Funded by BMGF | 2010-2014
This project will determine the population-based incidence, aetiology and antibiotic resistance profiles of community-acquired young infant infections in Bangladesh, India and Pakistan using community-based surveillance and standard and new diagnostic tests. The project also aims to identify risk factors for acquiring laboratory-confirmed infections and to describe clinical predictors of laboratory confirmed infections.
Most developing countries have witnessed substantial declines in mortality among children <5 years of age. In contrast, neonatal mortality has remained relatively constant, with an estimated 2.9 million annual neonatal deaths globally and now accounts for about 40-50% of under-five child deaths. Neonatal infections, including sepsis, pneumonia and meningitis account for an estimated 1.4 million neonatal deaths worldwide every year. About 60% of the deaths due to infections occur in the first week of life, and therefore, there is only a narrow window of opportunity to intervene. The risk of death in the second month of life is also high and a vast majority of these deaths occur in the poorest countries of Asia and Africa. Three South Asian countries, Bangladesh, India and Pakistan, account for more than a third of all global neonatal deaths, and a disproportionate portion of deaths in the second month of life. The majority of births and deaths in these countries occur at home.
A variety of preventive approaches, including maternal immunization, clean childbirth practices, emollient therapy, promotion of exclusive breastfeeding, and chlorhexidine cord cleansing hold promise in reducing the total number of infection-related young infant deaths. In addition, we and other investigators have demonstrated the feasibility and effectiveness of identifying young infants with serious infection using clinical algorithms, and safely treating them at the community level.
Several antibiotic regimens are currently used to treat young infant infections and other regimens are under evaluation. Most treatments, however, are presumptive and the diagnosis is based on clinical algorithms which are not specific for invasive bacterial infection. Although treatment regimens currently utilised can reduce neonatal mortality by up to 50%, appropriate formulation of antibiotic treatment regimens is hampered by lack of data on aetiology and antibiotic susceptibility patterns. A single regimen may not be optimal for management of newborn infections in different geographic regions since the aetiology of infections and antimicrobial susceptibility patterns of major isolates may vary across settings. Moreover, antibiotic regimens that are not targeted for the leading young infant pathogens may contribute to treatment failures and emergence of multidrug-resistant bacteria in the community.
In recent years, development of new and better molecular and genetic tools opens new opportunities for etiologic evaluations. Different molecular diagnostic platforms/methods have been developed based on real-time multiplex or multiple singleplex polymerase chain reactions (PCR) for simultaneous identification of multiple aetiological agents. Among them, MassTag, Taqman Low Density Assay (TLDA) and Fast Track are most promising for use in large-scale etiologic evaluations of respiratory and sepsis syndromes.
Our goals will be achieved by engaging a study team including leaders in the neonatal and infant health field to conduct population-based surveillance of pregnancies and newborns in defined catchment populations to identify suspected cases of infections in young infants and collect specimens for determination of bacterial and viral aetiologies. Surveillance will focus on 0-59 day old infants because WHO’s clinical algorithm for identifying young infants requiring referral and treatment for serious illness targets this group. Young infants with suspected infection based on the WHO-Young Infant-IMCI clinical algorithm will be transported to the nearest hospital or health centre for physician assessment and collection of blood, respiratory specimens, and CSF from eligible cases. Appropriate treatment of all sick infants will be facilitated.
Bacteria will be isolated using optimized and standardized blood culture techniques. In addition, real-time PCR methods will be used for detection of bacteria and viruses from blood, Cerebrospinal fluid (CSF) and respiratory specimens. All study sites will use the same extraction techniques, PCR method, and qualitative controls for each of the pathogens. In addition, we will attempt to identify likely bacterial infections missed by blood culture and pathogen-specific assays through detection of universal bacterial genomic sequences (16s rRNA). Specimens (or the extracted DNA) from such infants will be preserved for analysis by sequencing and precise identification of bacteria in a future proposed study. Antibiotic susceptibility patterns of significant bacterial isolates will be characterized using Clinical and Laboratory Standards Institute (CLSI)-approved methods. The study will maintain strict quality control and assurance, including external monitoring.
To guide the interpretation of aetiological results of respiratory and blood specimens and understand the significance of specific pathogens and 16s genomic sequence findings, we will randomly select a sample of the birth cohort at each field site for collection of respiratory and blood specimens to describe the background prevalence of pathogens. This sub-cohort will be stratified by postnatal age and calendar month for sampling. The methods for specimen collection, processing and testing will be same for cases and controls.
We will capture information on potential maternal, intra-partum, and postnatal risk factors for infections on the full surveillance cohort to identify factors that significantly contribute to disease burden; the emphasis will be on risk factors that are amenable to potential interventions. Finally, the study will describe clinical predictors of aetiology-proven severe infections. This project will generate comprehensive data for evidence-based policy and programs for prevention and treatment of infections in young infants and thus help to achieve Millennium Development Goal 4.