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Aetiology of Neonatal Infection in South Asia (ANISA): An Initiative to Identify Appropriate Program Priorities to Save Newborns

Saha, Samir K. PhD; Arifeen, Shams El DrPH; Schrag, Stephanie J. DrPhil

The Pediatric Infectious Disease Journal: May 2016 - Volume 35 - Issue 5 - p S6–S8
doi: 10.1097/INF.0000000000001099
ANISA Supplement

From the *Child Health Research Foundation, Department of Microbiology, Dhaka Shishu Hospital, Dhaka, Bangladesh; Centre for Child and Adolescent Health, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh; and Centers for Disease Control and Prevention, Atlanta, Georgia.

Accepted for publication January 10, 2016.

The ANISA study is funded by the Bill & Melinda Gates Foundation (Grant No. OppGH5307). The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: Samir K. Saha, PhD, Department of Microbiology, Dhaka Shishu (Children’s) Hospital, Sher-E-Bangla Nagar, Dhaka 1207, Bangladesh. E-mail: samir.sks@gmail.com.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially.

The global commitment to reduce child mortality was further augmented in 2000 with the declaration of the millennium development goals (MDGs). Combined efforts by countries, United Nations organizations, donors, civil society, private sector organizations and child health researchers have led to remarkable success in reducing child mortality worldwide. The number of under-5 deaths has been reduced from 12.7 million in 1990 to 6.3 million in 2013, which translates to 17,000 fewer deaths per day in 2013 compared with 1990. The rate of reduction has accelerated over time: 4.0% per year between 2005 and 2013 compared with 1.2% between 1990 and 1995 (http://www.unicef.org/media/files/Levels_and_Trends_in_Child_Mortality_2014.pdf).

However, the story is not as gratifying when achievement is further categorized by region. This is specifically true for South Asia and sub-Saharan Africa. Most of the countries in these regions performed suboptimally, particularly in preventing neonatal deaths, leading to an increased share of under-5 deaths that occur in the newborn period. In South Asia, neonatal deaths accounted for 54% of all under-5 deaths in 2013, a 33% increase from 1990. These figures demonstrate the failure of many countries to achieve MDG4, and challenge our efforts to adhere to global commitments. Saving neonatal lives is not an isolated challenge; it is deeply embedded in the overall reduction of child mortality, the achievement of Sustainable Development Goal 3 (ensure healthy lives and promote well-being for all at all ages; https://sustainabledevelopment.un.org/topics) and making the “Every Woman Every Child” (http://www.everywomaneverychild.org/) initiative a reality.

In the past decade, there has been copious literature in this field, and we are now clearer about the root causes of most neonatal deaths than we were in 1990. Neonatal deaths are primarily due to prematurity, intrapartum complications, severe infections and congenital anomalies.1 However, we have yet to delineate the distribution of these specific causes of death, and this remains a roadblock before we can precisely select and prioritize appropriate intervention strategies. Among all the known causes of deaths, severe infections are probably the easiest targets. We have the capacity to prevent and treat them, based on our successes with vaccines (eg, maternal tetanus toxoid immunization), clean delivery and postpartum newborn care [eg, thermal care, breastfeeding support, emollient therapy,2 kangaroo mother care (http://www.healthynewbornnetwork.org/topic/kangaroo-mother-care-kmc)] and antibiotic trials.3 However, before treating infections, we need to identify the causative organisms (etiology) along with their antibiotic susceptibility pattern, at least in the population concerned if not case-by-case.

To date, the infection slice in the global neonatal mortality pie is based on the existing World Health Organization definition of possible serious bacterial infection (pSBI), which has been adapted to capture cases at the community level. However, clinical signs of sepsis among newborns significantly overlap with the signs of other clinical syndromes (eg, asphyxia or prematurity). In 2012, an estimated 6.9 million neonates received treatment for pSBI worldwide.4 Almost all the treatment, specifically in developing countries, was empirical as there are few data on the etiology of neonatal infections and their antibiotic susceptibility. Furthermore, most of the available South Asian data are from hospital-based studies, where a large proportion of the infections were hospital acquired. The only population-based study from this region was carried out in a small rural population in Bangladesh.5 Our knowledge about etiology of neonatal infections is still vastly incomplete.

In recent years, there has been notable improvement in microbiology techniques. Blood culture systems have improved significantly with respect to reducing turn-around time for results, and supporting the growth of fastidious organisms in prestandardized media. Despite these refinements, blood culture-based etiology studies which utilize clinical judgment or the World Health Organization clinical algorithm for pSBI show that only 5%–10% of all cases of suspected serious infection are positive for any bacteria.6–10 This strikingly low rate of culture positivity questions the sensitivity of blood culture methods and draws the attention of researchers toward more investigative, modern molecular diagnostic tools with higher sensitivity for etiology detection. However, state-of-the-art molecular diagnostics are mainly available in well-resourced parts of the world, thus carrying little or no value for the settings where most children die. This situation leads to an information gap that hinders us from formulating definitive policies for treatment and/or prevention. We believe that we can break this barrier; in 2009 we decided to take these technologies where they are needed the most.

A large research initiative, Aetiology of Neonatal Infection in South Asia (ANISA), funded by the Bill & Melinda Gates Foundation, was conceived in 2009 to address questions around infections among newborns and bridge the gap of modern diagnostics. A multidisciplinary team, representing different organizations (Fig. 1), was formed to coordinate a major initiative consisting of 5 population-based sites in South Asia (Bangladesh, India and Pakistan). The study team designed a comprehensive plan to address anticipated challenges with surveillance in the field and assays in the laboratory. The ANISA coordination team invited experts from different disciplines and various parts of the world to form a Technical Advisory Group. Together, we designed our final plans and moved to the field and the laboratory bench, simultaneously.

FIGURE 1

FIGURE 1

In 2008, Baqui et al11,12 conclusively showed that 70% of neonatal deaths in a rural Indian community occurred within the first 7 days after birth. Taking this into consideration, ANISA started its surveillance activities by identifying all married women of reproductive age at each of the 5 sites to reach infants as soon as possible after birth. Visits were continued up to 59 days of life to identify cases of pSBI. The number of visits was carefully crafted to avoid an excessive number that might lead to a Hawthorne effect and influence natural disease progression and outcomes in the community. The team collected multiple specimens from each infant considering the pathophysiology of neonatal sepsis and the possible niche of the target pathogens during the disease process. The specimens were processed by culture (blood) and state-of-the-art molecular diagnostics (blood and respiratory specimens).

ANISA has thus bridged the gap between settings with high child mortality and availability of advanced diagnostics. In addition to an automated blood culture system, the project extended the best available molecular platforms to rural and suburban settings in South Asia, where the rate of neonatal mortality is high. This automated platform of singleplex polymerase chain reaction is capable of detecting a large number of diverse etiologies (bacteria and virus) and has minimal possibility of being affected by human error.13

In addition to placing advanced technologies at each site, innovation touched each and every segment of ANISA—starting from data form design to data management through control selection, harmonization of study procedures across the sites, specimen transportation and tracking, prevention of contamination, etc. This supplement contains the details of all methods applied for ANISA implementation and management. The success of ANISA is ensured through these novel approaches. We believe that these method papers and description of challenges at individual sites will be useful for future researchers working on etiology of infections in any age group and location.

With ambitious planning, management and implementation, ANISA has collected comprehensive and high-quality data on etiology of newborn infections. These data from a large cohort of ~68 000 newborns will significantly improve our understanding of the causes and epidemiology of neonatal infections in South Asian infants. Data generated by ANISA, along with those from other contemporary antibiotic treatment trials, will have a significant impact on the rational use of antibiotics. Thus, the study will contribute to restricting the emergence of antimicrobial resistance, another public health priority of the World Health Organization and global leaders of multiple disciplines. Altogether, ANISA results will facilitate evidence-based programmatic decisions which will reduce deaths and improve the well-being of newborns and age groups beyond.

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