Paul Newland

Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash

Background: Procalcitonin (PCT), a precursor of calcitonin, is a recognised marker of bacterial sepsis, and high concentrations correlate with the severity of sepsis. PCT has been proposed as an earlier and better diagnostic marker than C reactive protein (CRP) and white cell count (WCC). This comparison has never been reported in the differentiation of meningococcal disease (MCD) in children presenting with a fever and rash. Aim: To determine if PCT might be a useful marker of MCD in children presenting with fever and rash. Methods: PCT, CRP, and WCC were measured on admission in 108 children. Patients were classified into two groups: group I, children with a microbiologically confirmed clinical diagnosis of MCD (n = 64); group II, children with a self limiting illness (n = 44). Median ages were 3.57 (0.07–15.9) versus 1.75 (0.19–14.22) years respectively. Severity of disease in patients with MCD was assessed using the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS). Results: PCT and CRP values were significantly higher in group I than in group II (median 38.85 v 0.27 ng/ml and 68.35 v 9.25 mg/l; p < 0.0005), but there was no difference in WCC between groups. Sensitivity, specificity, and positive and negative predictive values were higher for PCT than CRP and WCC. In group I, procalcitonin was significantly higher in those with severe disease (GMSPS ≥8). Conclusions: PCT is a more sensitive and specific predictor of MCD than CRP and WCC in children presenting with fever and a rash.

Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis

BACKGROUND Respiratory syncytial virus (RSV) bronchiolitis is the most prevalent acute wheezing disorder in infants and is associated with recurrent wheeze and asthma in childhood. Interleukin 9, a type 2 cytokine has been proposed as a key cytokine in susceptibility to asthma. We aimed to investigate whether interleukin 9 was produced in the lungs of infants with severe RSV disease and if found, from which cells it originated. METHODS We did 150 non-bronchoscopic bronchoalveolar lavages during the course of ventilation in 24 term infants and 21 preterm infants ventilated for RSV bronchiolitis. We also did 10 bronchoalveolar lavages on the day of intubation in 10 control infants ventilated for non-respiratory causes. We measured pulmonary interleukin 9 mRNA and protein in samples from all groups. We used immunostaining to identify the cells that produce interleukin 9. FINDINGS Interleukin 9 mRNA expression, which persisted over the course of ventilation, was noted in all infants with bronchiolitis. Three of the control group also showed interleukin 9 mRNA expression. Median interleukin 9 protein concentration on day 1 (1.9 microg/L [range 0.1-36.2]) was significantly greater in term infants with bronchiolitis than either preterm infants (0.4 microg/L [0.1-2.9]; p<0.05) or the control group (0.7 microg/L [0.4-2.5]; p<0.05). There was a trend for interleukin 9 protein concentrations in term, but not preterm infants to decrease over time. Immunostained cell smears showed that most interleukin 9 expression in bronchoalveolar lavage was by neutrophils. INTERPRETATION In term infants with RSV bronchiolitis, we noted large amounts of interleukin 9 mRNA and interleukin 9 protein. Neutrophils seem to be the main source of this type 2 cytokine. Interleukin 9 production by neutrophils may contribute to the pathogenesis of RSV disease. These findings may be relevant to other disease processes in the lung where neutrophils are the predominant inflammatory cell type.

Cardiac troponin T in cord blood

BACKGROUND Perinatal asphyxia is associated with cardiac dysfunction. This may be secondary to myocardial ischaemia. Cardiac troponin T is the ideal marker for myocardial necrosis. Elevated levels in cord blood may be associated with intrauterine hypoxia and increased perinatal morbidity. AIMS To establish an upper limit of normal for cardiac troponin T concentration in the cord blood of infants. Relations between cardiac troponin T levels and other variables were investigated. METHODS Cord blood samples were collected from 242 infants and analysed. Data on gestation, birth weight, sex, Apgar scores, respiratory status, and mode of delivery were recorded. RESULTS A total of 242 samples were collected, and 215 samples from infants without respiratory distress were used to establish the 95th percentile of 0.050 ng/ml. The gestation of these infants ranged from 31 to 42 weeks and birth weight ranged from 1.4 to 5 kg. There were no relations between cardiac troponin T levels and the other variables in these healthy infants. Twenty seven infants developed respiratory symptoms requiring oxygen and/or ventilation. These infants had significantly higher cord cardiac troponin T levels than their healthy counterparts (median (interquartile range) 0.031 (0.010–0.084)v 0.010 (0.010–0.014) ng/ml respectively; p < 0.001). CONCLUSIONS Cardiac troponin T levels in the cord blood are unaffected by gestation, birth weight, sex, or mode of delivery. Infants with respiratory distress had significantly higher cord cardiac troponin T levels, suggesting that cardiac troponin T may be a useful marker for myocardial damage in neonates.

Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.

Objectives: To test the hypothesis that meningococcal septicemia-related pulmonary edema is associated with a systemic abnormality of epithelial sodium and chloride transport and to investigate an association with hormones regulating Na+ transport. Design: Prospective observational study. Setting: The 24-bed pediatric intensive care unit and pediatric wards of Royal Liverpool Childrens Hospital. Patients: Consecutive children admitted to the pediatric intensive care unit and pediatric wards with a diagnosis of meningococcal septicemia and children (controls) with noninfectious critical illness receiving ventilatory support in the pediatric intensive care unit. Measurements and Main Results: We measured sweat and saliva electrolytes, renal electrolyte excretion, nasal potential difference, and aldosterone, thyroxine, and cortisol levels. Pulmonary edema was diagnosed by chest radiography and its severity quantified by calculation of ventilation index at admission and duration of mechanical ventilation. We recruited 17 patients with severe meningococcal septicemia (nine patients with pulmonary edema), 14 patients with mild meningococcal septicemia, and 20 controls. Sweat andsaliva Na+ and Cl− concentrations and renal Na+ excretion were significantly (p < .05) higher in patients with pulmonary edema compared with controls. Nasal potential difference and amiloride response in patients with pulmonary edema were not significantly different to controls, but response to a low Cl− solution was reduced in the nasal airway of patients with pulmonary edema (p < .05). Sweat and saliva chloride concentrations correlated significantly and better with ventilation index and duration of ventilation than sodium concentrations. Aldosterone, thyroxine, and cortisol levels were not significantly different between groups. Conclusions: We have confirmed that meningococcal septicemia-related pulmonary edema is associated with reduced systemic sodium and chloride transport. Features of reduced Cl− transport were most closely associated with markers of respiratory compromise, and this was supported by the reduced chloride channel function detected on nasal potential difference measurement.

The Diagnostic and Prognostic Accuracy of Five Markers of Serious Bacterial Infection in Malawian Children with Signs of Severe Infection

Background Early recognition and prompt and appropriate antibiotic treatment can significantly reduce mortality from serious bacterial infections (SBI). The aim of this study was to evaluate the utility of five markers of infection: C-reactive protein (CRP), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), CD163 and high mobility group box-1 (HMGB1), as markers of SBI in severely ill Malawian children. Methodology and Principal Findings Children presenting with a signs of meningitis (n = 282) or pneumonia (n = 95), were prospectively recruited. Plasma samples were taken on admission for CRP, PCT, sTREM-1 CD163 and HMGB1 and the performance characteristics of each test to diagnose SBI and to predict mortality were determined. Of 377 children, 279 (74%) had SBI and 83 (22%) died. Plasma CRP, PCT, CD163 and HMGB1 and were higher in HIV-infected children than in HIV-uninfected children (p<0.01). In HIV-infected children, CRP and PCT were higher in children with SBI compared to those with no detectable bacterial infection (p<0.0005), and PCT and CD163 were higher in non-survivors (p = 0.001, p = 0.05 respectively). In HIV-uninfected children, CRP and PCT were also higher in children with SBI compared to those with no detectable bacterial infection (p<0.0005), and CD163 was higher in non-survivors (p = 0.05). The best predictors of SBI were CRP and PCT, and areas under the curve (AUCs) were 0.81 (95% CI 0.73–0.89) and 0.86 (95% CI 0.79–0.92) respectively. The best marker for predicting death was PCT, AUC 0.61 (95% CI 0.50–0.71). Conclusions Admission PCT and CRP are useful markers of invasive bacterial infection in severely ill African children. The study of these markers using rapid tests in a less selected cohort would be important in this setting.

Concentrations of cardiac troponin T in neonates with and without respiratory distress

Aims: To establish a practical postnatal reference range for cardiac troponin T in neonates and to investigate concentrations in neonates with respiratory distress. Methods: Prospective investigation in a tertiary neonatal unit, recruiting infants with and without respiratory distress (sick and healthy infants respectively). Concentrations of cardiac troponin T were compared between sick and healthy infants, accounting for confounding variables. Results: A total of 162 neonates (113 healthy and 49 sick infants) had samples taken. The median (interquartile range) cardiac troponin T concentration in the healthy infants was 0.025 (0.01–0.062) ng/ml, and the 95th centile was 0.153 ng/ml. There were no significant relations between cardiac troponin T and various variables. The median (interquartile range) cardiac troponin T concentration in the sick infants was 0.159 (0.075–0.308) ng/ml. This was significantly higher (p < 0.0001) than in the healthy infants. In a linear regression model, the use of inotropes and oxygen requirement were significant associations independent of other basic and clinical variables in explaining the variation in cardiac troponin T concentrations. Conclusions: Cardiac troponin T is detectable in the blood of many healthy neonates, but no relation with important basic and clinical variables was found. Sick infants have significantly higher concentrations than healthy infants. The variations in cardiac troponin T concentration were significantly associated with oxygen requirement or the use of inotropic support in a regression model. Cardiac troponin T may be a useful marker of neonatal and cardiorespiratory morbidity.

Sequential cardiac troponin T following delivery and its relationship with myocardial performance in neonates with respiratory distress syndrome.

We measured serial cardiac troponin T in babies with respiratory distress syndrome and in “healthy” controls (no cardiorespiratory support required). We investigated relationships between cardiac troponin T and myocardial performance in respiratory distress syndrome. This was a prospective observational study at a large tertiary maternity unit that recruited 104 “healthy” babies from whom individual samples were collected. A further 24 infants with respiratory distress syndrome and 14 “healthy” preterm infants had serial sampling over the first three days. We measured fractional shortening in 14 of the infants with respiratory distress syndrome. Cardiac troponin T rose from a median (interquartile range) of 10 (10–11) pg/mL on day one to 34 (22–46) pg/mL by day three, p=0.005, in “healthy” babies. In respiratory distress syndrome levels were higher, 91 (46–135) pg/mL at 6 (5–7) hours of age, p<0.001, and remained so for all three days. In babies with respiratory distress syndrome on day one cardiac troponin T correlated negatively with fractional shortening, Rho=−0.831, p<0.001, but this correlation did not persist. In “healthy” babies there is a minimal rise of cardiac troponin T by day 3. In respiratory distress syndrome there is an early and sustained elevation of cardiac troponin T, with a negative relationship with fraction shortening, suggesting significant myocardial damage of antenatal/intrapartum origin, giving rise to measurable dysfunction.

Cardiac Troponin T levels and myocardial involvement in children with severe respiratory syncytial virus lung disease.

Aims: To determine the prevalence of myocardial damage in severe respiratory syncytial virus (RSV) disease as evident from elevated cardiac Troponin T (cTnT) levels. To assess the nature of the myocardial involvement as manifested in electro‐and echocardiographic abnormalities. To compare severity of disease with and without myocardial involvement as evident from duration of ventilation, inotrope requirements and death. Methods: This was a prospective observational cohort study of children with RSV infection admitted to the paediatric intensive care unit at the Royal Liverpool Childrens Hospital during the winter season 2002/2003. cTnT concentrations were measured using a third generation monoclonal sandwich immunoassay (Roche Diagnostics). Results: 34 children were included in our study. 12 (35%) had elevated cTnT levels. The levels measured after admission had a median [interquartile range (IQR)] of 50 pg/ml (37.5–67.5). There was no significant difference (p > 0.05) between patients with and without elevated cTnT levels with regards to gender, gestational age at birth, history of neonatal intensive care, presence of congenital heart disease, chronic lung disease, inotrope requirements, duration of ventilation, death, fractional shortening on echocardiogram or arrhythmias. Children with elevated cTnT levels were significantly younger [median (IQR): 1.4 months (0.8–2.0)] than children without [median (IQR): 4.0 months (1.7–6.6)] (p= 0.04). The systolic blood pressure on admission was lower in children with increased cTnT compared to those with undetectable cTnT (p= 0.01).

SCAMP : standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care

BackgroundInfants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake.MethodsWe propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational ageTrial registrationCurrent controlled trials: ISRCTN76597892; EudraCT Number: 2008-008899-14

A reference interval for sweat chloride in infants aged between five and six weeks of age

Background This study was designed to establish a reference interval for sweat chloride for infants without evidence of cystic fibrosis (CF), aged between 5 wk and 6 wk, a time when sweat testing is an integral part of newborn screening for CF. In addition, we compared the gold standard method of sweat testing (quantitative pilocarpine iontophoresis [QPIT, coulometry]) with an emerging methodology (Macroduct™ [ISE]). Methods This was a prospective study on healthy infants at 5–6 wk of age. Sweat collection was undertaken at home on both outer thigh areas using two methods (QPIT and Macroduct™). The order of testing was randomly assigned. Filter paper samples (QPIT) were analysed using flame photometry and coulometry. Macroduct™ samples were analysed using ion-selective electrodes (ISE, Abbott Architect c8000, UK). Results Insufficient sweat was collected on 28 occasions with the QPIT (coulometry) method and on 31 with the Macroduct™ (ISE) capillary system. We achieved a 92% success rate in undertaking two sweat collections consecutively (n = 177). Sweat chloride concentrations were normally distributed with excellent limits of agreement between the two methods of sweat collection and analysis (n = 150). Median (IQR) sweat chloride was 11.2 mmol/L (8–13) with QPIT (coulometry) method with a 99.5th centile (n = 165) of 24 mmol/L. Conclusion The Macroduct™ (ISE) capillary sweat collection system is valid in this age group. Sweat chloride concentrations above 30 mmol/L should prompt assessment in a specialist CF centre.