Sepsis, defined as a “life-threatening organ dysfunction caused by a dysregulated host-response to infection” is a major health issue worldwide and still lacks a fully elucidated pathobiology and uniform diagnostic tests. The trace element zinc is known to be crucial to ensure an appropriate immune response. During sepsis a redistribution of zinc from serum into the liver has been observed and several studies imply a correlation between zinc and sepsis outcome. Therefore the alterations of zinc concentrations in different tissues might serve as one part of the host’s defense mechanism against pathogens during sepsis by diverse mechanisms. It has been suggested that zinc is involved in nutritional immunity, acts as a hepatoprotective agent, or a differentiation signal for innate immune cells, or supports the synthesis of acute phase proteins. Further knowledge about these events could help in the evaluation of how zinc could be optimally applied to improve treatment of septic patients. Moreover, the changes in zinc homeostasis are substantial and correlate with the severity of the disease, suggesting that zinc might also be useful as a diagnostic marker for evaluating the severity and predicting the outcome of sepsis.

Zinc and Sepsis.

Background Sepsis remains the largest preventable source of neonatal mortality in the world. Heart rate variability (HRV) analysis and noninvasive cardiac output have been shown to be useful adjuncts to sepsis detection in many patient groups. Methods With Institutional Review Board approval, 4 septic and 6 nonseptic extremely low birth weight patients were enrolled. Data from septic and healthy patients were collected for 5 hours. Electrocardiogram waveform and traditional vital signs were collected and the RR intervals were calculated; then HRV analysis was performed in both the time and frequency domain. Results HRV measurements in time domain, heart rate, and pulse oximetry (SpO2) were significantly different in septic patients vs nonseptic controls. Conclusions These results indicate that nonconventional vital signs such as HRV are more sensitive than traditionally used vital signs, such as cardiac output and mean arterial pressure, in the confirmation of sepsis in extremely low birth weight neonates. HRV may allow for earlier identification of septic physiology.

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Heart rate variability analysis is more sensitive at identifying neonatal sepsis than conventional vital signs

Sepsis is a life-threating condition with dysregulated systemic host response to microbial pathogens leading to disproportionate inflammatory response and multi-organ failure. Various biomarkers are available for the diagnosis and prognosis of sepsis; however, these laboratory parameters may show limitations in these severe clinical conditions. MicroRNAs (miRNA) are single-stranded non-coding RNAs with the function of post-transcriptional gene silencing. They normally control numerous intracellular events, such as signaling cascade downstream of Toll-like receptors (TLRs) to avoid excessive inflammation after infection. In contrast, abnormal miRNA expression contributes to the development of sepsis correlating with its clinical features and outcomes. Based on recent clinical studies altered levels of circulating miRNAs can act as potential diagnostic and prognostic biomarkers in sepsis. In this review, we summarized the available data about TLR-mediated inflammatory signaling with its intracellular response in immune cells and platelets upon sepsis, which are, at least in part, under the regulation of miRNAs. Furthermore, the role of circulating miRNAs is also described as potential laboratory biomarkers in sepsis.

Role of sepsis modulated circulating microRNAs.

To evaluate the efficacy of short term zinc supplementation on the mortality rate and neurodevelopment outcome in neonates with sepsis at 12 mo corrected age. The clinical trial was undertaken in the neonatal intensive care unit of JIPMER during the time period from September 2013 through December 2016. Neonates with clinical manifestations of sepsis who exhibited two positive screening tests (microESR, C- reactive protein, band cell count) were included and randomized into no zinc and zinc group. The intervention was zinc sulfate monohydrate given at a dose of 3 mg/kg twice a day orally for 10 d along with standard antibiotics. The no zinc group was on antibiotic treatment. Blood samples from both groups were collected at baseline and after day 10. Babies were carefully discharged from the hospital. The babies were followed up till 12 mo corrected age using DASII (Development Assessment Scale for Indian Infants). At the time of enrolment, patient characteristics were similar in both the groups. The mortality rate was significantly higher in no zinc compared to zinc group (5 vs. 13; P = 0.04). Although motor development quotient was similar, mental development quotient was significantly better among babies who received zinc supplementation. Short term zinc supplementation of newborns with sepsis reduces mortality and improves mental development quotient at 12 mo of age.

Short Term Oral Zinc Supplementation among Babies with Neonatal Sepsis for Reducing Mortality and Improving Outcome - A Double-Blind Randomized Controlled Trial.

This manuscript includes (1) a narrative review of Zinc as an essential nutrient for fetal and neonatal growth and brain growth and development and (2) a scoping review of studies assessing the effects of Zinc supplementation on survival, growth, brain growth, and neurodevelopment in neonates. Very preterm infants and small for gestational age infants are at risk for Zinc deficiency. Zinc deficiency can cause several complications including periorificial lesions, delayed wound healing, hair loss, diarrhea, immune deficiency, growth failure with stunting, and brain atrophy and dysfunction. Zinc is considered essential for oligodendrogenesis, neurogenesis, neuronal differentiation, white matter growth, and multiple biological and physiological roles in neurobiology. Data support the possibility that the critical period of Zinc delivery for brain growth in the mouse starts at 18 days of a 20-21-day pregnancy and extends during lactation and in human may start at 26 weeks of gestation and extend until at least 44 weeks of postmenstrual age. Studies are needed to better elucidate Zinc requirement in extremely low gestational age neonates to minimize morbidity, optimize growth, and brain growth, prevent periventricular leukomalacia and optimize neurodevelopment. IMPACT: Zinc is essential for growth and brain growth and development. In the USA, very preterm small for gestational age infants are at risk for Zinc deficiency. Data support the possibility that the critical period of Zinc delivery for brain growth in the mouse starts at 18 days of a 20-21-day pregnancy and extends during lactation and in human may start at 26 weeks' gestation and extend until at least 44 weeks of postmenstrual age. Several randomized trials of Zinc supplementation in neonates have shown improvement in growth when using high enough dose, for long duration in patients likely to or proven to have a Zinc deficiency. Studies are needed to better elucidate Zinc requirement in extremely low gestational age neonates to minimize morbidity, optimize growth and brain growth, prevent periventricular leukomalacia and optimize neurodevelopment.

Role of zinc in neonatal growth and brain growth: review and scoping review

The high mortality rate of neonatal sepsis is directly connected with time-consuming diagnostic methods that have low sensitivity and specificity. The need of the hour is to develop novel diagnostic techniques that are rapid and more specific. In this study, we estimated the expression levels of circulating microRNAs (miRNAs) that are involved in regulating immune response genes and underlying inflammatory responses, which may be used for sepsis diagnosis. The total circulating miRNA was isolated and the candidate miRNAs (miR-132, miR-146a, miR-155, and miR-223) were quantified by real-time polymerase chain reaction technique. Statistical analysis revealed that miR-132 (P < .01) and miR-223 (P < .05) were downregulated in septic newborns compared with healthy babies. The decrease in expression of miR-132 and miR-223 may be associated with increased expression of immune-related genes involved in TLR (Toll-like receptor) signaling pathway. Further case-control studies with large sample size are required to identify the potential of miRNAs in neonatal sepsis diagnosis.

https://journals.sagepub.com/doi/pdf/10.1177/1178631018797079

Expression Levels of Candidate Circulating microRNAs in Early-Onset Neonatal Sepsis Compared With Healthy Newborns.

To find the effect of zinc supplementation on the outcome of neonatal sepsis at one month of age. This randomized controlled trial was conducted in a tertiary care neonatal unit, enrolling neonates with clinical features of sepsis and positive blood culture or positive sepsis screening tests. The treatment group received 3 mg/kg/twice a day of zinc sulfate monohydrate orally for 10 d along with standard antibiotic therapy. The control group received standard antibiotic treatment without zinc. Samples were collected from both the groups before and after the treatment. Babies were monitored till discharge and followed up as out-patients till one month of age. Demographic characteristics were similar between the cases and controls. After 10 d of treatment, the mean serum zinc level between the two groups was 737.09 ± 219.97 vs. 801.26 ± 405.56, (p = 0.20). Outcome measures like days of hospital stay (15 vs. 15; p = 0.69) and mortality rate (4.5 % vs. 13.6 %; p = 0.27) were not found to be significantly different between the groups. At one month of age, more number of control neonates had abnormal neurological findings as compared to the zinc supplemented group [(P = 0.02); RR (95%CI) = 0.28 (0.11–0.73)]. Zinc supplementation in neonates with sepsis improves the neurological status at one month of age although the mortality reduction was not statistically significant.

Effect of Zinc Supplementation on Early Outcome of Neonatal Sepsis - A Randomized Controlled Trial

Sepsis is associated with exacerbated inflammatory response which subsequently results in multiple organ dysfunction. Sepsis accounts for high mortality and morbidity among newborns worldwide. Narciclasine is a plant alkaloid which has shown to possess anti-inflammatory properties. In this study we investigated the effect and mechanism of action of narciclasine in neonatal sepsis rat models. The excessive release of S100A8/A9 or calprotectin in neonatal sepsis could be detrimental as it could exacerbate the inflammatory responses. We found that narciclasine significantly reduced the plasma levels of S100A8/A9 and also suppressed its expression in the liver and lung. The systemic and local bacterial load was also reduced in the narciclasine treated rats. The systemic and local production of pro-inflammatory cytokines in plasma and organs (liver and lungs) was significantly reduced in the narciclasine treated rats. The histopathological studies showed that narciclasine prevents the organ damage associated with sepsis and improved the survival of neonatal rats. Sepsis increased the phosphorylated NF-κβ p65 protein expression in the liver. Narciclasine suppressed the phosphorylation of NF-κβ p65 and the degradation of NF-κβ inhibitory protein alpha. It could also suppress the expression of adaptor proteins of the toll like receptor signaling pathway viz., myeloid differentiation factor 88 (MyD88), Interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6). These results suggest that narciclasine protects against sepsis in neonatal rats through the inhibition of calprotectin, pro-inflammatory cytokines and suppression of NF-κβ signaling pathway.

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Narciclasine improves outcome in sepsis among neonatal rats via inhibition of calprotectin and alleviating inflammatory responses.

To find out whether gDNA methylation can be used as a diagnostic/prognostic method for neonatal sepsis. The study was conducted in the neonatal division of a tertiary care referral hospital. Fifty one newborns as cases and thirty seven newborns as controls were enrolled in the study. Using 5-mC DNA ELISA method, the percentage of genomic DNA methylated in these newborns was established. Highly significant difference in percentage of gDNA methylated was found between the cases and controls (Cases: 2.4 ± 0.39; Controls: 2.07 ± 0.35; P < 0.0001). Culture proven and possible cases were also significantly distinguishable (P < 0.05). No significant differences in methylation were observed in terms of gestational age, birth weight and outcomes such shock, thrombocytopenia, except for renal failure. The index results showed that genomic DNA methylation varies significantly among newborns with sepsis (clinical, probable and culture positive) and without sepsis. Although the global DNA methylation was not a highly sensitive diagnostic method, this study reveals that DNA methylation might play a vital role in neonatal sepsis susceptibility. Identification of the specific differentially methylated genes might serve as a promising future diagnostic/prognostic marker for neonatal sepsis.

Global DNA Methylation in Neonatal Sepsis

The era of personalized medicine has already begun and now it is time to initiate personalized prevention strategies against diseases. Infectious diseases have a higher mortality than any other illness, especially in developing countries. Among newborns and young children the situation is even worse. The microorganisms are becoming resistant to almost all known antibiotics. Hence, it is imperative to improve the preventive strategies against infections. 'Pathogens are everywhere, but not every individual is getting diseased,' - this basic logical thinking needs to look into the genetic predisposition/host susceptibility to sepsis. Interestingly, genetic studies have shown that the type of infecting organism, outcome of infections, and mortality can be predetermined by analyzing an individual's genome. Exploration of inter-individual genetic variations and their association with sepsis will help in the development of new prognostic markers to provide novel personalized therapeutics and predict the outcome. In this review article, we discuss the genetic variations and their association with sepsis, studied by various researchers in different regions.

Benet Bosco Dhas

Papers

Expression Levels of Candidate Circulating microRNAs in Early-Onset Neonatal Sepsis Compared With Healthy Newborns.

Effect of Zinc Supplementation on Early Outcome of Neonatal Sepsis - A Randomized Controlled Trial

Narciclasine improves outcome in sepsis among neonatal rats via inhibition of calprotectin and alleviating inflammatory responses.

Global DNA Methylation in Neonatal Sepsis

Sepsis genomics: Stepping forward toward sepsis prevention?