A predominantly anti-inflammatory cytokine profile is associated with disease severity in meningococcal sepsis.

OBJECTIVE: This study aimed to determine whether an anti-inflammatory profile in meningococcal disease is associated with an increased risk of severe disease or septic shock. DESIGN AND SETTING: Prospective observational study in a tertiary care children's hospital. PATIENTS AND PARTICIPANTS: 63 children with confirmed meningococcal disease. INTERVENTIONS: Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF) were assayed on admission. Receiver operator characteristic curve analysis was used to determine optimum thresholds for IL-1Ra:TNF, IL-1Ra:IL-6 and IL-1Ra:IL-8 ratios. MEASUREMENTS AND RESULTS: Median IL-1Ra:TNF and IL-1Ra:IL-6 ratios were significantly higher in severe disease with septic shock than in severe disease without septic shock and in non severe disease (IL-1Ra:TNF 263 vs. 185 vs. 108; IL-1Ra:IL-6 139 vs. 23 vs. 17). Median IL-1Ra:IL-8 ratios were not significantly different in the three groups. A significantly larger proportion of children with high IL-1Ra:TNF-alpha and IL-1Ra:IL-6 ratios developed severe disease with septic shock than those with a low ratios (95.2% vs. 4.8%; 76.2% vs. 23.8%). CONCLUSIONS: An anti-inflammatory profile appears to be associated with the development of severe disease and septic shock in meningococcal sepsis. This may imply that experimental new therapies of pro-inflammatory cytokine inhibition and anti-inflammatory cytokines in meningococcal disease could be detrimental.

Changes in the sublingual microcirculation and endothelial adhesion molecules during the course of severe meningococcal disease treated in the paediatric intensive care unit.

PURPOSE: The sublingual microcirculation can be visualised in real time using sidestream dark-field (SDF) imaging. Endothelial activation mediated through adhesion molecules may alter flow patterns in the microcirculation. We studied sublingual microcirculatory disturbances in children with meningococcal disease (MCD) and simultaneously measured plasma levels of adhesion molecules. METHOD: Twenty children admitted to the paediatric intensive care unit (PICU) with MCD were studied. Forty healthy children were controls. The sublingual microcirculation was assessed at admission and at timed intervals until extubation. The microvascular flow index (MFI), capillary density (CD), proportion of perfused vessels (PPV) and perfused vessel density (PVD) were measured using SDF imaging. Plasma intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin were measured at admission and at timed intervals during the course of PICU treatment. RESULTS: Significant reductions in MFI, CD, PPV and PVD were found in children with MCD compared with controls (p < 0.005). These differences had resolved prior to extubation. Initial MFI values predicted the duration of mechanical ventilation, irrespective of the stage of illness at the time of presentation to PICU. There were negative correlations between the ICAM-1, VCAM-1 and E-selectin levels and the microcirculatory MFI and PPV values at the time of admission to PICU (p < 0.005). CONCLUSIONS: Microcirculatory dysfunction is present in children with severe MCD with improvement alongside clinical recovery. Microcirculatory dysfunction correlated with markers of endothelial activation. Sublingual SDF imaging is feasible in children ventilated on PICU for severe sepsis and may prove useful in studies assessing illness severity and therapy.

Meningococcal disease in children in Merseyside, England: a 31 year descriptive study.

Meningococcal disease (MCD) is the leading infectious cause of death in early childhood in the United Kingdom, making it a public health priority. MCD most commonly presents as meningococcal meningitis (MM), septicaemia (MS), or as a combination of the two syndromes (MM/MS). We describe the changing epidemiology and clinical presentation of MCD, and explore associations with socioeconomic status and other risk factors. A hospital-based study of children admitted to a tertiary children's centre, Alder Hey Children's Foundation Trust, with MCD, was undertaken between 1977 to 2007 (n = 1157). Demographics, clinical presentations, microbiological confirmation and measures of deprivation were described. The majority of cases occurred in the 1-4 year age group and there was a dramatic fall in serogroup C cases observed with the introduction of the meningococcal C conjugate (MCC) vaccine. The proportion of MS cases increased over the study period, from 11% in the first quarter to 35% in the final quarter. Presentation with MS (compared to MM) and serogroup C disease (compared to serogroup B) were demonstrated to be independent risk factors for mortality, with odds ratios of 3.5 (95% CI 1.18 to 10.08) and 2.18 (95% CI 1.26 to 3.80) respectively. Cases admitted to Alder Hey were from a relatively more deprived population (mean Townsend score 1.25, 95% CI 1.09 to 1.41) than the Merseyside reference population. Our findings represent one of the largest single-centre studies of MCD. The presentation of MS is confirmed to be a risk factor of mortality from MCD. Our study supports the association between social deprivation and MCD.

Prognostic value of procalcitonin in children with meningococcal sepsis.

OBJECTIVE: To compare procalcitonin, lactate, and C-reactive protein as prognostic markers in children with meningococcal septic shock. DESIGN: Prospective observational study. SETTING: Alder Hey Children's Hospital, Liverpool, UK. PATIENTS: Children admitted to our hospital during a 16-month period with a diagnosis of meningococcal sepsis. RESULTS: Plasma procalcitonin at admission was significantly higher in children with septic shock (median, 73.80 vs. 16.44 ng/mL), those requiring ventilation (median, 47.02 vs. 12.00 ng/mL), and those with a duration of hospital stay >10 days (median, 131.35 vs. 19.26 ng/mL). Both procalcitonin and lactate reliably discriminated between those children with septic shock (area under the curve [AUC] = 0.85 and 0.84, respectively) and durations of hospital stay exceeding 10 days (AUC = 0.87 and 0.79, respectively) and those without, but C-reactive protein did not. Procalcitonin alone reliably discriminated between those children requiring ventilation and those who did not (AUC = 0.72). CONCLUSION: Procalcitonin is a reliable prognostic marker of septic shock, requirement for ventilation, and prolonged hospital stay in children with meningococcal sepsis and performs better than lactate and C-reactive protein.

Prospective validation of the Glasgow Meningococcal Septicaemia Prognostic Score. Comparison with other scoring methods.

UNLABELLED: A prospective observational study was done to derive performance characteristics for the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS) and compare it with nine other severity scores (Stokland, Stiehm and Damrosch, Ansari, Niklasson, Leclerc, Kahn and Blum, Lewis, Istanbul and Bjark) and laboratory markers of disease severity. In the paediatric departments of six hospitals in Merseyside, UK, 278 children with confirmed or probable meningococcal disease were admitted between November 1988 and August 1990 ( n=152) and between September 1992 and April 1994 ( n=126); 26 of whom died. GMSPS was recorded on admission and again if there was clinical deterioration. Laboratory markers of disease severity (including endotoxin and cytokine levels) were measured on admission. The nine other scores were recorded on the first cohort. "Maximum" GMSPS (before referral to the paediatric intensive care unit) was achieved within 12 h of arrival in 97% of children. A GMSPS > or =8 had sensitivity 100%, specificity 75% and positive predictive value for death of 29%, GMSPS > or =10 had 100%, 88% and 46% respectively. All 26 who died scored >10, before referral to the paediatric intensive care unit. GMSPSs calculated by other medical staff had similar characteristics to those calculated by research fellows. All scores correlated significantly with white cell count, coagulopathy, endotoxin and cytokine levels. However, the predominantly clinical scores were the most robust. GMSPS had amongst the best performance characteristics of all scores and was more sensitive than laboratory markers. CONCLUSION: the Glasgow Meningococcal Septicaemia Prognostic Score is an easily performed, repeatable, clinical score that can rapidly identify children with fulminant meningococcal disease. When performed prospectively, a score > or =8 had a positive predictive value for death of 29%. This score can identify those children who should be offered intensive care and can select those who may benefit from novel therapies.

Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism.

Critical illness outcome may be causally related to inflammatory response severity. Given that tissue angiotensin-converting-enzyme (ACE) regulates such responses and that the deletion (D) [rather than insertion (I)] variant of the ACE gene is associated with higher tissue ACE levels, DD genotype might be associated with a poorer outcome in a uniform infectious disease state. Illness severity (Pediatric RIsk of Mortality score, the Glasgow Meningococcal Septicaemia Prognostic Score [GMSPS], and clinical course) was recorded for consecutive white patients with meningococcal disease (n = 110, 34 DD genotype, 61 male, aged 49.4 +/- 5.4 months) referred to the Royal Liverpool Children's Hospital, UK. Compared with children with > or = I allele, DD genotype was associated with 14% higher predicted risk of mortality (p = 0.038), higher GMSPS (DD 9.4 +/- 0.5, ID/II 7.7+/- 0.4 [mean +/- SEM], p = 0.013), greater prevalence of inotropic support (76% versus 55%, p = 0.03) and ventilation (82% versus 63%, p = 0.04), and longer Pediatric Intensive Care Unit (PICU) stay (5.8 versus 3.9, p = 0.02). DD genotype frequency was 6% (1 case) for the 18 children who did not require PICU care, 33% for the 84 PICU survivors, and 45% for those who died (p = 0.01). ACE DD is associated with increased illness severity in meningococcal disease.