Zinc-Sepsis

Adjunct Treatment with Zinc for Probable Serious Bacterial Infection in Young Infants – New Evidence from India and Nepal

Each year, almost 3 million infants die within their first two months of life, mainly in South Asia and sub-Saharan Africa. Severe infections, mainly sepsis and pneumonia, are among the leading causes of these young infant deaths. While antibiotics are the mainstay of treatment, they are sometimes not enough to prevent these babies from dying. Furthermore, effective antibiotics are not always accessible or affordable. Zinc, which is an essential nutrient for immune function but which may also have direct pharmacological effects, is beneficial as adjunct treatment of childhood diarrhea, and smaller studies have suggested it might improve survival in young infants with sepsis.

Previous research

In 2012, as the CISMAC collaboration was taking shape, we reported in The Lancet that adding zinc to standard antibiotic treatment reduced the risk of treatment failure in Indian infants up to 4 months of age with probable serious bacterial infection, which we defined as possible serious bacterial infection (PSBI) combined with elevated blood levels of C-reactive protein (CRP >12 mg/L) (1). Such CRP elevation is an indication of extensive inflammation, reflective of a more serious generalized infection. PSBI is a clinical sepsis syndrome with a high case fatality risk (CFR), estimated to be almost 10% in South Asia (2). Our findings contributed to a meta-analysis of zinc supplementation, which suggested that zinc could lower the risk of antibiotic treatment failure in PSBI and possibly death, primarily among young infants with elevated CRP levels, i.e. in those with probable serious bacterial infection (3), which carries a particularly high CFR.

The new trial

From 2017 to 2022, CISMAC conducted the largest randomized trial (the “zinc sepsis trial”) to date assessing whether adding oral zinc to standard antibiotic therapy reduces CFR or treatment failure in 3–59-day-old infants with clinical severe infection (a diagnostic entity very similar to PSBI), across seven hospitals in India and Nepal (4). We enrolled over 3100 infants aged 3–59 days with “clinical severe infection”. All participants received antibiotics; half were randomized to also receive oral zinc for 14 days, the other half to get placebo. In the main analysis, soon to be published in PLOS Medicine, the babies who were randomised to receive zinc had a slightly lower risk of dying (4.1%) than those who received placebo (4.9%) but this difference could well have been due to chance (5). In conclusion, this “negative” trial indicates that adjunct zinc treatment does not reduce the CFR of clinical severe infection in young infants. 

Reanalysis which takes previous evidence into account 

Together with her CISMAC PhD supervisor at the University of Bergen, prospective PhD candidate Ms. Ayushi has recently reanalysed the data using Bayesian statistical methods, which allow combining our results with prior evidence from findings in earlier trials. This provides a fuller picture of the likely true effect of adjunct zinc treatment (6) for PSBI. In this reanalysis, we found a 94% probability that zinc was approximately 20% efficacious in reducing CFR. Among infants with high CRP levels (>10 mg/L), i.e. with an entity very similar to probable serious bacterial infection, the most likely effect was found to be 30%.

Sub-studies and follow-up studies contributing additional scientific and program-relevant information

Building on the zinc sepsis trial, a suite of embedded sub-studies and advanced analyses is broadening scientific impact and research capacity while contributing to training early-career investigators. A mechanistic sub-study profiles immune cells, intracellular zinc, and host gene expression at baseline and 48–72 h thereafter, comparing the participants in the zinc vs. placebo trial arm. In collaboration with Bergen Centre for Ethics and Priority Setting in Health (BCEPS), an equity and economics sub-study leverages the findings of the trial and Bayesian follow-up analysis measure financial risk protection, equity impact, and cost-effectiveness. As part of the economic evaluation work, we have published a paper on hospitalization costs and their determinants in infants with clinical severe infection at a public tertiary hospital in Nepal (7); the equity manuscript is in preparation, and the financial risk protection analysis is underway.

Methodological work includes (i) Bayesian re-analysis of time-to-event outcomes using informative priors; (ii) development of internally validated risk-prediction models for in-hospital death and treatment failure to support triage and targeted adjunct zinc therapy; and (iii) the above-mentioned UiB PhD project (Ms. Ayushi) for developing a novel data-driven prior-elicitation framework using optimization algorithms and/or machine learning to select and validate optimal prior distributions. The application of this framework to the trial will serve as a case study, to inform future Bayesian analyses.

Together, these efforts are broadening the translational value of the trial, building a durable cadre of investigators and promoting further scientific development in the field.

Summary of findings

These updated findings suggest that oral adjunct zinc treatment is unlikely to substantially reduce case fatality risk among all young infants with clinical signs of sepsis, i.e. with PSBI. They also indicate that those with probable serious bacterial infection, i.e. those who also have laboratory findings of generalized bacterial infection, may benefit substantially from such adjunct treatment. Our studies also illustrate how more sophisticated statistical approaches can better use all available evidence and spur further research.

References

 1. Bhatnagar S, Wadhwa N, Aneja S, Lodha R, Kabra SK, Natchu UCM, Sommerfelt H, Dutta AK, Chandra J, Rath B, Sharma M, Sharma VK, Kumari M, Strand TA. Zinc as adjunct treatment in infants aged between 7 and 120 days with probable serious bacterial infection: a randomised, double-blind, placebo-controlled trial. (external link) Lancet. 2012 Jun 2;379:2072–2078. doi:10.1016/S0140-6736(12)60477-2. Available from: https://doi.org/10.1016/S0140-6736(12)60477-2 (external link)

 2. Seale AC, Blencowe H, Manu AA, Nair H, Bahl R, Qazi SA, Zaidi AK, Berkley JA, Cousens SN, Lawn JE, Campbell H; pSBI Investigator Group. 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 (external link). Lancet Infect Dis. 2014;14:731–41. doi:10.1016/S1473-3099(14)70804-7. 
Available from: https://www.thelancet.com/action/showPdf?pii=S1473-3099%2814%2970804-7 (external link)

 3. Irfan O, Black RE, Lassi ZS, Bhutta ZA. Zinc supplementation and the prevention and treatment of sepsis in young infants: a systematic review and meta-analysis (external link). Neonatology. 2022;119:164–75. doi:10.1159/000518891. 
Available from: https://karger.com/neo/article-pdf/119/2/164/3757412/000521275.pdf (external link)

 4. Nitya Wadhwa, Sudha Basnet, Uma Chandra Mouli Natchu, Laxman P Shrestha, Shinjini Bhatnagar, Halvor Sommerfelt, Tor A Strand; the zinc sepsis study group, Siddarth Ramji, K C Aggarwal, Harish Chellani, Anuradha Govil, Mamta Jajoo, N B Mathur, Meenakshi Bhatt, Anup Mohta, Imran Ansari, Srijana Basnet, Ram H Chapagain, Ganesh P Shah, Binod M Shrestha. Zinc as an adjunct treatment for reducing case fatality due to clinical severe infection in young infants: study protocol for a randomized controlled trial. (external link) BMC Pharmacol Toxicol 2017 Jul 10;18:56. doi: 10.1186/s40360-017-0162-5. 
Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5504606/pdf/40360_2017_Article… (external link)

 5. Wadhwa N, Sinha A, Basnet S, Arya S, Singh R, Jajoo M, Ayushi, Sharma D, Kumar A, Pemde HK, Singh V, Chapagain RH, Govil A, Purakayastha DR, Shah GP, Mittal M, Shrestha LP, Chellani H, Sommerfelt H, Strand TA, Bhatnagar S and and the Zinc sepsis study group. Zinc as adjunct treatment for suspected clinical severe infection in young infants: a randomized double-blind placebo-controlled trial in India and Nepal (external link). PLOS Medicine. 2025. 

 6. Ayushi, Desiraju BK, Sinha A, Sharma D, Basnet S, Arya S, Singh R, Jajoo M, Thiruvengadam R, Sommerfelt H, Bhatnagar S, Wadhwa N, Strand TA, and the Zinc Sepsis Study Group. Zinc as an adjunct treatment for clinical severe infection in young infants: A Bayesian reanalysis of a randomised controlled trial. 2025. Manuscript in preparation. 

 7. Suchita Shrestha, Ram Hari Chapagain, Debjani Ram Purakayastha, Srijana Basnet, Nitya Wadhwa, Tor A. Strand, Sudha Basnet. Assessment of hospitalization costs and its determinants in infants with clinical severe infection at a public tertiary hospital in Nepal (external link). PLoS One. 2021. Nov29;16:e0260127.doi:10.1371/journal.pone.0260127. eCollection 2021.

Principal Investigators:
Nitya Wadhwa (external link), Translational Health Science and Technology Institute (THSTI), India
Tor A. Strand, Innlandet Hospital Trust and University of Bergen, Norway