In this study the mortality rate due to neonatal pneumonia was found to be 8.2%. The blood culture positivity was an independent predictor of mortality, though the type of organism did not affect mortality. The mortality rate is less than that reported (12%) in the multicenter national neonatal perinatal database report [11]. In the DeNIS cohort [3] though the overall blood culture positivity among neonates with pneumonia was almost similar to our study (15% vs 19%, respectively), the mortality rate was lower (45% vs 16%, respectively) and was probably due to differences in inclusion criteria and the higher prevalence of multidrug resistant organisms. In the present study, 50% of the bacterial isolates were Gram negative, Klebsiella being the commonest organism reflecting community prevalence. On the other hand, two-third of the culture positive isolates were Gram negative in DeNIS study, Acinetobacter being the commonest isolate [3]. Streptococcus pneumoniae, increasingly found in possible serious bacterial infections (pSBI) among young infants, has been reported to contribute to mortality [12]. However, we did not isolate any S. pnemoniae, possibly due to inherent difficulty in isolating in blood cultures and the need for additional techniques. The overall microbiological yield was 53%, which is double than that reported in community-acquired serious bacterial infections [12].

The incidence of community-acquired fungal pneumonia in our cohort, confirmed by molecular diagnosis (MALDI TOF), was very high (25% of culture positive), compared to other studies [3,12], although this did not translate into higher mortality. This is intriguing as none of the neonates received any antibiotic nor were admitted in any hospital prior to enrolment.

The viral positivity rate in our study (38%) was similar to that of a community-based surveillance study (42%) involving infants with respiratory illness from Bangladesh, but neonatal pneumonia constituted only 11% in their cohort [13]. Several hospital based studies in neonates, from Asia, have reported 30% incidence of viral lower respiratory tract infections, especially due to RSV [14]. The in-hospital case fatality rate of viral pneumonia was 0.2% which is significantly lower than the reported incidence in LMIC countries [5·3% (95% CI 2·8 to 9·8)] possibly due to better management in tertiary care centers [15]. Moreover, neonates with viral pneumonia had higher body weight and presented at a later age in the neonatal period, which could possibly explain better outcome., The most common viral isolate in the present study was RSV, consistent with the global burden, but unlike the usual pattern, type B strain was dominant, which could be another reason for better survival [14-16].

The symptoms and signs used in our study were similar to those in integrated management of neonatal and childhood illness (IMNCI) and young infant study [17,18]. Though they have been shown to predict the occurrence of pBSI, our data failed to show their association with mortality.

The strength of our study was the use of a very strict case definition, which, to the best of our knowledge, is the first and largest of its kind. The limitation of the study was the inability to enroll the originally planned 1500 neo-nates, due to logistic constraints. Other etiological agents like Mycoplasma, Chlamydia, and Pneumococcus requiring special techniques for isolation, were not evaluated. The investigators involved in the inter-pretation of X-rays were not blinded to clinical features.

In conclusion we found blood culture positivity in neonatal pneumonia as an independent predictor of mortality. The role of fungus in community acquired neonatal pneumonia needs further exploration and there is need to be vigilant and consider early antifungal therapy especially in those who do not seem to respond. The high incidence of viral pneumonias in our study emphasizes the need to consider nasopharyngeal swab in the neonatal pneumonia work up. Vaccination against RSV immediately after birth may be a potential strategy to lower the burden of neonatal pneumonia. [19]

Acknowledgements: Technical advisory group constituting Prof Dr Lalitha Krishnan, Prof Dr Siddharth Ramji and Prof Dr Ramesh Agarwal for their critical appraisal of the project and for providing technical guidance. INCLEN, especially Dr Manoj K Das, for providing continuous technical and logistic support for the study. Dr Murali Reddy and his team from Beyond P value for providing statistical assistance. We also thank the project coordinator Mrs. Pavani Soujanya for supervising and coordinating the project, and also analyzing the viral isolates.

Ethics clearance: (i) Ethics committee of Osmania medical college, Hyderabad; Reg No ECR/300/Inst/AP/2013 Date of approval June 23, 2015; (ii) Ethics committee of Gandhi Medical college, Hyderabad, ECR/180/Inst/AP/2013- October 13, 2015; and (iii) Ethics committee of Fernandez hospital, Hyderabad; ECR/933/Inst/TG/2017 – December 09, 2015.

Contributors: SK, SS, SM, JVR, MB: involved in the conception, design of the project; SK,SS,SM were also involved in data analysis, drafting of manuscript; MB, SP, NPB: designed and conducted the microbiological aspects of the study; HS, AM, SL, SB, BN: involved in case enrolment and supervision. All the authors were involved in critical appraisal and have reviewed and approved the manuscript.

Funding: This work was supported by Bill and Melinda Gates Foundation through The INCLEN Trust International (Grant number: OPP1084307). The funding source had no contribution in study design, implementation, collection and interpretation of data and report writing. Competing interests: None stated.

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