The NeoSep Severity and Recovery scores to predict mortality in hospitalized neonates and young infants with sepsis derived from the global NeoOBS observational cohort study
Authors: Russell Neal , Stöhr Wolfgang , Cook Aislinn , Berkley James A , Adhisivam Bethou , Agarwal Ramesh , Ahmed Nawshad Uddin , Balasegaram Manica , Chami Neema , Bekker Adrie , Bilardi Davide , Carvalheiro Cristina G. , Chaurasia Suman , Favarin Colas Viviane Rinaldi , Cousens Simon , Dantas de Assis Ana Carolina , Dong Han , Dramowski Angela , Dung Nguyen Trong , Feng Jinxing , Glupczynski Youri , Goel Srishti , Goossens Herman , Huong Hao Doan Thi , Hasan Mahmudul , Huertas Tatiana Munera , Khavessian Nathalie , Kontou Angeliki , Kostyanev Tomislav , Laoyookhon Premsak , Lochindarat Sorasak , De Luca Maia , Malhotra-Kumar Surbhi , Mondal Nivedita , Mundhra Nitu , Musoke Philippa , Mussi-Pinhata Marisa M. , Nanavati Ruchi , Nakwa Firdose L. , Nangia Sushma , Nardone Alessandra , Nyaoke Borna , Obiero Christina W , Ping Wang , Preedisripipat Kanchana , Qazi Shamim , Qi Lifeng , Riddell Amy , Romani Lorenza , Roysuwan Praewpan , Saggers Robin , Saha Samir , Sarafidis Kosmas , Tusibira Valerie , Velaphi Sithembiso , Vilken Tuba , Wang Xiaojiao , Wang Yajuan , Yang Yonghong , Ellis Sally , Bielicki Julia , Walker A Sarah , Heath Paul T. , Sharland Mike 
Published: June 2022

Background

Sepsis severity scores are used in clinical practice and trials to define risk groups. There are limited data to derive hospital-based sepsis severity scores for neonates and young infants in high-burden low- and middle-income country (LMIC) settings where trials are urgently required. We aimed to create linked sepsis severity and recovery scores applicable to hospitalized neonates and young infants in LMIC which could be used to inform antibiotic trials.

Methods & Findings

A prospective observational cohort study was conducted across 19 hospitals in 11 countries in sub-Saharan Africa, Asia, Latin America and Europe. Infants aged <60 days with clinical sepsis fulfilling at least two clinical or laboratory criteria (≥1 clinical) were enrolled. Primary outcome was 28-day mortality. Two prediction models were developed for 1) 28-day mortality from factors at sepsis presentation (baseline NeoSep Severity Score), and 2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation.

3204 infants were enrolled between 2018-2020. Median age was 5 days (IQR 2-15), 90.4% (n=2,895) were <28 days. Median birth weight was 2500g (1400-3000g), and a median of 4 clinical (IQR 2-5) and 1 laboratory (0-2) signs were present. Overall mortality was 11.3% (95%CI 10.2-12.5%; n=350). A baseline NeoSep Severity Score from infants characteristics, respiratory support, and clinical signs (no laboratory tests) at presentation had a C-index 0.77 (95%CI: 0.75-0.80) and 0.76 (0.69-0.82) in derivation and validation samples, respectively. Mortality in the validation sample was 1.6% (3/189; 95%CI: 0.5-4.6%), 11.0% (27/245; 7.7-15.6%), and 27.3% (12/44; 16.3-41.8%) in low (score 0-4), medium (5-8) and high (9-16) risk groups, respectively, with similar performance across subgroups.

A related NeoSep Recovery Score based on evolving post-baseline clinical signs and supportive care discriminated well between infants who died or survived the following day or subsequent few days. The area under the ROC curve for score on day 2 and death in the following 5 days was 0.82 (95%CI 0.78-0.85) and 0.85 (95%CI 0.78-0.93) in the derivation and validation data, respectively.

Conclusion

The baseline NeoSep Severity Score predicted 28-day mortality and could identify infants with high risk of mortality for inclusion in hospital-based sepsis trials. The NeoSep Recovery Score predicts day-by-day inpatient mortality and could, with further validation, help to identify poor response to antibiotics.

Author Summary

Why was this study done?

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Evidence to guide hospital-based antibiotic treatment of sepsis in neonates and young infants is scarce, and clinical trials are particularly urgent in low- and middle-income (LMIC) settings where antimicrobial resistance threatens to undermine existing guidelines

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There is limited data to inform the design of antibiotic trials in LMIC settings, particularly to define risk stratification and inclusion and escalation criteria in hospitalised neonates and young infants

What did the researchers do and find?

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To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with extensive daily data collection on clinical status, antibiotic use and outcomes.

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There was a high mortality among infants with sepsis in LMIC hospital settings. 4 non-modifiable and 6 modifiable factors predicted mortality and were included in a NeoSep Severity score which defines patterns of mortality risk at baseline

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A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during the course of treatment.

What do these findings mean?

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The NeoSep Severity Score and NeoSep Recovery score are now informing inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis

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The NeoSep Severity Score could be used to predict mortality at baseline in future studies of targeting resources in routine care. With further validation, the NeoSep Recovery Score could potentially be used to identify poor response to empiric antibiotic treatment