Zinc as adjunct treatment for clinical severe infection in young infants: A randomized double-blind placebo-controlled trial in India and Nepal

Abstract

Background: Annually, an estimated 2.3 million infants die within their first month of life, primarily in sub-Saharan Africa and South Asia. Infections, including sepsis are among the major contributors to these deaths. Effective interventions added to standard antimicrobial therapy can reduce sepsis mortality. A recent meta-analysis suggests that adjunct zinc treatment of young infants with sepsis could reduce case fatality risk. This study evaluated the efficacy of zinc as an adjunct to antibiotics in young infants with suspected sepsis, defined as clinical severe infection (CSI).

Methods and findings: We conducted a randomized, double-blind, placebo-controlled trial across seven hospitals in India and Nepal from February 28, 2017, to February 22, 2022. Infants aged 3-59 days hospitalized with suspected sepsis, defined as CSI, adapted from the WHO Integrated Management of Childhood Illness (IMCI) criteria, were randomly assigned to receive 10 mg of elemental zinc daily or placebo orally for 14 days, in addition to standard of care. The primary outcomes were death during hospitalization and death within 12 weeks after enrollment. Among 3,153 enrolled infants (1,203 [38%] females), the median age at enrollment was 25 days (interquartile range 13-41 days), and the mean weight was 2.9 kg (standard deviation 0.8). During the hospital stay, 64 (4.1%) of 1,576 infants died in the zinc arm compared to 77 (4.9%) of 1,577 in the placebo arm (relative risk [RR] 0.83 (95% CI [0.60, 1.15]; p = 0.267)). Among those who completed 12 weeks of follow-up, 140 of 1,554 infants (9.0%) died in the zinc arm, and 133 of 1,550 (8.6%) in the placebo arm (RR 1.05 (95% CI [0.84, 1.32]; p = 0.674)). Adverse events were similar across trial arms, except for a slight increase in vomiting in the zinc arm; no events were attributed to the intervention. The main limitation of the study is that it was underpowered due to lower-than-anticipated event rates and a shortfall in the achieved sample size.

Conclusions: In this setting, we found little evidence for an effect of adjunct zinc therapy on young infants with CSI on the risk of dying during hospitalization or for the subsequent 3 months. Our findings contrast previous studies that used more specific case definitions. This underscores the need for further RCTs to evaluate the effect of zinc in young infant sepsis before it can be recommended in treatment guidelines.

Trial registration: Clinical Trials Registry-India (CTRI/2017/02/007966) on February 27, 2017, and Universal Trial Number is U1111-1187-6479.

Fig 1. Study flowchart.

Fig 2. Kaplan–Meier curves of mortality and recovery in young infants with clinical severe infection.

Time-to-event analyses using a Cox proportional hazards regression model. (A) Time-to-death until the end of 12-week study period in the zinc arm (n = 1,576) compared with placebo (n = 1,577). Median (IQR) time to death: zinc, 18 days (6–37 days); placebo, 12 days (4–32 days). Hazard ratio (HR) 1.05 (95% CI [0.83, 1.33]; p = 0.681). (B) Time-to-recovery from clinical severe infection in the zinc arm (n = 1,576) compared with placebo (n = 1,577). Median (IQR) time to recovery: zinc, 1.46 days (0.77–3.20 days); placebo, 1.36 days (0.75–3.07 days). HR 0.97 (95% CI [0.90, 1.04]; p = 0.340).

Fig 3. Subgroup analyses of death in young infants with clinical severe infection.

The figure depicts prespecified and post-hoc subgroup analyses of death during hospitalization and death in the 12-week study period in young infants with clinical severe infection. Risk difference (RD) with 95% CI is derived from generalized linear models of the binomial family with the identity link function. (A) Prespecified subgroup analyses for death during hospitalization. Infants were classified as sepsis positive if they had presence of either: (i) positive blood culture with potentially pathogenic bacteria, or (ii) positive septic screen, indicated by any two or more of the following laboratory parameters: total leucocyte count <5 × 10⁹ cells/L; absolute neutrophil count <1.5 × 10⁹ cells/L; band cell to neutrophil ratio >0.2; micro ESR >15mm in the first hour; and C-reactive protein levels >10 mg/L. (B) Post-hoc subgroup analyses for death during hospitalization by baseline characteristics. (C) Prespecified subgroup analyses for death in the 12-week study period. Infants were classified as sepsis positive if they had presence of either: (i) positive blood culture with potentially pathogenic bacteria, or (ii) positive septic screen, indicated by any two or more of the following laboratory parameters: total leucocyte count <5 × 10⁹ cells/L; absolute neutrophil count <1.5 × 10⁹ cells/L; band cell to neutrophil ratio >0.2; micro ESR >15 mm in the first hour; and C-reactive protein levels >10 mg/L. (D) Post-hoc subgroup analyses for death in the 12-week study period.