Hugh S. Lam

Diagnostic markers for neonatal sepsis

Purpose of review To review the current evidence on the use of infection markers for diagnostic evaluation of sepsis in neonates. Recent findings Recent research in immunology has led to the discovery of cell surface antigens, chemokines, cytokines and acute phase proteins that can potentially be used to ‘rule in’ or ‘rule out’ sepsis. The diagnostic utilities of key inflammatory mediators, including CD11b, CD64, interleukin-6 and interleukin-8, are promising and likely to become increasingly used as markers of infection for both diagnostic and prognostic purposes. Summary Serial measurements and use of combinations of markers have been reported to improve sensitivity and negative predictive value of these tests. Current markers are not infallible, however, and do not permit neonatologists to withhold antibiotics in sick infants with suspected infection. Thus, many have emerged as useful indicators for early discontinuation of unnecessary antimicrobial therapy. Some infection markers are also useful for identifying infants with severe infection and adverse prognosis. Advances in flow cytometry have allowed simultaneous measurement of key markers using only minimal blood volume. Judicious selection of a panel of markers with complementary properties could greatly increase the ability of neonatologists to diagnose infection and discern valuable prognostic information.

The impact of psychological abuse by an intimate partner on the mental health of pregnant women

Objective  The objective of this first population‐based study in Hong Kong was to assess the impact of psychological abuse by an intimate partner on the mental health of pregnant women.

Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants

Preterm infants are highly susceptible to life-threatening infections that are clinically difficult to detect, such as late-onset septicemia and necrotizing enterocolitis (NEC). Here, we used a proteomic approach to identify biomarkers for diagnosis of these devastating conditions. In a case-control study comprising 77 sepsis/NEC and 77 nonsepsis cases (10 in each group being monitored longitudinally), plasma samples collected at clinical presentation were assessed in the biomarker discovery and independent validation phases. We validated the discovered biomarkers in a prospective cohort study with 104 consecutively suspected sepsis/NEC episodes. Proapolipoprotein CII (Pro-apoC2) and a des-arginine variant of serum amyloid A (SAA) were identified as the most promising biomarkers. The ApoSAA score computed from plasma apoC2 and SAA concentrations was effective in identifying sepsis/NEC cases in the case-control and cohort studies. Stratification of infants into different risk categories by the ApoSAA score enabled neonatologists to withhold treatment in 45% and enact early stoppage of antibiotics in 16% of nonsepsis infants. The negative predictive value of this antibiotic policy was 100%. The ApoSAA score could potentially allow early and accurate diagnosis of sepsis/NEC. Upon confirmation by further multicenter trials, the score would facilitate rational prescription of antibiotics and target infants who require urgent treatment.

Biochemical markers of neonatal sepsis

The use of biochemical markers in neonatal infection has remained an important area of research in the past decades. Many infection markers are components of the inflammatory cascade and reflect the hosts immunological status and response to infection. Cytokines and chemokines such as interleukin (IL)-6 and IL-8 have been demonstrated to have good diagnostic utilities as early phase markers, while acute phase reactants such as C-reactive protein and procalcitonin have superior diagnostic properties during the later phases. Other markers, including inter-alpha-inhibitor proteins, IL-10 and regulated upon activation normal T cells expressed and secreted (RANTES) have been demonstrated to yield important prognostic information and may help the clinician identify infants who will develop fulminant infection from the outset of presentation. The advent of flow cytometry and molecular techniques have made crucial contributions to the field and promise to further improve the diagnostic accuracy and clinical management of infected infants.

Rescue treatment of infants with intestinal failure and parenteral nutrition-associated cholestasis (PNAC) using a parenteral fish-oil-based lipid

Four preterm infants with intestinal failure and severe parenteral nutrition-associated cholestasis (PNAC) received fish-oil-based parenteral lipid as rescue treatment in substitution for the standard soybean-based lipid preparation. The progression of liver disease was halted in 3 infants and they recovered with complete resolution of PNAC. The condition in two of these infants would almost certainly have progressed to end-stage hepatic failure if they had continued to receive long-term parenteral nutrition and <30% of total nutrition enterally. The remaining infant with residual inflamed bowel, protracted feeding intolerance and repeated episodes of sepsis did not respond. Our findings suggest that fish-oil-based parenteral lipid emulsion may contribute to effective treatment of PNAC in selected patients, which should be further evaluated in randomized controlled trials.

High-Dose Oral Erythromycin Decreased the Incidence of Parenteral Nutrition-Associated Cholestasis in Preterm Infants

Background & Aims: Feeding intolerance because of functional gastrointestinal dysmotility and parenteral nutrition-associated cholestasis (PNAC) are common problems in preterm, very-low-birth-weight (VLBW) infants. This double-blind, randomized, placebo-controlled study aimed to assess the effectiveness of “high-dose” oral erythromycin as a prokinetic agent in decreasing the incidence of PNAC. Two secondary end points, including the time to achieve full enteral feeding and the duration of parenteral nutrition, were also evaluated. Methods: Infants consecutively admitted to the neonatal unit were randomized to receive erythromycin (12.5 mg/kg/dose every 6 hours for 14 days) or an equivalent volume of normal saline (placebo) if they attained less than half the total daily fluid intake (<75 mL/kg/day) as milk feeds on day 14 of life. Results: Of 182 VLBW infants enrolled, 91 received erythromycin. The incidence of PNAC was significantly lower in erythromycin-treated infants (18/91) compared with placebo infants (37/91; P = .003). Treated infants achieved full enteral nutrition significantly earlier (mean, 10.1; SE, 1.7 days; P < .001), and the duration of parenteral nutrition was also significantly decreased by 10 days (P < .001). Importantly, fewer infants receiving erythromycin had 2 or more episodes of septicemia (n = 4) compared with placebo patients (n = 13, P = .03). No serious adverse effect was associated with erythromycin treatment. Conclusions: High-dose oral erythromycin can be considered as a rescue measure for VLBW infants who fail to establish adequate enteral nutrition and in whom anatomically obstructive pathologies of the gastrointestinal tract have been excluded.

Biomarkers for Late-Onset Neonatal Sepsis: Cytokines and Beyond

Acute phase reactants, pro and antiinflammatory mediators including chemokines and cytokines, and cell-surface antigens are nonspecific biomarkers that have been extensively studied for the diagnosis and management of late-onset neonatal sepsis (LONS) and necrotizing enterocolitis. It is expected that the next generation of biomarkers and tests will be more specific, will pinpoint the precise disease entity, and will provide crucial information on the exact pathogen or category of microorganism and its antibiotic profile within hours of clinical presentation. Research on molecular pathogen detection and proteomic profiling has shown promising results. Academic-industry partnerships are vital for successful development of new diagnostic biomarkers for LONS, which are sensitive, inexpensive, fully automated, and easy to measure, allowing a quick turnaround time for clinical decision making.

Renal screening in children after exposure to low dose melamine in Hong Kong: cross sectional study

Objective To investigate the renal outcomes of children after exposure to low dose melamine in Hong Kong. Design Cross sectional study. Setting Special assessment centres, Hong Kong. Participants 3170 children (1422 girls and 1748 boys) aged 12 years or less referred from territory-wide primary care clinics after daily consumption for one month or more of milk products tainted with melamine. Main outcome measures Presence of renal stones and haematuria. Results One child had a confirmed renal stone, seven were suspected of having melamine related renal deposits, and 208 (6.6%) were positive for blood in urine by reagent strip. A proportion of these children were followed up at the special assessment centre, but only 7.4% of those positive for blood on reagent strip were confirmed by microscopy, suggesting an overall estimated prevalence of less than 1% for microscopic haematuria. Conclusions No severe adverse renal outcomes, such as acute renal failure or urinary tract obstruction, were detected in children after exposure to low dose melamine. Our results were similar to territory-wide findings in Hong Kong. Even including the seven children with suspected renal deposits, the prevalence of suspected melamine related abnormalities on ultrasonography was only 0.2%. None of these children required specific treatment. The prevalence of microscopic haematuria was probably overestimated by the reagent strip. These data suggest that large scale and urgent screening programmes may not be informative or cost effective for populations who have been exposed to low dose melamine.

Attitudes Toward Neonatal Intensive Care Treatment of Preterm Infants With a High Risk of Developing Long-term Disabilities

OBJECTIVES. To assess (1) the differences in attitudes toward disabilities of 3 groups of subjects involved in neonatal care decision-making: health care workers, mothers of term infants, and parents of preterm infants, and (2) the impact of subject characteristics on these attitudes including parental education level, religion, and severity of disability. METHODS. Five hundred seventy-eight subjects were interviewed, of whom 135 were health care workers, 155 were mothers of term infants, and 288 were parents of preterm infants. We assessed between-group differences of the (1) health state ranking permutations, (2) proportion of subjects willing to save the infant at all costs, (3) pivotal risks of each group to the 5 health states comprising varying combinations of mental, physical, and social disabilities, and (4) impact of personal characteristics on decision-making. RESULTS. Most health care workers ranked the most severe disability health state as worse than death, whereas most parents of preterm infants ranked death as the worst outcome. Significantly more parents of preterm infants chose to save the infant at all costs, compared with mothers of term infants and health care workers, and the pivotal risks of the parents of preterm infants group were highest for all health states. Religious worship was associated with increased probability of saving at all costs and pivotal risks. Increased severity of neonatal complications was associated with decreased probability of saving at all costs and pivotal risks in parents of preterm infants. CONCLUSIONS. Our findings suggest that parents of preterm infants as a group were most likely to save the infant at all costs and prepared to tolerate more severe disability health states. However, personal characteristics, in particular religious belief and severity of neonatal complications, have overriding influence on these attitudes. We suggest inclusion of experienced parents of preterm infants for more effective counseling of parents in making life-and-death decisions.

Gut-associated biomarkers L-FABP, I-FABP, and TFF3 and LIT score for diagnosis of surgical necrotizing enterocolitis in preterm infants.

Objectives: To evaluate the use of gut barrier proteins, liver-fatty acid binding protein (L-FABP), intestinal-fatty acid binding protein (I-FABP), and trefoil factor 3 (TFF3), as biomarkers for differentiating necrotizing enterocolitis (NEC) from septicemic/control infants and to identify the most severely affected surgical NEC from nonsurgical NEC infants. Background: Clinical features and routine radiologic investigations have low diagnostic utilities in identifying surgical NEC patients. Methods: The diagnostic utilities of individual biomarkers and the combination of biomarkers, the LIT score, were assessed among the NEC (n = 20), septicemia (n = 40), and control groups (n = 40) in a case-control study for the identification of proven NEC and surgical NEC infants. Results: Plasma concentrations of all gut barrier biomarkers and the LIT score were significantly higher in the NEC than in the septicemia or control group (P < 0.01). Using median values of biomarkers and the LIT score in the NEC group as cutoff values for identifying NEC from septicemic/control cases, all had specificities of 95% or more and sensitivities of 50%. Significantly higher levels of biomarkers and the LIT score were found in infants with surgical NEC than in nonsurgical NEC cases (P ⩽ 0.02). The median LIT score of 4.5 identified surgical NEC cases with sensitivity and specificity of 83% and 100%%, respectively. A high LIT score of 6 identified nonsurvivors of NEC with sensitivity and specificity of 78% and 91%, respectively. Conclusions: The LIT score can effectively differentiate surgical NEC from nonsurgical NEC infants and nonsurvivors of NEC from survivors at the onset of clinical presentation. Frontline neonatologists and surgeons may, therefore, target NEC infants who are most in need of close monitoring and those who may benefit from early surgical intervention.