a 223% increase in mortality in those aged 12—23 months.

Table 1Table image 

Interventions common to both childhood diarrhoea and pneumonia

We assessed the effect of various educational and promotional strategies on rates of exclusive, predominant, partial, and no breastfeeding.28 Rates of exclusive breastfeeding increased significantly because of breastfeeding promotional interventions; rates of not breastfeeding reduced significantly. The effects reported for rates of predominant and partial breastfeeding were not significant. After 6 months, educational interventions had no significant effect, but did increase rates of partial breastfeeding by 19%. Subgroup analyses suggested that combined individual and group counselling was more effective than either technique alone. Overall, in developing countries, facility and combined facility-based and community-based interventions led to greater improvements in breastfeeding rates, with greater effects of breastfeeding promotion and support interventions, than routine care.

Strategies for improved water provision, use, sanitation, and hygiene promotion

Consensus exists about the importance of improved water supply and excreta disposal for prevention of diseases, especially diarrhoeal diseases. Waddington and colleagues32 assessed the effectiveness of these interventions and concluded that those for water quality (protection or treatment of water at source or point of use) were more effective than those to improve water supply (improved source of water or improved distribution, or both). Interventions for water quality were associated with a 42% relative reduction in diarrhoea morbidity in children, whereas those for water supply had no significant effects. Overall, sanitation interventions led to an estimated 37% reduction in childhood diarrhoea morbidity and hygiene interventions to a 31% reduction. Subgroup analysis suggests that provision of soap was more effective than education only. Cairncross and colleagues29 estimated the effect of water, sanitation, and hygiene strategies and estimated risk reductions for diarrhoea of 48% for hand washing with soap, 17% with improved water quality, and 36% with excreta disposal. Although the investigators regarded much of the evidence to be of poor quality, the findings were consistent enough to support the provision of water supply, sanitation, and hygiene for all.

Preventive zinc supplementation

About 17·3% of the world's population is zinc deficient and this deficiency is most prevalent in children younger than 5 years in developing countries.33 Yakoob and colleagues30 assessed 18 studies from developing countries and showed that preventive zinc supplementation was associated with a non-significant reduction of 9% in all-cause mortality (table 1). Zinc alone resulted in a non-significant reduction of 18% in diarrheoa mortality and of 15% in pneumonia mortality. Preventive zinc supplementation was associated with a 13% reduction in the incidence of diarrhoea (relative risk [RR] 0·87, 95% CI 0·81—0·94) and a 19% reduction in pneumonia morbidity (0·81, 0·73—0·90).

Preventive interventions

Table 2 summarises the evidence and effect estimates for interventions to prevent and manage diarrhoea. Rotavirus is the most common cause of severe dehydrating diarrhoea in infants worldwide.5 In their review of six studies assessing the effectiveness of new rotavirus vaccines, Munos and colleagues34 estimated that use of these vaccines was associated with a 74% reduction in very severe rotavirus infections, a 61% reduction in severe infections, and reduced rotavirus-related hospital admission in young children by 47%. These summary effects do not show the reduced effectiveness of the vaccine in different geographic settings, with studies reporting 54% effectiveness in Malawi,40 and even lower efficacy (43%) in Mali.41

Table 2Table image 

Interventions for the prevention and management of diarrhoea

Although case management with oral rehydration therapy has substantially improved case-fatality rates for cholera, the infection can still kill rapidly, especially in outbreak settings.42 Old-generation injectable cholera vaccines have been abandoned since the 1970s because of their restricted effectiveness and local side-effects. We identified 12 studies, all from developing countries, which assessed the efficacy and effectiveness of oral cholera vaccine.35 We estimated that this vaccine reduced risk of cholera infection in children younger than 5 years by 52%. Such evidence for the effectiveness of oral cholera vaccines makes them good candidates for cholera control in endemic areas. Research shows that because of herd protection, even moderate coverage levels of targeted populations with killed oral cholera vaccine could lead to almost complete control of cholera;43, 44 however, this control would not prevent outbreaks in other populations.

Therapeutic interventions

Because the immediate cause of death in most cases of diarrhoea is dehydration, deaths are almost entirely preventable if dehydration is prevented or treated. In a review of the efficacy and effectiveness of oral rehydration solution and recommended home fluids, Munos and colleagues36 assessed 205 studies, mostly from developing countries. Use of oral rehydration solution reduced diarrhoea specific mortality by 69% and rates of treatment failure by 0·2% (table 2). Since 2004, WHO and UNICEF have recommended zinc for the treatment of diarrhoea. Walker and colleagues37 reviewed 13 studies from developing countries of zinc supplementation for diarrhoea and concluded that zinc administration was associated with a significant reduction of 46% in all-cause mortality and of 23% in diarrhoea-related hospital admissions. The effects on prevalence of diarrhoea and mortality were not significant. Several of the large studies of zinc treatment for diarrhoea were also associated with reported benefits for pneumonia mortality, hospital admission, and prevalence, albeit not significantly.

Current WHO guidelines for the management and treatment of diarrhoea in children strongly recommend continued feeding alongside administration of oral rehydration solution and zinc therapy. However, some debate surrounds what the optimum diet or dietary ingredients are to hasten recovery and maintain nutritional status in children with diarrhoea. We did an extensive review38 of all studies of feeding strategies and food-based interventions in children younger than 5 years with diarrhoea in low-income and middle-income countries. Although illness duration was shorter and risk of treatment failure 47% lower in children with acute diarrhoea who consumed lactose-free rather than lactose-containing liquid feeds, we noted no effect of lactose avoidance on stool output or weight gain. Pooled analyses of trials comparing commercial preparations or specialised ingredients to foods available in the home showed no beneficial effects in either acute or persistent diarrhoea, suggesting that locally available ingredients can be used to manage childhood diarrhoea at least as effectively as can commercial preparations or specialised ingredients. Moreover, when we restricted this analysis to lactose-free diets only, weight gain in acute diarrhoea was higher in children who consumed foods available in the home.

Antibiotics are used to treat some forms of bacterial diarrhoea, especially dysentery. A review by Traa and colleagues45 assessed the effectiveness of WHO-recommended antibiotics—ciprofloxacin, ceftriaxone, and pivmecillinam—for the treatment of dysentery, and concluded that antibiotics are effective in reducing the clinical and bacteriological signs and symptoms of this disorder and can thus be expected to decrease diarrhoea mortality attributable to dysentery by more than 99%. We assessed the effectiveness of WHO-recommended antibiotics in diarrhoea in relation to cholera, shigella, and cryptosporidium infections.39 The mainstay of treatment in cholera is rehydration; WHO recommends antibiotics for severe cases. We identified two46, 47 randomised trials from developing countries and showed that antibiotic management of cholera resulted in a 63% reduction in rates of clinical failure and a 75% reduction in rates of bacteriological failure.39

A range of antibiotics are used to treat shigella dysentery, dependent on variations in resistance patterns by region. We analysed four studies48—51 from developing countries, which showed that antibiotic management of shigella resulted in an 82% reduction in rates of clinical failure and a 96% reduction in rates of bacteriological failure.39 Cryptosporidium can cause life-threatening disease in people with AIDS and contributes greatly to morbidity in children in developing countries. We systematically analysed three studies52—54 from developing countries. Antibiotics for treatment of cryptosporidiosis reduced mortality by 76%, rates of clinical failure by 52%, and rates of parasitological failure by 38%.39 None of these studies assessed the effect of a given treatment regimen on emergence of antibiotic resistance over time; however, the investigators noted that use of nalidixic acid for treatment of shigellosis could be associated with rapid emergence of quinolone resistance.55

Preventive interventions

Table 3 summarises the evidence and effect estimates for interventions to prevent and manage pneumonia. Several effective vaccines are available for prevention of various causes of pneumonia. In regions where measles is a substantial cause of childhood morbidity and mortality, measles vaccination is an important intervention that can also affect risk of subsequent complications, including secondary bacterial infections and diarrhoea. Sudfeld and colleagues56 proposed that measles vaccination was 85% effective for prevention of measles in children younger than 1 year.

Table 3Table image 

Interventions for the prevention and management of pneumonia

We assessed the effectiveness of Haemophilus influenzae type b and pneumococcal conjugate vaccines.57 For prevention of invasive H influenzae type b and pneumonia, we identified six studies from developing countries yielding estimates of an 18% non-significant reduction in radiologically confirmed pneumonia, a 6% reduction in severe pneumonia, and a 7% non-significant reduction in pneumonia-specific mortality. We reviewed six studies from developing countries for the prevention of invasive pneumococcal disease and pneumonia with pneumococcal conjugate vaccines, which were associated overall with a 29% significant reduction in radiologically confirmed pneumonia, an 11% reduction in severe pneumonia, and an 18% non-significant reduction in pneumonia-specific mortality.57 Large-scale use of these vaccines is associated with important positive effects related to herd immunity and population benefits, and negative indirect effects related to serotype replacement and emergence of resistant strains. The magnitude and importance of these indirect effects is likely to vary by setting.

Therapeutic interventions

Treatment with appropriate antibiotics and supportive management in neonatal nurseries is the cornerstone of management of neonatal sepsis and pneumonia, with strong biological plausibility that such treatment saves lives. A review60 of community-based management of neonatal pneumonia showed a 27% reduction in all-cause neonatal mortality and a 42% reduction in pneumonia-specific mortality. Zaidi and colleagues57 estimated the effect of provision of oral or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis. Results suggested a 25% reduction in all-cause neonatal mortality and a 42% reduction in neonatal pneumonia mortality. Similar studies in older infants and children younger than 5 years have focused on choice and duration of antibiotic treatment for pneumonia in various settings.61—63

Information is scarce about the effect of low-cost pulse oximetry and oxygenation systems. A large multihospital quasi-experimental study59 in Papua New Guinea with an intervention of hypoxaemia detection by pulse oximetry, together with oxygen therapy with an assured oxygen supply from oxygen concentrators, resulted in a 35% significant reduction in mortality from severe pneumonia in patients admitted to hospital.

Community-based promotion and case management

Although evidence shows the efficacy and effectiveness of many interventions, these interventions are not accessible to people in need; hence, focus on delivery strategies has increased. One of the main contributors to the delay in meeting the targets of Millennium Development Goal 4 is the paucity of trained human resource professionals in first-level health services, and the reduced awareness of and accessibility to services for those living in large socioeconomically, geographically deprived, ethnically marginalised populations. One method of community-based case management is to provide these amenities through community health workers with home visitation and community-based sessions for education and promotion of care seeking. These approaches have been assessed for both newborn babies and children aged 1—59 months.

Lassi and colleagues64, 65 estimated that community-based packaged interventions delivered by community health workers significantly increase levels of care-seeking behaviour for neonatal morbidy by 52%. The role of these health workers has also been assessed in various settings in large-scale programmes in which their presence improved immunisation uptake and care seeking for childhood illnesses.66 We estimated the effect of community-based delivery strategies with community health workers on the coverage and uptake of essential commodities for diarrhoea and pneumonia: oral rehydration solution, zinc therapy for diarrhoea, and antibiotics for pneumonia.67 We also assessed the effect of these interventions on care-seeking behaviour and on potentially harmful practices, such as prescription of unnecessary antibiotics for diarrhoea. Theodoratou and colleagues68 estimated that community case management of pneumonia could result in a 70% reduction in pneumonia mortality in children younger than 5 years. We updated the previous estimate and also estimated the effect of case management on diarrhoea mortality. We included 26 studies and estimated that community-based interventions are associated with a 160% significant increase in use of oral rehydration solution (RR 2·60, 95% CI 1·59—4·27) and an 80% increase in use of zinc in diarrhoea.67 Furthermore, findings showed a 13% (1·13, 1·08—1·18) increase in care-seeking for pneumonia, and a 9% (1·09, 1·06—1·11) increase in that for diarrhoea. We noted a 75% significant decline (0·25, 0·12—0·51) in inappropriate use of antibiotics for diarrhoea, and a 40% (0·60, 0·51—0·70) reduction in rates of treatment failure for pneumonia. Community case management for pneumonia by community health workers was associated with a 32% (0·68, 0·53—0·88) reduction in pneumonia-specific mortality, whereas evidence for diarrhoea-related mortality was weak.67

Reduction of financial barriers

Financial incentives are becoming widely used as policy strategies to alleviate poverty, to promote care seeking, and to improve the health of populations. Additionally, such incentives have been recommended as an important strategy to reduce barriers to access to health care.69 An extensive review was undertaken to identify relevant studies reporting the effect of financial incentives on coverage of health interventions and behaviours targeting children younger than 5 years.12 Investigators assessed the effect of financial incentive programmes on five categories of intervention: breastfeeding practices, immunisation coverage, diarrhoea management, health-care use, and other preventive strategies. Findings showed that financial incentives could promote increased coverage of several important child health interventions, but the quality of available evidence was low. Of all financial incentive programmes, more pronounced effects seem to be achieved by those that directly removed user fees for access to health services. Some indication of effect was also reported for programmes that conditioned financial incentives on the basis of participation in health education and attendance to health-care visits.

Research priorities to develop and deliver interventions

We undertook a systematic analysis of various emerging interventions for diarrhoea and pneumonia on the basis of priorities emerging from the global research priority review process.70, 71 Preventive interventions assessed were reductions in levels of household air pollution,72, 73 and vaccines for Shigella43,74—77 and enterotoxigenic Escherichia coli.43 Therapeutic interventions were probiotics for diarrhoea78 and antiemetics for gastroenteritis.79 The appendix summarises the evidence for some of these interventions, which are promising, but not yet recommended for inclusion in programmes.

We undertook two expert panel methods to assess the feasibility and effectiveness of ten emerging health interventions for childhood diarrhoea and 23 for pneumonia (appendix). We undertook a method to develop research priorities in line with the CHNRI80—82 with various experts worldwide.83 For diarrhoea, we expanded on previous methods84, 85 by identifying priorities to reduce morbidity and mortality caused by childhood diarrhoea in the next 15—20 years.83 For pneumonia, we used a research method to define priorities to reduce mortality caused by childhood pneumonia by 2015,86 including health policy and systems research. The panel shows the highest ranked research questions in these two areas. In these areas, research priorities including identification of barriers to health-care access—eg, implementation barriers to increase coverage of existing, effective interventions—and identification of drivers of care-seeking behaviour, ranked highly. Respondents prioritised assessment of the effect of Integrated Community Case Management and Integrated Management of Childhood Illness (IMCI) on early and equitable administration of appropriate treatment. Furthermore, prioritisation process for pneumonia identified the need to establish whether community health workers or community volunteers could be trained to adequately assess, recognise danger signs of, refer, or treat acute respiratory infections effectively.

Panel

Research priorities to prevent childhood diarrhoea and pneumonia mortality

We undertook two expert panel methods to assess feasibility and potential effectiveness of ten emerging health interventions against childhood diarrhoea and 23 against pneumonia (see appendix for the list of interventions for both illnesses). For each method we assembled a group of 20 leading international experts from international agencies, industry, basic science, and public health research, who took part in a Child Health and Nutrition Research Initiative (CHNRI) priority setting process. The experts used nine different criteria relevant to successful development and implementation of emerging interventions. They assessed the likelihood of answerability (in an ethical way), affordable cost of development and implementation of the intervention, efficacy and effectiveness against the disease, deliverability, sustainability, maximum effect on mortality reduction, acceptability to health workers, acceptability to end users, and positive effect on equity. Further details about the modified CHNRI framework, the criteria used, and the process of the expert opinion exercise have been published elsewhere.82

For pneumonia interventions, when the scores against all nine criteria were analysed, the experts showed mostly collective optimism towards improvement of low-cost pneumococcal conjugate vaccines, development of non-liquid and mucosal antibiotic paediatric formulations, and development of common-protein pneumococcal vaccines. The second level of priority was assigned to improvements in existing vaccines (eg, measles or Haemophilius influenzae type b) to enable needle-free delivery and heat stability. This assignment was followed by assessments of maternal immunisation, improved use of oxygen systems, and the development of combination vaccines and vaccines against major viral pathogens. The fourth level of priority was assigned to improved point-of-care diagnostic techniques. The lowest scores were assigned to passive immunisation, action on risk factors such as indoor air pollution or poor sanitation, or development of vaccines against neonatal bacterial pathogens that cause sepsis. The method suggested that most of the emerging interventions are still not feasible.

Pneumococcal conjugate vaccines, which were still regarded as an emerging intervention because of low uptake in low-income and middle-income countries at the time, achieved scores of more than 80% for all criteria apart from low product cost, which became the main point of discussion once they were introduced. By comparison, common protein pneumococcal vaccines are still hindered by concerns about answerability (although answerability is getting closer to 80%), and about all criteria related to their future cost. Other interventions have quite different score profiles. For example, antirespiratory syncytial virus vaccine for use in infants showed no feasibility for all criteria apart from acceptance for health workers, whereas monoclonal antibodies for passive immunisation against respiratory syncytial virus was completely unfeasible for product cost, affordability, and sustainability concerns; however, product development cost was considered to be feasible. Introduction of oxygen systems was considered answerable and there were no major cost concerns, but these systems were not deemed sustainable, sufficiently acceptable, or equitable. By comparison, common protein vaccines for influenza were considered sustainable, acceptable, and equitable, but concerns remained about answerability and costs of development. Emerging point-of-care diagnostic techniques were restricted with suboptimum levels of access to care, care-seeking behaviour, and the availability of first-line and second-line antibiotics.

The top ten research areas in the delivery categories for both the diarrhea and pneumonia process are:

• Identify the barriers to increases in coverage and ensure that hard to reach populations have access to effective interventions—ie, oral rehydration solution, zinc, Haemophilius influenza type b and pneumococcal vaccines, WHO's seven-point plan, and WHO's strategy for acute respiratory infection
• Identify contextual or cultural factors that positively or negatively affect care-seeking behaviour and which factors most effectively drive care-seeking behaviour
• Investigate the effectiveness of culture-appropriate health education and public health messages on changes in health-seeking behaviour, hospital admission, and mortality, and which communication strategies are best to spread knowledge and generate care-seeking behaviour
• Identify the main barriers to increase demand for and compliance with vaccination schedules for available vaccines in different contexts and settings
• Identify the added effect of integrated Community Case Management or Integrated Management of Childhood Illness on early and equitable administration of appropriate treatment for acute diarrhoea and for pneumonia
• Identify the best indicators for measurement of uptake of interventions and effectiveness of communication strategies
• Identify the effect on child health outcomes of interventions to support mothers, for example to reduce maternal depression, strengthen maternal coping, and develop problem-solving skills for child health
• Identify the capacity of health systems worldwide to correctly diagnose and manage childhood pneumonia, and the obstacles to correct diagnosis and case management in developing countries
• Identify how trained health workers can be effectively trained and sustained and whether they can be trained to adequately assess, recognise danger signs, refer, and treat acute respiratory infections, including safe and effective administration of antibiotics
• Identify the effectiveness of a community-led approach to total sanitation

We selected a set of interventions from those reviewed for modelling on the basis of their proven benefits and availability in public-health programmes. We used LiST to model the potential effect of introduction of these interventions with a standard sequential introduction in health systems of the 75 high-burden Countdown countries. LiST estimates the effect of increases in intervention coverage on deaths from one or more causes, or in reduction of the prevalence of a risk factor (appendix). We modelled the effect of increased coverage of individual interventions from present levels for each country (figure 2) on child mortality. We used two approaches—historical trends and ambitious scale-up—to project coverage trends and scaling up of various interventions identified to 2025.

 

Figure 2 Full-size image (36K) Download to PowerPoint

Coverage of interventions in 75 Countdown countries by quartiles

Figure shows medians and IQRs. Hib=Haemophilus influenzae type b.

With the first approach (historic trends), we assessed the pragmatic trends of increased coverage on the basis of historical rates of change for the individual interventions in each country to predict the coverage of specific interventions to 2025 if trends continued unchanged. In the second approach (ambitious scale-up) we used a predefined target coverage level of 80% for all interventions except vitamin A supplementation and vaccines, for which we used a 90% target coverage. Table 4 shows the effect of these two approaches on diarrhoea and pneumonia deaths by 2025. The data show that based on country-specific historic trends 54% of diarrhoea and 51% of pneumonia deaths in children younger than 5 years can be averted by implementation of these interventions by 2025. However, ambitious scaling up of interventions would eliminate almost all diarrhoea deaths, but only two-thirds of pneumonia deaths, which shows the continued need to develop and implement more effective interventions to prevent and treat pneumonia (figure 3).

Table 4Table image 

Diarrhoea and pneumonia deaths averted in the 75 high-burden Countdown countries between 2011 and 2025 with the historical trends and ambitious scale-up approaches

 

Figure 3 Full-size image (35K) Download to PowerPoint

Additional effect of the ambitious scale-up approach on diarrhoea and pneumonia deaths averted for the 75 Countdown countries up to 2025

We also assessed the potential effect of individual interventions on lives saved by scaling up interventions to reach 90% coverage for vaccines and vitamin A, and 80% coverage for all other interventions and projected lives saved due to diarrhoea and pneumonia up to 2025. The analysis showed that water, sanitation, and hygiene interventions could prevent almost 0·5 million child deaths due to diarrhoea and pneumonia by 2025; almost the same number as that shown for the projected effect of H influenzae type b, pneumococcal, and rotavirus vaccines. Similar effects are noted in scaling up of community case management in children younger than 5 years (figure 4, appendix). These findings have policy relevance and suggest that countries should consider a range of best buys to address childhood diarrhoea and pneumonia.

 

Figure 4 Full-size image (47K) Download to PowerPoint

Sequential effect of individual interventions on deaths due to diarrhoea and pneumonia

Haemophilus influenzae type b.

Table 5 shows results of our cost analysis with LiST of interventions and packages in 2025 for the 75 Countdown countries. The costs are based on four components: personnel and labour, drugs and supplies, other direct costs, and indirect costs. We obtained assumptions about time needed for an intervention and costs for drugs and supplies from the One Health Model87 developed by the UN. Costs shown for daily zinc supplementation are for 6—36 months. For breastfeeding, there was difficulty in translation of breastfeeding prevalence to breastfeeding promotion for our costing analysis; therefore, breastfeeding costs for the trend scenario were done by hand with country-specific unit costs, prevalence, and births. For scaling up of low-cost latrines, we estimated costs for all households, not just those with children younger than 5 years, and for H influenzae type b vaccine we used the present cost of pentavalent vaccine for our estimates (US$2·95 per dose; appendix).

Table 5Table image 

Estimated incremental costs (US$ million) by packages in 2025 for the 75 Countdown countries

On the basis of estimates of historic trend coverage, $3·8 billion dollars would be needed to avert 882 274 deaths due to diarrhoea and pneumonia, and for the ambitious scale-up plan, $6·715 billion dollars would be needed—an extra $2·914 billion to save an additional 557 163 lives. Drugs and supplies are the main cost items. The cost breakdown by intervention showed that for some interventions (oral rehydration solution and antibiotic treatment of dysentery), our analysis indicates cost savings because the number of diarrhoea cases has fallen substantially in most places, whereas for other interventions the costs increase because initial coverage levels are low and any increase in use results in a net increase in cost (appendix).

A major limitation in previous strategies used to establish outcomes has been relatively little emphasis on reducing of inequities and targeting. We assessed the effect of interventions across equity strata for three countries (Pakistan, Bangladesh, and Ethiopia). We estimated the potential effect and cost-effectiveness of targeting of the same set of interventions to address neonatal mortality and mortality in children younger than 5 years within wealth quintiles. We computed all inputs except cause of death for the two wealth quintiles by reanalysing the most recent Demographic and Health Survey for the country (appendix). We estimated the effect of interventions on lives saved for the two quintiles of socioeconomic status: poorest (Q1) and poorer (Q2). The effect of various evidence-based interventions is greatest in the poorest quintiles (figure 5, appendix). Scaling up of these interventions would not only reduce the overall burden of childhood mortality but would also greatly reduce the discrepancies in provision of health care across various strata of socioeconomic status. To assess the effect of reaching the poorest individuals through community-based platforms, we assessed the benefit of three strategies (breastfeeding promotion, scale up of interventions for zinc or oral rehydration solution, and case management of pneumonia) deploying community health workers in these strata. Our model showed that if 90% coverage were achieved for these three interventions, 64% of diarrhoea deaths and 74% of pneumonia deaths could be averted in the poorest quintiles in the three countries assessed. This finding shows that community-based platforms deploying community health workers could not only reduce overall burden, but also ensure equitable delivery of these interventions to those who need them most (appendix).

 

Figure 5 Full-size image (30K) Download to PowerPoint

Equity analysis for Bangladesh, Ethiopia, and Pakistan

Our findings are in line with those from previous reviews and studies, emphasising that effective interventions exist to address childhood diarrhoea and pneumonia, which are still major killers of children younger than 5 years worldwide. We refined and updated the evidence for a range of preventive, promotive, and therapeutic interventions, and by application of these estimates to the LiST model, reaffirmed that these interventions could potentially eliminate diarrhoea deaths and prevent almost two-thirds of childhood pneumonia deaths by 2025 if implemented at scale. Many of these interventions would clearly affect morbidity and other outcomes, although our present models do not allow for assessment of effect on disease incidence and adverse outcomes contributing to overall disability.

Most the interventions exist within present health systems, although their coverage and availability to poor and marginalised populations varies greatly. Strategies for scaling up and emerging evidence of delivery platforms for key interventions have received relatively little focus. In addition to structural changes needed to reduce environmental pollution and provide safe water and sanitation, many of the risks associated with development of diarrhoea and pneumonia also need behavioural change at the household level. Our analysis emphasised the importance of focus on delivery strategies that target the poor, and hence a balance of demand creation and service delivery is needed to address these issues.

Our data show that key nutrition interventions for prevention of childhood diarrhoea and pneumonia have received scant attention, which is shown by poor rates of exclusive breastfeeding worldwide, especially in low-income and middle-income countries. Several reasons exist for this finding, including low awareness of the benefits of exclusive breastfeeding. In many low-income and middle-income countries there is no enabling environment for exclusive breastfeeding. Few laws are in place to protect the employment and work conditions that allow mothers to practise exclusive breastfeeding for the first 6 months after childbirth and implementation of the International Code on Marketing of Breast Milk Substitutes is insufficient. The same situation applies for interventions to address intrauterine growth retardation, a recognised risk factor for neonatal mortality and childhood illnesses including diarrhoea and pneumonia. In view of the global burden of low birthweight, which encompasses both prematurity and intrauterine growth retardation, this problem is a crucial risk factor that must receive greater attention.

The remarkably low coverage of oral rehydration solution for diarrhoeal episodes, and the almost negligible use of zinc for the management of diarrhoea, emphasises the fundamental challenges faced in public health. About four decades after findings showed the effectiveness of oral rehydration solution in population settings,88 global coverage rates are negligible. Even a decade after WHO and UNICEF released recommendations for treatment of diarrhoea with improved oral rehydration solution and zinc, global uptake of zinc for the treatment of diarrhoea is abysmally low. Our findings show that several opportunities exist for scaling up the use of these interventions with community health-worker programmes, free distribution, social marketing, and co-packaging of zinc and oral rehydration solution, which can increase coverage by several times.89 Promising indications show that such scaling up is beginning to happen and is being recommended as a strategy to reduce inequities in child survival in high-burden countries.90

The forthcoming Decade of Vaccines initiative offers a unique possibility that reductions in diarrhoea and pneumonia burden can be achieved with some of the new effective vaccines for pneumonia and diarrhoea through global financing and country-support mechanisms.91 Our estimates show that 27% of childhood diarrhoea and pneumonia deaths can be averted by deployment of three key vaccines: H influenzae type b, pneumococcal conjugate, and rotavirus vaccines. A 90% improvement in coverage of a package of life-saving childhood vaccines in 72 countries eligible for support from the GAVI Alliance between 2011 and 2020 would prevent the deaths of roughly 6·4 million children younger than 5 years, corresponding to $231 billion (uncertainty range $116—$614 billion) in the value of statistical lives saved.91 The maximum benefits accrued from pneumococcal and H influenzae type b vaccines, contributing $105 billion ($52—$270 billion) from scale up of pneumonia and rotavirus vaccines contributed $54 billion ($27—$138 billion) to these estimates.91

Despite persistent burden, childhood deaths from diarrhoea and pneumonia are avoidable and 15 interventions delivered at scale can save most of these avoidable deaths. In some of the high-burden countries with existing inequities in intervention coverage and a high burden of mortality in poor populations, strategies exist that can reach these individuals and reduce the disproportionate burden of diarrhoea and pneumonia mortality therein. With an increasing number of countries deploying community health-worker programmes to reach the unreached, real opportunities exist to scale up community advocacy and education programmes and early case detection and management strategies. The new vaccines for H influenzae type b, pneumococcal pneumonia, and rotavirus diarrhoea could save at least 0·5 million lives in the next decade. Nevertheless, major gaps remain in implementation and strategies for scaling up. Operational research needs to be done urgently to establish the best strategies to improve community uptake of the best practices and encourage household-level behaviour change. Furthermore, the best delivery channels need to be identified to reach marginalised and disenfranchised populations, especially the urban poor. In view of the need to optimise treatment strategies and reduce inappropriate use of antibiotics, the balance of antibiotic access and excess92 must be defined and research to address the benefits and population-level safety of programmes for Integrated Community Case Management should be done. Major advances in improvement of practical aspects of point-of-use water purification, low-cost sanitary facilities, and improved housing and living conditions offer an opportunity to address some of the fundamental challenges in reducing diarrhoea and pneumonia burden, but these methods need cost-effectiveness analyses.

For the Child Health Epidemiology Reference Group see http://www.cherg.org

For more on Countdown to 2015 see http://www.countdown2015mnch.org/

Contributors

ZAB conceptualised the review of interventions and led the process, supported by JKD and REB. The following members contributed to specific reviews: LL to community case management, strategies for oral rehydration solution, and financial platforms; MG to feeding practices in diarrhoea and financial platforms; DB and KW to financial platforms; RAS to cholera vaccines, antiemetics, antibiotics for cholera and shigella, and community case management; and ZL to community case management. KW and AZ led the Child Health and Nutrition Research Initiative (CHNRI) method for setting of research priorities, overseen by ZAB. HC and IR contributed to the review of strategies to prevent and treat pneumonia. ZAB wrote the first draft of the review with substantial input from JKD. NW and AR contributed to the lives saved estimates in the Lives Saved Tool (LiST). IF and NW contributed estimates for costs with LiST.

The Lancet Diarrhoea and Pneumonia Interventions Study Group

Zulfiqar A Bhutta, Jai K Das, Rehana A Salam, Zohra Lassi (Aga Khan University, Pakistan); Robert E Black, Neff Walker, Ingrid Friberg (Johns Hopkins Bloomberg School of Public Health, USA); Harry Campbell, Igor Rudan (University of Edinburgh, UK); Lindsey Lenters, Diego Bassani, Kerri Wazny, Michelle Gaffey, Alvin Zipursky (Sick Kids, Toronto).

Conflicts of interest

We declare that we have no conflicts of interests.

Acknowledgments

Funding was provided by an unrestricted grant from the Bill & Melinda Gates Foundation to Aga Khan University and to collaborating universities and institutions (Bloomberg School of Public Health, Johns Hopkins University, Boston; University School of Public Health and Program for Global Pediatric Research, Hospital for Sick Children, Toronto). The funding source had no role or control over the content and process of development of these papers, or in drafting of the report. The views expressed in this report are solely those of the authors. We thank Yvonne Tam (Johns Hopkins University) for assisting with LiST modelling, Margaret Manley (Program for Global Pediatric Research, Toronto), and Asghar Ali (Aga Khan University, Karachi) for administrative support.

Supplementary appendix

PDF (228K)

1 UNICEF. Levels and trends in child mortality, estimates developed by the UN Inter-agency Group for Child Mortality Estimation. New York: UNICEF, 2012.

2 Countdown to 2015. Building a future for women and children: the 2012 report. http://www.countdown2015mnch.org/documents/2012Report/2012-Complete.pdf. (accessed March 18, 2013).

3 Liu L, Johnson HL, Cousens S, et al. Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2010; 379: 2151-2161. Summary | Full Text | PDF(721KB) | CrossRef | PubMed

4 Fischer Walker CL, Perin J, Aryee MJ, Boschi-Pinto C, Black RE. Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. BMC Public Health 2012; 12: 220. CrossRef | PubMed

5 Fischer Walker CL, Rudan I, Liu L, et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013. published online April 12. http://dx.doi.org/10.1016.S0140-6736(13)60222-6.

6 Nair H, Simões EAF, Rudan I, et alfor the Severe Acute Lower Respiratory Infections Working Group. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet 2013. published online Jan 29. http://dx.doi.org/10.1016/S0140-6736(12)61901-1.

7 Feng XL, Theodoratou E, Liu L, et al. Social, economic, political and health system and program determinants of child mortality reduction in China between 1990 and 2006: a systematic analysis. J Glob Health 2012; 2: 10405. PubMed

8 Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SSthe Bellagio Child Survival Study Group. How many child deaths can we prevent this year?. Lancet 2003; 362: 65-71. Summary | Full Text | PDF(105KB) | CrossRef | PubMed

9 Bhutta ZA, Ahmed T, Black RE, et althe Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417-440. Summary | Full Text | PDF(286KB) | CrossRef | PubMed

10 Fischer Walker CL, Friberg IK, Binkin N, et al. Scaling up diarrhea prevention and treatment interventions: a Lives Saved Tool analysis. PLoS Med 2011; 8: e1000428. CrossRef | PubMed

11 Ozawa S, Stack ML, Bishai DM, et al. During the ‘decade of vaccines,’ the lives of 6.4 million children valued at $231 billion could be saved. Health Aff (Millwood) 2011; 30: 1010-1020. CrossRef | PubMed

12 Chopra M, Sharkey A, Dalmiya N, Anthony D, Binkin Nthe UNICEF Equity in Child Survival, Health and Nutrition Analysis Team. Strategies to improve health coverage and narrow the equity gap in child survival, health, and nutrition. Lancet 2012; 380: 1331-1340. Summary | Full Text | PDF(104KB) | CrossRef | PubMed

13 Walker N, Fischer-Walker C, Bryce J, Bahl R, Cousens Sthe CHERG Review Groups on Intervention Effects. Standards for CHERG reviews of intervention effects on child survival. Int J Epidemiol 2010; 39 (suppl 1): i21-i31. PubMed

14 Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417-440. Summary | Full Text | PDF(286KB) | CrossRef | PubMed

15 Bhutta ZA, Shekar M, Ahmed T. Mainstreaming interventions in the health sector to address maternal and child undernutrition. Matern Child Nutr 2008; 4 (suppl 1): 1-4. CrossRef | PubMed

16 Bhutta ZA, Ali S, Cousens S, et al. Alma-Ata: Rebirth and Revision 6 Interventions to address maternal, newborn, and child survival: what difference can integrated primary health care strategies make?. Lancet 2008; 372: 972-989. Summary | Full Text | PDF(340KB) | CrossRef | PubMed

17 Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis Lfor the Lancet Neonatal Survival Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save?. Lancet 2005; 365: 977-988. Summary | Full Text | PDF(147KB) | CrossRef | PubMed

18 Kerber KJ, de Graft-Johnson JE, Bhutta ZA, Okong P, Starrs A, Lawn JE. Continuum of care for maternal, newborn, and child health: from slogan to service delivery. Lancet 2007; 370: 1358-1369. Summary | Full Text | PDF(209KB) | CrossRef | PubMed

19 Imdad A, Bhutta ZA. Nutritional management of the low birth weight/preterm infant in community settings: a perspective from the developing world. J Pediatr 2013; 162 (3 suppl): S107-S114. CrossRef | PubMed

20 Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SSBellagio Child Survival Study Group. How many child deaths can we prevent this year?. Lancet 2003; 362: 65-67. Summary | Full Text | PDF(105KB) | CrossRef | PubMed

21 Victora CG, Barros AJ, Axelson H, et al. How changes in coverage affect equity in maternal and child health interventions in 35 Countdown to 2015 countries: an analysis of national surveys. Lancet 2012; 380: 1149-1156. Summary | Full Text | PDF(408KB) | CrossRef | PubMed

22 Barros FC, Bhutta ZA, Batra M, Hansen TN, Victora CG, Rubens CE. Global report on preterm birth and stillbirth (3 of 7): evidence for effectiveness of interventions. BMC Pregnancy Childbirth 2010; 10 (suppl 1): S3. CrossRef | PubMed

23 UNICEF. Diarrhoea: why children are dying and what can be done. New York: UNICEF, 2009.

24 WHO. Global action plan for the prevention and control of pneumonia in children aged under 5 years. Wkly Epidemiol Rec 2009; 84: 451-452. PubMed

25 UNICEF. Pneumonia and diarrhoea: tackling the deadliest diseases for the world's poorest children. New York: UNICEF, 2012.

26 WHO. The optimal duration of exclusive breastfeeding: results of a WHO systematic review. Indian Pediatr 2001; 38: 565-567. PubMed

27 Lamberti L, Walker CF, Noiman A, Victora C, Black R. Breastfeeding and the risk for diarrhea morbidity and mortality. BMC Public Health 2011; 11 (suppl 3): S15. CrossRef | PubMed

28 Haroon S, Das JK, Salam RA, Imdad A, Bhutta ZA. Breastfeeding promotion interventions and breastfeeding practices: a systematic review. BMCPH (in press).

29 Cairncross S, Hunt C, Boisson S, et al. Water, sanitation and hygiene for the prevention of diarrhoea. Int J Epidemiol 2010; 39 (suppl 1): i193-i205. PubMed

30 Yakoob MY, Theodoratou E, Jabeen A, et al. Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health 2011; 11 (suppl 3): S23. CrossRef | PubMed

31 WHO. Guidelines on HIV and infant feeding 2010. Principles and recommendations for infant feeding in the context of HIV and a summary of evidence. http://whqlibdoc.who.int/publications/2010/9789241599535_eng.pdf. (accessed March 18, 2013).

32 Waddington H, Snilstveit B, White H, Fewtrell L. Water, sanitation and hygiene interventions to combat childhood diarrhoea in developing countries. New Delhi: International Initiative for Impact Evaluation, 2009.

33 Wessells KR, Brown KH. Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS One 2012; 7: e50568. CrossRef | PubMed

34 Munos MK, Walker CLF, Black RE. The effect of rotavirus vaccine on diarrhoea mortality. Int J Epidemiol 2010; 39 (suppl 1): i56-i62. PubMed

35 Das JK, Tripathy A, Hassan A, Ali A, Dojosoeandy C, Bhutta ZA. Vaccines for the prevention of diarrhea due to cholera, shigella, ETEC and rotavirus. BMCPH (in press).

36 Munos MK, Walker CL, Black RE. The effect of oral rehydration solution and recommended home fluids on diarrhoea mortality. Int J Epidemiol 2010; 39 (suppl 1): i75-i87. PubMed

37 Walker CLF, Black RE. Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes. Int J Epidemiol 2010; 39 (suppl 1): i63-i69. PubMed

38 Gaffey MF, Wazny K, Bassani DG, Bhutta ZA. Dietary management of childhood diarrhea in low- and middle-income countries: a systematic review. BMCPH (in press).

39 Das JK, Ali A, Salam RA, Bhutta ZA. Antibiotics for the treatment of Cholera, Shigella and Cryptosporidium in children. BMCPH (in press).

40 Cunliffe NA, Witte D, Ngwira BM, et al. Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: a randomized, double-blind, placebo controlled trial. Vaccine 2012; 30 (suppl 1): A36-A43. CrossRef | PubMed

41 Sow SO, Tapia M, Haidara FC, et al. Efficacy of the oral pentavalent rotavirus vaccine in Mali. Vaccine 2012; 30 (suppl 1): A71-A78. CrossRef | PubMed

42 Piarroux R, Barrais R, Faucher B, et al. Understanding the cholera epidemic, Haiti. Emerg Infect Dis 2011; 17: 1161-1168. PubMed

43 Ali M, Emch M, von Seidlein L, et al. Herd immunity conferred by killed oral cholera vaccines in Bangladesh: a reanalysis. Lancet 2005; 366: 44-49. Summary | Full Text | PDF(350KB) | CrossRef | PubMed

44 Longini IM, Nizam A, Ali M, Yunus M, Shenvi N, Clemens JD. Controlling endemic cholera with oral vaccines. PLoS Med 2007; 4: e336. CrossRef | PubMed

45 Traa BS, Walker CL, Munos M, Black RE. Antibiotics for the treatment of dysentery in children. Int J Epidemiol 2010; 39 (suppl 1): i70-i74. PubMed

46 Kabir I, Khan WA, Haider R, Mitra AK, Alam AN. Erythromycin and trimethoprim-sulphamethoxazole in the treatment of cholera in children. J Diarrhoeal Dis Res 1996; 14: 243-247. PubMed

47 Roy SK, Islam A, Ali R, et al. A randomized clinical trial to compare the efficacy of erythromycin, ampicillin and tetracycline for the treatment of cholera in children. Trans R Soc Trop Med Hyg 1998; 92: 460-462. CrossRef | PubMed

48 Zimbabwe, Bangladesh, South Africa (Zimbasa) Dysentery Study Group. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. Pediatr Infect Dis J 2002; 21: 1136-1141. CrossRef | PubMed

49 Alam AN, Islam MR, Hossain MS, Mahalanabis D, Hye HK. Comparison of pivmecillinam and nalidixic acid in the treatment of acute shigellosis in children. Scand J Gastroenterol 1994; 29: 313-317. CrossRef | PubMed

50 Salam MA, Dhar U, Khan WA, Bennish ML. Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis. Lancet 1998; 352: 522-527. Summary | Full Text | PDF(56KB) | CrossRef | PubMed

51 Varsano I, Eidlitz-Marcus T, Nussinovitch M, Elian I. Comparative efficacy of ceftriaxone and ampicillin for treatment of severe shigellosis in children. J Pediatr 1991; 118: 627-632. CrossRef | PubMed

52 Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. Lancet 2002; 360: 1375-1380. Summary | Full Text | PDF(96KB) | CrossRef | PubMed

53 Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of Nitazoxanide. J Infect Dis 2001; 184: 103-106. CrossRef | PubMed

54 Wittenberg DF, Miller NM, van den Ende J. Spiramycin is not effective in treating cryptosporidium diarrhea in infants: results of a double-blind randomized trial. J Infect Dis 1989; 159: 131-132. CrossRef | PubMed

55 Gu B, Cao Y, Pan S, et al. Comparison of the prevalence and changing resistance to nalidixic acid and ciprofloxacin of Shigella between Europe-America and Asia-Africa from 1998 to 2009. Int J Antimicrob Agents 2012; 40: 9-17. CrossRef | PubMed

56 Sudfeld CR, Navar AM, Halsey NA. Effectiveness of measles vaccination and vitamin A treatment. Int J Epidemiol 2010; 39 (suppl 1): i48-i55. PubMed

57 Theodoratou E, Johnson S, Jhass A, et al. The effect of Haemophilus influenzae type b and pneumococcal conjugate vaccines on childhood pneumonia incidence, severe morbidity and mortality. Int J Epidemiol 2010; 39 (suppl 1): i172-i185. PubMed

58 Zaidi AKM, Ganatra HA, Syed S, et al. Effect of case management on neonatal mortality due to sepsis and pneumonia. BMC Public Health 2011; 11 (suppl 3): S13. CrossRef | PubMed

59 Duke T, Wandi F, Jonathan M, et al. Improved oxygen systems for childhood pneumonia: a multihospital effectiveness study in Papua New Guinea. Lancet 2008; 372: 1328-1333. Summary | Full Text | PDF(94KB) | CrossRef | PubMed

60 Bhutta ZA, Zaidi AKM, Thaver D, Humayun Q, Ali S, Darmstadt GL. Management of newborn infections in primary care settings: a review of the evidence and implications for policy?. Pediatr Infect Dis J 2009; 28 (suppl): S22-S30. CrossRef | PubMed

61 Punpanich W, Groome M, Muhe L, Qazi SA, Madhi SA. Systematic review on the etiology and antibiotic treatment of pneumonia in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2011; 30: e192-e202. CrossRef | PubMed

62 Addo-Yobo E, Anh DD, El-Sayed HF, et althe Multicenter Amoxicillin Severe pneumonia Study (MASS) Group. Outpatient treatment of children with severe pneumonia with oral amoxicillin in four countries: the MASS study. Trop Med Int Health 2011; 16: 995-1006. CrossRef | PubMed

63 Haider BA, Saeed MA, Bhutta ZA. Short-course versus long-course antibiotic therapy for non-severe community-acquired pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev 2008; 2. CD005976.

64 Lassi ZS, Haider BA. ZA B. Community-based intervention packages for reducing maternal morbidity and mortality and improving neonatal outcomes. J Dev Effect 2012; 4: 151-187. PubMed

65 Lassi ZS, Haider BA, Bhutta ZA. Community-based intervention packages for reducing maternal and neonatal morbidity and mortality and improving neonatal outcomes. Cochrane Database Syst Rev 2010; 11. CD007754

66 Bhutta ZA, Lassi ZS, Pariyo GLH. Global experience of community health workers for delivery of health related Millennium Development Goals: a systematic review, country case studies, and recommendations for integration into national health systems. Geneva: WHO/Global Health Workforce Alliance, 2010.

67 Das JK, Lassi ZS, Salam RA, Bhutta ZA. Effect of community based interventions on childhood diarrhea and pneumonia: uptake of treatment modalities and impact on mortality. BMCPH (in press).

68 Theodoratou E, Al-Jilaihawi S, Woodward F, et al. The effect of case management on childhood pneumonia mortality in developing countries. Int J Epidemiol 2010; 39 (suppl 1): i155-i171. PubMed

69 Bassani DG, Arora P, Wazny K, Gaffey MF, Lenters L, Bhutta ZA. Financial incentives and coverage of child health interventions: a systematic review and meta-analysis. BMCPH (in press).

70 Bhutta ZA, Zipursky A, Wazny K, Levine MM, Black RE, Bassani D. Setting priorities for development of emerging interventions against childhood diarrhoea. J Glob Health 2013; 3: 010301. PubMed

71 Smith KR, McCracken JP, Weber MW, et al. Effect of reduction in household air pollution on childhood pneumonia in Guatemala (RESPIRE): a randomised controlled trial. Lancet 2011; 378: 1717-1726. Summary | Full Text | PDF(621KB) | CrossRef | PubMed

72 Thompson LM, Bruce N, Eskenazi B, Diaz A, Pope D, Smith KR. Impact of reduced maternal exposures to wood smoke from an introduced chimney stove on newborn birth weight in rural Guatemala. Environ Health Perspect 2011; 119: 1489-1494. CrossRef | PubMed

73 Kotloff KL, Winickoff JP, Ivanoff B, et al. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull World Health Organ 1999; 77: 651-666. PubMed

74 Van De Verg LL, Bendiuk NO, Kotloff K, et al. Cross-reactivity of Shigella flexneri serotype 2a O antigen antibodies following immunization or infection. Vaccine 1996; 14: 1062-1068. CrossRef | PubMed

75 Noriega FR, Liao FM, Maneval DR, Ren S, Formal SB, Levine MM. Strategy for cross-protection among Shigella flexneri serotypes. Infect Immun 1999; 67: 782-788. PubMed

76 Applegate JA, Fischer Walker CL, Ambikapathi R, Black RE. Systematic review of probiotics for the treatment of community-acquired diarrhea in children. BMCPH (in press).

77 Bruce N, Dherani M, Das JK, et al. Control of household air pollution for child survival: estimates for intervention impacts. BMCPH (in press).

78 Das JK, Kumar R, Salam RA, Freedman S, Bhutta ZA. The efffect of antiemetics in childhood gastroenteritis. BMCPH (in press).

79 Rudan I, Chopra M, Kapiriri L, et al. Setting priorities in global child health research investments: universal challenges and conceptual framework. Croat Med J 2008; 49: 307-317. CrossRef | PubMed

80 Rudan I, Gibson J, Kapiriri L, et althe Child Health and Nutrition Research Initiative (CHNRI). Setting priorities in global child health research investments: assessment of principles and practice. Croat Med J 2007; 48: 595-604. PubMed

81 Rudan I, Gibson JL, Ameratunga S, et althe Child Health and Nutrition Research Initiative. Setting priorities in global child health research investments: guidelines for implementation of CHNRI method. Croat Med J 2008; 49: 720-733. CrossRef | PubMed

82 Wazny K, Zipursky A, Black RE, et al. Setting research priorities to reduce mortality and morbidity of childhood diarrhoeal disease in the next 15 years. PLoS Med (in press).

83 Fontaine O, Kosek M, Bhatnagar S, et al. Setting research priorities to reduce global mortality from childhood diarrhoea by 2015. PLoS Med 2009; 6: e41. CrossRef | PubMed

84 Kosek M, Lanata CF, Black RE, et al. Directing diarrhoeal disease research towards disease-burden reduction. J Health Popul Nutr 2009; 27: 319-331. PubMed

85 Rudan I, El Arifeen S, Bhutta ZA, et althe WHO/CHNRI Expert Group on Childhood Pneumonia. Setting research priorities to reduce global mortality from childhood pneumonia by 2015. PLoS Med 2011; 8: e1001099. CrossRef | PubMed

86 International Health Partnership. OneHealth Tool. http://www.internationalhealthpartnership.net/en/tools/one-health-tool/. (accessed Jan 1, 2013).

87 Chatterjee A, Mahalanabis D, Jalan KN, et al. Oral rehydration in infantile diarrhoea. Controlled trial of a low sodium glucose electrolyte solution. Arch Dis Child 1978; 53: 284-289. CrossRef | PubMed

88 Lenters LM, Das JK, Bhutta ZA. Systematic review of strategies to increase use of oral rehydration solution at the household level. BMCPH (in press).

89 Chandani Y, Noel M, Pomeroy A, Andersson S, Pahl MK, Williams T. Factors affecting availability of essential medicines among community health workers in Ethiopia, Malawi, and Rwanda: solving the last mile puzzle. Am J Trop Med Hyg 2012; 87 (suppl): 120-126. CrossRef | PubMed

90 Stack ML, Ozawa S, Bishai DM, et al. Estimated economic benefits during the ‘decade of vaccines’ include treatment savings, gains in labor productivity. Health Aff 2011; 30: 1021-1028. PubMed

91 Ozawa S, Mirelman A, Stack ML, Walker DG, Levine OS. Cost-effectiveness and economic benefits of vaccines in low- and middle-income countries: a systematic review. Vaccine 2012; 31: 96-108. CrossRef | PubMed

92 Bhutta ZA. Drug resistant infections in poor countries: a major burden on children. BMJ 2008; 336: 948-949. CrossRef | PubMed

a Division of Woman and Child Health, Aga Khan University, Karachi, Pakistan

b Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

c Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, Scotland, UK

Correspondence to: Prof Zulfiqar A Bhutta, Division of Woman and Child Health, Aga Khan University, Karachi 74800, Pakistan

† Members listed at end of paper