Improving management of neonatal infections
Authors: Anna C Seale, Ramesh Agarwal
Journal: The Lancet (2018)

Infections causing sepsis, meningitis, or pneumonia contributed directly to around 0·6 million neonatal deaths worldwide in 2016,1Liu L Oza S Hogan D et al.Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals.Lancet. 2016; 388: 3027-3035Summary Full Text Full Text PDF PubMed Scopus (1723) Google Scholar and indirectly to many more through pathways leading to preterm birth and neonatal encephalopathy. Despite this knowledge, understanding of the causes of neonatal infection, particularly in resource-poor settings, is limited. Treatment in these settings usually relies on the sensitive but non-specific clinical diagnosis of possible serious bacterial infection (pSBI),2Young Infants Clinical Signs Study GroupClinical signs that predict severe illness in children under age 2 months: a multicentre study.Lancet. 2008; 371: 135-142Summary Full Text Full Text PDF PubMed Scopus (297) Google Scholar made by front-line health-care workers and defined according to set criteria. Of the almost 7 million neonates needing treatment worldwide each year based on this diagnosis,3Seale AC Blencowe H Manu AA et al.Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis.Lancet Infect Dis. 2014; 14: 731-741Summary Full Text Full Text PDF PubMed Scopus (183) Google Scholar most are not tested for specific infectious causes and many are likely to have non-infectious conditions (figure). In The Lancet, Samir Saha and colleagues report the Aetiology of Neonatal Infection in South Asia (ANISA) study,4Saha SK Schrag SJ El Arifeen S et al.Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.Lancet. 2018; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(18)31127-9Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar which is an important step forward in understanding the infectious causes of neonatal pSBI. The community-based study design is an advance on previous studies, which have been mostly facility-based, and often performed limited microbiological investigations. ANISA enrolled 84 971 mothers antenatally across five sites in Bangladesh, India, and Pakistan, and used community health-care workers to follow up neonates after birth. Antenatal recruitment of mothers meant that neonates who died shortly after birth were counted and that pSBIs were quickly identified by community health-care worker follow-up. Systematic sampling and testing with conventional and molecular laboratory methods maximised pathogen detection. Reductions in specificity of diagnosis and identification of multiple organisms by molecular diagnostics were mitigated by use of control data and Bayesian partially latent class modelling to estimate attributable proportions for specific infectious causes. Saha and colleagues' findings for the causes of pSBIs and the non-specificity of this classification as a diagnosis are important. Of 6022 pSBI episodes, only 16% had attributed bacterial causes, and 102 (2%) of 4859 tested blood samples had clinically significant pathogens isolated by culture. More specific clinical algorithms and point-of-care diagnostics are needed to direct antibiotic treatment to those who need it, especially as antibiotic treatment for neonatal pSBI is scaled up; WHO guidelines recommend that when referral to hospital is not possible, antibiotic treatment should be given to outpatients to expand access to care.5WHOGuideline: managing possible serious bacterial infection in young infants when referral is not feasible.http://www.who.int/maternal_child_adolescent/documents/bacterial-infection-infants/en/Date: 2015Date accessed: June 27, 2018Google Scholar Of note, however, this recommendation was informed by pragmatic antibiotic trials that used pSBI as a clinical diagnosis and tested equivalence of regimens.6Baqui AH Saha SK Ahmed AS et al.Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial.Lancet Glob Health. 2015; 3: e279-e287Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 7Mir F Nisar I Tikmani SS et al.Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial.Lancet Glob Health. 2017; 5: e177-e185Summary Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 8Tshefu A Lokangaka A Ngaima S et al.Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial.Lancet. 2015; 385: 1767-1776Summary Full Text Full Text PDF PubMed Scopus (98) Google Scholar The ANISA study findings add to concerns about the use of non-specific clinical diagnoses for such trials9Mulholland K Carlin JB Duke T Weber M The challenges of trials of antibiotics for pneumonia in low-income countries.Lancet Respir Med. 2014; 2: 952-954Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar and underscore the uncertainty in their findings. As well as what it found, ANISA is important for what it did not find. Among 71 361 livebirths, 3061 (4%) babies died by the end of follow-up, most of these soon after birth. Despite active follow-up by community health-care workers, only 689 (23%) babies who died were assessed by a physician before death, and only 349 (11%) had samples taken in the 7 days before death.4Saha SK Schrag SJ El Arifeen S et al.Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.Lancet. 2018; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(18)31127-9Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar Under-representation of deaths is a limitation in terms of attributing infectious causes, but showing how many neonates who die and who are not seen or investigated for infection is important. These data are often not captured, or are not reported, and the extent to which the sickest neonates in the community, in research or in clinical practice, are not seen is unknown in many resource-poor settings. Improving understanding of the causes of these deaths is crucial. Infection is likely to be an important direct and indirect contributor, as are preterm birth and neonatal encephalopathy. In ANISA, the number of attributed infections was nearly double that among babies who died than among those who survived, and more than 90% of the infectious causes in those who died were bacterial.4Saha SK Schrag SJ El Arifeen S et al.Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.Lancet. 2018; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(18)31127-9Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar Further development of the evidence base to better direct interventions towards the highest burden of neonatal mortality at and in the few days after birth will need new approaches. One such approach is post-mortem investigation with minimally invasive tissue sampling, which may be more acceptable than complete diagnostic autopsy and could allow investigation of stillbirths and neonates not seen or assessed before death.10Bassat Q Castillo P Martinez MJ et al.Validity of a minimally invasive autopsy tool for cause of death determination in pediatric deaths in Mozambique: an observational study.PLoS Med. 2017; 14: e1002317Crossref PubMed Scopus (67) Google Scholar The Child Health and Mortality Prevention Surveillance study aims to use such techniques.11Farag TH Koplan JP Breiman RF et al.Precisely tracking childhood death.Am J Trop Med Hyg. 2017; 97: 3-5Crossref PubMed Scopus (24) Google Scholar Another potential approach is the use of maternal vaccines in the context of trials, and surveillance after implementation, to determine the contributions of specific infectious causes. Maternal vaccines are being developed for various pathogens, such as respiratory syncytial virus and group B streptococcus.12Sobanjo-Ter Meulen A Abramson J Mason E et al.Path to impact: a report from the Bill and Melinda Gates Foundation convening on maternal immunization in resource-limited settings; Berlin—January 29–30, 2015.Vaccine. 2015; 33: 6388-6395Crossref PubMed Scopus (22) Google Scholar The ANISA study has advanced understanding of neonatal infection and highlighted the limitations of current management strategies. Ways to address these issues must be urgently sought, and it must be remembered that the neonates not seen matter as much as those that are. We declare no competing interests. Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort studyNon-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Full-Text PDF Open Access