Opportunity:
Pneumonia is the second leading cause of death amongst children globally, accounting for approximately 1 million deaths per year. There is an urgent need for new and better ways to prevent, diagnose and treat childhood pneumonia and historically, The Bill & Melinda Gates Foundation has primarily focused on pneumococcal conjugate vaccine and other vaccines aimed at protecting young infants through a maternal immunization platform.
However, given the currently high levels of child mortality attributable to pneumonia as well as limits of vaccines in preventing all cases of pneumonia, we are also focused on improving mortality-impacting treatment commodities, with the ultimate goal of ensuring their inclusion in key global and national policies. Where such commodities exist, it is paramount that their use be informed by accurate and cost effective diagnostic tools that can easily diagnose pneumonia at the frontline, the first point of patient interaction. In addition to treatment at the frontline, early identification of children at risk for treatment failure or at increased risk for death will help improve overall health outcomes.
The Challenge:
Children with pneumonia in highest burden countries face many risks and obstacles that impede access and adherence to timely and appropriate treatment. The severely malnourished child has up to a nine-fold greater risk of death from pneumonia, highlighting the importance of timely recognition, treatment with appropriate antibiotics and referral of the child for administration of acute nutritional support. However, accurate recognition or diagnosis of pneumonia represents a huge challenge, complicated by multiple factors including, but not limited to, lack of access to the site of infection and the need to differentiate colonization from infection. Novel diagnostic approaches for pneumonia are therefore needed to ensure successful execution of our Treatment Innovation and Delivery Initiative and ensure all children are either appropriately treated or referred.
Within this call to reduce pneumonia fatalities through innovations that improve diagnosis of pneumonia and referral of the high risk, malnourished child, we are looking for innovative ideas in the following specific areas:
- Identification of host response biomarkers for differentiation of bacterial and non-bacterial causes of pneumonia
- Field friendly, simple to use tools for assessment of malnutrition status in the sick child
Examples of ideas we will consider funding:
Identification of host response biomarkers for differentiation of bacterial and non-bacterial causes of pneumonia
Finding an ideal diagnostic biomarker for bacterial pneumonia is not an easy task. Not only should it allow an early diagnosis of the condition, but it should also allow differential diagnosis from non-bacterial causes of pneumonia as well as other non-infectious conditions. Host response biomarkers have the potential to emerge as indispensable tools. Developing an array of specific and validated biomarkers that could be translated into simple and easy to use test formats appropriate for use by a frontline healthcare worker in a developing country would be a big leap forward for pneumonia diagnosis and treatment.
A number of proteins found in the blood, which are elevated in response to inflammation and/or infection, have been investigated as possible markers of bacterial pneumonia. The most frequently studied markers are C-Reactive Protein (CRP) and Procalcitonin (PCT), but considerable variation in the performance of these markers, depending on the population of study and presence of comorbidities such as malaria, have been observed. Beyond blood, host response biomarkers for bacterial pneumonia have been described in exhaled breath condensate as well as specific volatile substances identified in breath. Successful applicants must be able to demonstrate improved performance of their host response biomarker (s) over PCT or CRP, using well characterized clinical samples for bacterial pneumonia.
Measurement of lung injury markers, assuming a simple, feasible and non-invasive method for obtaining a lower respiratory tract sample can be developed, may provide a mechanism for determining the presence of bacterial pneumonia, as well as severity of infection. Identification or validation of lung injury biomarkers in blood or breath will also be considered responsive to this call.
Things we will not consider funding include:
- Evaluations of existing biomarkers, such as CRP and PCT, when used in isolation
- Discovery and/or validation of pathogen specific biomarkers (e.g. biomarker for pneumococcus only)
- Biomarkers that cannot be translated to a simple, point of care diagnostic test suitable for use by frontline health care workers in developing countries
Field friendly, simple to use tools for assessment of malnutrition status in the sick child
About 167 million[1] children under five years of age, almost one-third of the developing world's children, are malnourished. Of these children, the severely malnourished child is up to nine times more likely to die from pneumonia. Identification of children with pneumonia that are either moderately or severely malnourished, and in need of referral to higher levels of care for administration of acute nutritional support, is a priority focus for the foundation's Treatment Innovation and Delivery Initiative. Malnutrition status in developing countries is currently assessed by Measurement of Upper Arm Circumference (MUAC), measured on the left arm at the mid-point between the tip of the shoulder and the tip of the elbow. MUAC, the major determinants of which are muscle and sub-cutaneous fat, is a useful tool for fast assessment of nutritional status and in some studies MUAC alone,[2] or MUAC for age,[3] has predicted death in children better than any other anthropometric indicator.
Although measurement of MUAC requires only a tape measure and is easy to perform even on the most debilitated individuals, it does require careful training and supervision in order to prevent wrapping the measuring tape too tightly or too loosely, which results in an erroneous estimate and some degree of observer variability. Beyond MUAC, alternative approaches to measure malnutrition status in a child may include use of novel technologies to measure density of fat deposits beneath the skin or application of cell phone, or other electronic technologies, to create easy to use anthropometric assessments of malnutrition status.
Things we will not consider funding include:
- Training programs to improve the utility of MUAC in field settings
- Minor technical improvements to the MUAC tape measure
- Population based assessments of malnutrition status using MUAC or other measurement tool
We will also not consider funding for:
- Ideas that are not directly relevant to developing countries;
- Ideas without a clearly articulated and testable hypothesis and metrics;
- Ideas for which a relevant indicator of success cannot be demonstrated within the scope of the GCE Phase 1 award ($100,000 over 18 months);
- Basic research without clear relevance to the goals of this topic;
- Solely infrastructure or capacity-building initiatives.
References
[1] Smith, LC & Haddad, L J (February 28, 2000). Overcoming child malnutrition in developing countries: past achievements and future choices. A 2020 Vision for Food, Agriculture & the Environment.
[2] Briend A, Zimick S. (1986) Validation of arm circumference as an index of risk in 1 to 4 year olds.Nutrition Research 1986; 6:249-61
[3] Chen LC, Chowdhury A, Huffman SL. (1980) Anthropometric assessment of energy-protein malnutrition and subsequent risk of mortality among preschool children. American Journal of Clinical Nutrition 33:1836-1845