Enitan D. Carrol

Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease

Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D<E), P = 2.2 × 10−11) and in CFH-related protein 3 (CFHR3)(rs426736, P = 4.6 × 10−13). N. meningitidis is known to evade complement-mediated killing by the binding of host CFH to the meningococcal factor H–binding protein (fHbp). Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen.

Procalcitonin as a marker of sepsis

Prompt diagnosis and treatment with appropriate antimicrobial chemotherapy is of paramount importance to reduce morbidity and mortality associated with sepsis. Inflammatory markers currently in use, such as C-reactive protein (CRP) do not reliably differentiate between the systemic inflammatory response and sepsis. Procalcitonin (PCT), a precursor of calcitonin, is a 116 amino acid protein that has been proposed as a marker of disease severity in conditions such as septicaemia, meningitis, pneumonia, urinary tract infection (UTI) and fungal and parasitic infection. In particular, serial measurements are useful in order to monitor response to therapy. Together with good clinical judgement and judicious use of antimicrobial agents, PCT should serve as a valuable adjunct in the diagnosis and management of sepsis.

High pneumococcal DNA loads are associated with mortality in malawian children with invasive pneumococcal disease

Background: In bacteremia owing to Streptococcus pneumoniae, high bacterial counts at presentation have been shown to be predictive of the development of serious invasive disease. Using real-time PCR, we aimed to determine pneumococcal DNA loads in blood and CSF, and their relationship to cytokine concentrations, clinical presentation and outcome. Methods: Children with confirmed meningitis (n = 82) or pneumonia (n = 13) were prospectively recruited, and blood and CSF samples taken for pneumococcal bacterial DNA loads and cytokine determination. Results: At the time of admission, the median bacterial load in blood was 1.6 × 103 DNA copies/mL (range 0.00–1.54 × 106) and in CSF it was 5.77 × 107 DNA copies/mL (range 4.42 × 102 to 6.15 × 108). Median blood and CSF bacterial loads (log DNA copies/mL) were significantly higher in nonsurvivors than in survivors; blood (3.80 vs. 2.97, P = 0.003), CSF (8.17 vs. 7.50, P = 0.03). In HIV-infected children (n = 59), blood and CSF loads and plasma tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6 and IL-10 were all significantly higher in nonsurvivors than in survivors, but in HIV-uninfected children (n = 36) this difference was not significant. Blood bacterial loads and plasma cytokine concentrations were significantly associated, and were all significantly higher in children with meningitis than in those with pneumonia. In children with meningitis, median CSF cytokine concentrations were significantly higher than median plasma cytokine concentrations (P < 0.001) and CSF bacterial loads were significantly associated with CSF IL-1β (P = 0.002) and IL-10 (P = 0.001) concentrations. Conclusions: Pneumococcal DNA loads are associated with plasma cytokine concentrations, and are higher in meningitis than in pneumonia. High blood and CSF pneumococcal DNA loads are associated with a fatal outcome.

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.

Pathophysiology of meningococcal sepsis in children.

Abstract Septic shock with purpura is a syndrome frequently diagnosed in children and predominantly caused by Neisseria meningitidis. Despite improvements in management and therapy the mortality and morbidity in these patients are still high. During the last few years much effort has been put into understanding of the systemic host response during this acute infectious disease. This host response can be divided into the process of recognition of endotoxin, the cascade of pro- and counter inflammatory mediators, the endothelial damage resulting in capillary leakage and inappropriate vascular tone, and the procoagulant state. Conclusion This paper reviews the recent insights in the pathophysiology of the host response and their possible consequences for novel therapies in meningococcal sepsis.

The role of angiogenic factors in predicting clinical outcome in severe bacterial infection in Malawian children.

IntroductionSevere sepsis is a disease of the microcirculation, with endothelial dysfunction playing a key role in its pathogenesis and subsequent associated mortality. Angiogenesis in damaged small vessels may ameliorate this dysfunction. The aim of the study was to determine whether the angiogenic factors (vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin-1 (Ang-1) and -2 (Ang-2)) are mortality indicators in Malawian children with severe bacterial infection.MethodsIn 293 children with severe bacterial infection, plasma VEGF, PDGF, FGF, and Ang-1 and Ang-2 were measured on admission; in 50 of the children with meningitis, VEGF, PDGF, and FGF were also measured in the CSF. Healthy controls comprised children from some of the villages of the index cases. Univariable and multivariable logistic regression analyses were performed to develop a prognostic model.ResultsThe median age was 2.4 years, and the IQR, 0.7 to 6.0 years. There were 211 children with bacterial meningitis (72%) and 82 (28%) with pneumonia, and 154 (53%) children were HIV infected. Mean VEGF, PDGF, and FGF concentrations were higher in survivors than in nonsurvivors, but only PDGF remained significantly increased in multivariate analysis (P = 0.007). Mean Ang-1 was significantly increased, and Ang-2 was significantly decreased in survivors compared with nonsurvivors (6,000 versus 3,900 pg/ml, P = 0.03; and 7,700 versus 11,900 pg/ml, P = 0.02, respectively). With a logistic regression model and controlling for confounding factors, only female sex (OR, 3.95; 95% CI, 1.33 to 11.76) and low Ang-1 (OR, 0.23; 95% CI, 0.08 to 0.69) were significantly associated with mortality. In children with bacterial meningitis, mean CSF VEGF, PDGF, and FGF concentrations were higher than paired plasma concentrations, and mean CSF, VEGF, and FGF concentrations were higher in nonsurvivors than in survivors (P = 0.02 and 0.001, respectively).ConclusionsLower plasma VEGF, PDGF, FGF, and Ang-1 concentrations and higher Ang-2 concentrations are associated with an unfavorable outcome in children with severe bacterial infection. These angiogenic factors may be important in the endothelial dysregulation seen in severe bacterial infection, and they could be used as biomarkers for the early identification of patients at risk of a poor outcome.

Neurological Manifestations of Influenza Infection in Children and Adults: Results of a National British Surveillance Study

BACKGROUND The emergence of influenza A(H1N1) 2009 was met with increased reports of associated neurological manifestations. We aimed to describe neurological manifestations of influenza in adults and children in the United Kingdom that presented at this time. METHODS A 2-year surveillance study was undertaken through the British adult and pediatric neurological surveillance units from February 2011. Patients were included if they met clinical case definitions within 1 month of proven influenza infection. RESULTS Twenty-five cases were identified: 21 (84%) in children and 4 (16%) in adults. Six (29%) children had preexisting neurological disorders. Polymerase chain reaction of respiratory secretions identified influenza A in 21 (81%; 20 of which [95%] were H1N1) and influenza B in 4 (15%). Twelve children had encephalopathy (1 with movement disorder), 8 had encephalitis, and 1 had meningoencephalitis. Two adults had encephalopathy with movement disorder, 1 had encephalitis, and 1 had Guillain-Barré syndrome. Seven individuals (6 children) had specific acute encephalopathy syndromes (4 acute necrotizing encephalopathy, 1 acute infantile encephalopathy predominantly affecting the frontal lobes, 1 hemorrhagic shock and encephalopathy, 1 acute hemorrhagic leukoencephalopathy). Twenty (80%) required intensive care, 17 (68%) had poor outcome, and 4 (16%) died. CONCLUSIONS This surveillance study described a cohort of adults and children with neurological manifestations of influenza. The majority were due to H1N1. More children than adults were identified; many children had specific encephalopathy syndromes with poor outcomes. None had been vaccinated, although 8 (32%) had indications for this. A modified classification system is proposed based on our data and the increasing spectrum of recognized acute encephalopathy syndromes.

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.

Ten years of surveillance for invasive Streptococcus pneumoniae during the era of antiretroviral scale-up and cotrimoxazole prophylaxis in Malawi.

Objective To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis. Methods Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection. Results 4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearsons correlation r = −0.91; p<0.001). Conclusion During 2004–2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes.

Susceptibility to invasive bacterial infections in children with sickle cell disease

Individuals with sickle cell disease (SCD) demonstrate an increased susceptibility to invasive bacterial infections (IBI). The most common organisms causing IBI are Streptococcus pneumoniae, nontyphi Salmonella species and Haemophilus influenzae type b (Hib). IBI are the most common causes of death in children below 5 years of age with SCD. Increased susceptibility to IBI is because of several factors including dysfunctional antibody production and opsonophagocytosis as well as defective splenic clearance. Early diagnosis of Hib and pneumococcal infections combined with antibiotic prophylaxis and immunization programs, could lead to significant improvements in mortality, especially in Africa. Pediatr Blood Cancer. 2010;55:401–406.