[Serious complications of chickenpox: healthy children are at risk as well]. / Ernstige complicaties van waterpokken.

Three immunocompetent children were admitted to the hospital because of varicella-related complications. The first patient developed a bacterial pneumonia secondary to a varicella infection which ultimately lead to a debridement using Video Assisted Thoracoscopic Surgery. The second patient presented with a left peripheral facial paralysis and vesicular lesions in de left auricle. Liquor investigations were positive for the varicella zoster virus and she was diagnosed with Ramsay Hunt syndrome. The last patient was referred to the emergency department with possible absence seizures. These seizures turned out to be caused by an ischemic stroke due to post-varicella arteriopathy. All patients were previously healthy and had no risk factors for varicella-related complications. We conclude that varicella-related complications should also be considered in immunocompetent children, even when the primary infection took place months ago. Patients with severe varicella-related complications need to be referred to a medical specialist where anti-viral therapy should be considered.

Circulating nucleosomes and severity of illness in children suffering from meningococcal sepsis treated with protein C.

OBJECTIVE: Cell death leading to circulating nucleosomes and histones is a critical step in the pathogenesis of sepsis and contributes to lethality. Activated protein C was demonstrated to attenuate the harmful effects of histones. The objective of this retrospective study was to evaluate whether nucleosomes correlate with the severity of the inflammatory response and mortality in children suffering from severe meningococcal sepsis. Furthermore, we wanted to study the effects of infusion of protein C on nucleosome levels in children with septic purpura. DESIGN: Retrospective analysis of nucleosome levels in children suffering from meningococcal sepsis treated with either placebo or protein C. SETTING: Pediatric intensive care unit of a tertiary care university center. PATIENTS: In a randomized, placebo-controlled study, either protein C or placebo was administered to 38 children suffering from meningococcal sepsis. Nucleosome levels have been measured retrospectively in these 38 children suffering from meningococcal sepsis. MEASUREMENTS AND MAIN RESULTS: Twenty-eight children were treated with protein C and 10 received placebo. Nucleosome levels were significantly higher in nonsurvivors (n = 9) at any time point measured as compared to survivors (n = 29). Nucleosome levels significantly correlated with organ dysfunction scores, cytokines, and parameters for coagulation. Patients treated with protein C had significantly higher activated protein C levels than children receiving placebo. We could not find a clear effect of activated protein C on nucleosome levels in these patients. CONCLUSION: Circulating nucleosomes correlated with the severity of the inflammatory response and were associated with mortality in children suffering from meningococcal sepsis. We show that protein C administration does not decrease nucleosome levels in these patients.

CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity.

INTRODUCTION: Chemokines are a superfamily of small peptides involved in leukocyte chemotaxis and in the induction of cytokines in a wide range of infectious diseases. Little is known about their role in meningococcal sepsis in children and their relationship with disease severity and outcome. METHODS: Monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP) 1alpha, growth-related gene product (GRO)-alpha and interleukin (IL)-8 were measured in 58 children with meningococcal sepsis or septic shock on admission and 24 hours thereafter. Nine patients died. Serum chemokine levels of survivors and nonsurvivors were compared, and the chemokine levels were correlated with prognostic disease severity scores and various laboratory parameters. RESULTS: Extremely high levels of all chemokines were measured in the children's acute-phase sera. These levels were significantly higher in nonsurvivors compared with survivors and in patients with septic shock compared with patients with sepsis (P < 0.0001). The cutoff values of 65,407 pg/ml, 85,427 pg/ml and 460 pg/ml for monocyte chemoattractant protein, for IL-8 and for macrophage inflammatory protein 1alpha, respectively, all had 100% sensitivity and 94-98% specificity for nonsurvival. Chemokine levels correlated better with disease outcome and severity than tumor necrosis factor (TNF)-alpha and correlated similarly to interleukin (IL)-6. In available samples 24 hours after admission, a dramatic decrease of chemokine levels was seen. CONCLUSION: Initial-phase serum levels of chemokines in patients with meningococcal sepsis can predict mortality and can correlate strongly with disease severity. Chemokines may play a key role in the pathophysiology of meningococcal disease and are potentially new targets for therapeutic approaches.

Serum lipids and disease severity in children with severe meningococcal sepsis.

OBJECTIVE: To evaluate the role of cholesterol and lipoproteins in children with severe meningococcal sepsis. DESIGN: Retrospective observational study. SETTING: A university-affiliated pediatric intensive care unit. PATIENTS: Fifty-seven patients admitted to the pediatric intensive care unit with meningococcal sepsis or septic shock. INTERVENTIONS: Total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) concentrations were measured in serum samples drawn within 6 hrs after admission to the pediatric intensive care unit and 12, 24, 48, 72 hrs, 7 days, and 1-3 months afterward. Standard deviation scores of these variables (sd scores) were calculated to correct for age-related differences. To assess disease severity, the Pediatric Risk of Mortality (PRISM) score, the Sepsis-related Organ Failure Assessment (SOFA) score, and the Disseminated Intravascular Coagulation (DIC) score were determined as well as selected laboratory variables. MEASUREMENTS AND MAIN RESULTS: Ten patients died. Total serum cholesterol on admission was very low in all patients. This hypocholesterolemia was caused by low HDL concentrations but in particular by low LDL cholesterol levels. Eight patients had undetectable LDL levels on admission. Total cholesterol levels were significantly lower in nonsurvivors than in survivors (0.97 vs. 1.60, p = .013), whereas levels of LDL and HDL did not significantly differ between both groups. Total cholesterol sd scores were similar between survivors and nonsurvivors. Within survivors, cholesterol sd score was significantly lower in patients with shock compared with those with sepsis. The total cholesterol, HDL, and LDL levels correlated with clinical variables of disease severity and with levels of cytokines. Total cholesterol, HDL, and LDL levels normalized rapidly in survivors and were completely normal 1-3 months after admission. CONCLUSIONS: Extremely low levels of total serum cholesterol, HDL, and LDL are found in the initial phase of children with severe meningococcal disease. Total cholesterol levels are significantly lower in nonsurvivors than in survivors, but not the sd score. Total cholesterol, HDL, and LDL levels on admission are inversely associated with disease severity. Hypocholesterolism is associated with hypocortisolism. The concentrations of total cholesterol and lipoproteins steadily increase after 24 hrs in survivors and are normalized 1-3 months after pediatric intensive care unit admission.

Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study.

BACKGROUND: Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial. METHODS: Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products. RESULTS: Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes. CONCLUSIONS: Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.

Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease.

OBJECTIVES: To study the correlation between serum concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in relation to severity of disease in children with meningococcal sepsis. METHODS: Subjects were children with meningococcal sepsis, admitted to the pediatric intensive care unit. Clinical data, laboratory values and blood samples were selected. Arterial cortisol, ACTH, interleukin 6 and tumor necrosis factor alpha concentrations were measured on admission and studied for their relation to severity of disease (sepsis, septic shock/survivors, septic shock/nonsurvivors). RESULTS: Seventy-two patients fulfilled the criteria for meningococcal sepsis. Sixty-two of these children with positive blood cultures of Neisseria meningitidis, who were not treated with corticosteroids before admission, were included. Fifty of the 62 patients had septic shock. Twelve of those children (24%) died. The median age of the subjects was 2.6 years (range, 0.3 to 16.1 years). Cortisol values were significantly lower in non-survivors (median, 654 nmol/l) than in survivors (median, 2184 nmol/l) (P < 0.01). ACTH values were significantly higher in children who died (median, 1271 ng/l) than in survivors (85 ng/l) (P < 0.01). The median cortisol:ACTH ratio decreased significantly depending on the disease severity categories. CONCLUSIONS: Low serum cortisol concentrations in combination with high ACTH concentrations are associated with poor outcome in children with severe meningococcal disease.