Trends in the incidence of possible severe bacterial infection and case fatality rates in rural communities in Sub-Saharan Africa, South Asia and Latin America, 2010–2013: a multicenter prospective cohort study

The annual global burden of mortality in children under age 5 years decreased by 36 % from 9.9 million in 2000 to 6.3 million in 2013, mostly due to reductions in mortality due to pneumonia, diarrhea and measles in children aged 2–59 months [1]. Over the same time period, there was only a 30 % reduction in the annual neonatal mortality rate from 4 million to 2.8 million, so that the proportion of under age 5 deaths that occurred in neonates increased from 38 to 44 % [2]. Most of the neonatal deaths continue to be attributed to preterm birth, intrapartum related complications (birth asphyxia) and neonatal sepsis/meningitis/pneumonia due to possible severe bacterial infections (pSBI) [1]. The recently published studies of simplified antibiotic regimens for treatment of neonatal pSBI provide a potential way to reduce part of the burden of neonatal mortality in settings where hospitalization is not accepted or available [3,4], but the impact of these new regimens and optimal ways to make them available globally is not clear, [5,6] because there is limited information on the incidence and case fatality rates of pSBI. To our knowledge, only one systematic review and meta-analysis estimates the global incidence and mortality due to neonatal infection, in one year - 2012 [7]. There is an important need to confirm these estimates of neonatal pSBI incidence and case fatality rates using prospectively collected, population based data, in which the outcomes of all pregnancies are recorded and to evaluate recent trends over time, particularly as facility births and survival of preterm infants increase.

The diagnosis of possible severe bacterial infection/neonatal sepsis is challenging even in well-equipped tertiary care facilities in resource rich settings [8,9]. In resource limited settings where there is a lack of access to microbiologic, hematologic and biochemical laboratory studies, the World Health Organisation’s (WHO) Integrated Management of Childhood Illness (IMCI) algorithm is used to make a clinical diagnosis of possible severe bacterial infection (pSBI), which includes sepsis, meningitis and pneumonia in young infants and neonates [10]. However, the signs can be difficult to detect and non-specific. The algorithm, initially developed in the first WHO Young Infants Study in the 1990s, found 14 clinical signs and symptoms that predicted isolation of bacteria in blood or cerebrospinal fluid, or culture positive severe bacterial disease [11]. These signs and symptoms were simplified in the second WHO Young Infants Clinical Signs Study (YICSS) published in 2008 [10]. The YICSS evaluated clinical signs in neonates presenting to primary health care facilities, as detected by primary care health workers, in 6 countries (Bangladesh, Bolivia, Ghana, India, Pakistan, and South Africa). Presence of any one of seven clinical signs and symptoms predicted severe illness (based on an expert pediatrician’s assessment) and was associated with a sensitivity and specificity of 85 and 75 % respectively in 0–6 day old neonates and 74 and 79 % respectively in infants aged 7–59 days [10]. Since the YICSS signs and symptoms were not evaluated against blood or cerebrospinal fluid culture results, the diagnosis likely includes respiratory distress associated with preterm birth, birth asphyxia, and viral respiratory infections, but based on available data, neonates with these signs and symptoms should be treated for pSBI.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Global Network (GN) for Women and Children’s Health Research supports a population based Maternal and Newborn Health (MNH) Registry of pregnant women and their babies living in rural communities in six low and lower middle income countries. The Registry has focused on documentation of pregnancy histories, details of labor and delivery, accurate and timely measurement of birth weight and early and late neonatal morbidity and mortality through day 42 of life, including signs and symptoms similar to those used in the YICSS, and cause of death [12]. We used data from live born neonates collected by the MNH Registry between 2010 and 2013 to estimate the incidence of pSBI using the clinical signs and symptoms from YICSS, the case fatality rate, and trends in pSBI incidence and mortality over time.

In a cohort of 248,539 infants born alive between 2010 and 2013 at 7 population based Global Network sites in Latin America, Africa, and Asia 32,088 (13 %) neonates met symptomatic criteria for pSBI. The incidence of pSBI in the first 6 weeks of life, trends in incidence, and in case fatality rates in the first 6 weeks for infants with pSBI varied widely across sites with a 10–fold variation in incidence of pSBI from 3 % (Zambia) to 36 % (Pakistan) and an 8 fold variation in case fatality from 5 % (Kenya) to 42 % (Zambia). Our incidence estimates are in range or somewhat higher than the upper range recently estimated by Seale et al. [7] in a systematic review and meta-analysis of global incidence of pSBI in 2012 (7.6 %, 95 % confidence interval 6.1–9.2 %), except for our two extreme sites, Zambia (lower rates) and Pakistan (higher rates). Unlike Seale et al., we included all live born infants not just those with birth weight ≥ 1,500 g, which may have comparatively inflated our rates because low birth weight babies may be premature and may be more likely to have breathing problems that are not caused by pSBI. Our incidence estimates are likely higher than Seale’s in some cases because we were unable to match the most common sign of pSBI per YICSS, respiratory rate of 60 breaths per minute, and had to use a less specific data point of breathing problems and difficulty breathing. It is likely that these respiratory variables increased the proportion of our pSBI cases that had respiratory distress due to preterm birth or birth asphyxia, both of which are difficult to distinguish from possible severe bacterial infection, particularly in the first few days of life. Our case fatality rates are within the range estimated by Seale et al. (9.8, 95 % confidence interval 7.4–12.2 %) for Argentina and Pakistan, lower for Kenya and higher for Guatemala, Zambia, and the two Indian sites. Although a common protocol was used for prospective data collection, we note that Zambia had the lowest incidence of pSBI but the highest case fatality rate, suggesting that signs and symptoms may have been underreported in this site. In contrast, Pakistan had the highest incidence of pSBI and one of the lower case fatality rates, suggesting there may have been over-reporting of respiratory symptoms or that these symptoms were due to the higher rates of preterm birth and birth asphyxia reported in Pakistan [14]. Overall, our estimates, on average, align with Seale et al. [7], which lends support to the credibility of these findings particularly as these data from the studies contributing to Seale’s paper and the MNH registry (as described in the methods above) were obtained in very different ways. However, the wide variations in pSBI incidence and case fatality rates, even in our prospective registry with trained data collectors, indicate continued need for objective criteria to make a diagnosis of pSBI.

Between 2010 and 2013 there were significant increases in facility deliveries and survival of neonates born preterm in our study sites as well as in the countries our sites represent. Against this background, we found decreases in the incidence of pSBI in the first 6 weeks of life during the period in Argentina, Kenya, and Nagpur, India after accounting for clustering and maternal and neonatal factors. Argentina was the one site where nearly all infants were born in hospital throughout the study period, and the decrease in Kenya occurred among infants born at home as well as in a facility suggesting that changes at these sites cannot be attributed simply to facility birth. In contrast, in Nagpur, India, the decrease in pSBI rate occurred among facility births alone with no significant change in pSBI incidence among infants born at home. While facility births increased from 49 to 62 % of all births in Pakistan, pSBI incidence increased during the period for infants born in a facility as well as for those born at home, after accounting for birth weight and other factors. Reporting or diagnostic changes may have contributed to the increase in Pakistan.

Our prospective study has several important strengths. First, we attempted to define pSBI based on the presence of any one of seven signs found to be predictive of severe illness in young infants [10]. However, we were limited in our ability to match all of these signs, mainly respiratory rate of 60 breaths or more per minute, severe chest indrawing, and movement when stimulated because they were not included in the MNH Registry. We recognize the overlap that breathing problems and difficulty breathing have with problems of prematurity, birth asphyxia, and non-bacterial illnesses. However, the proportions of infants with specific signs and symptoms are highly consistent with the ranges published in recent clinical trials that assessed community based treatment of neonatal sepsis [3,4]. There was extensive training on identification of signs and symptoms of pSBI in these trials, but there was still wide variation in the proportion of infants with signs such as chest indrawing across the study sites. Our data are also limited by lack of microbiologic confirmation in the rural communities and facilities. Further, we did not have the precise details of timing of the symptoms in the first 42 days of life, so it is possible that our incidence estimates are higher than in other studies reporting pSBI between day 0–27 of life and lower than in studies reporting pSBI in young infants between day 0–59 of life. We also do not have information on precise treatment practices by site for access to health care facilities, care seeking, antibiotic access across and over time and how these variables may have impacted case fatality rates. Finally, the MNH registry does not currently collect reliable information on referral practices because the ability to refer infants depends on the availability of referral facilities. Similarly, location of death is not captured currently and would be difficult to interpret because of variable access to referral facilities across the Global Network sites. We recognize that many of our limitations could have resulted in misclassification of pSBI that could have varied by site and over time, but to move forward, improved diagnostics for pSBI are urgently needed. Despite these limitations, the incidence of pSBI at each site is likely indicative of a significant portion of the neonatal illness burden given that infants identified as having pSBI were at greatly increased risk of death during the first 6 weeks of life compared to other infants. We believe that our data are generalizable based on the similarity with the Seale data and the standardized data collection across the 7 Global Network sites.

The high burden of pSBI in neonates and young infants, regardless of definitions and changes in location of birth, is an important reminder that investment in ways to reduce delays in early recognition /diagnosis and treatment of pSBI continues to be needed and is consistent with the research priorities outlined in the Every Newborn Action Plan [5]. Priorities for the future include ways to improve early detection of pSBI in the community, risk stratification, early access to referral of those at the greatest risk of mortality and ways to prevent pSBI particularly in the era of increased delivery of babies in health care facilities.

In a prospective population based registry with trained data collectors, there were wide variations in the reported incidence and case fatality of pSBI in rural communities and in trends over time. Regardless of these variations, the burden of pSBI is still high and strategies to implement timely diagnosis and treatment are still urgently needed to reduce neonatal mortality.