Nelly Ninis

Clinical recognition of meningococcal disease in children and adolescents

BACKGROUND Meningococcal disease is a rapidly progressive childhood infection of global importance. To our knowledge, no systematic quantitative research exists into the occurrence of symptoms before admission to hospital. METHODS Data were obtained from questionnaires answered by parents and from primary-care records for the course of illness before admission to hospital in 448 children (103 fatal, 345 non-fatal), aged 16 years or younger, with meningococcal disease. In 373 cases, diagnosis was confirmed with microbiological techniques. The rest of the children were included because they had a purpuric rash, and either meningitis or evidence of septicaemic shock. Results were standardised to UK case-fatality rates. FINDINGS The time-window for clinical diagnosis was narrow. Most children had only non-specific symptoms in the first 4-6 h, but were close to death by 24 h. Only 165 (51%) children were sent to hospital after the first consultation. The classic features of haemorrhagic rash, meningism, and impaired consciousness developed late (median onset 13-22 h). By contrast, 72% of children had early symptoms of sepsis (leg pains, cold hands and feet, abnormal skin colour) that first developed at a median time of 8 h, much earlier than the median time to hospital admission of 19 h. INTERPRETATION Classic clinical features of meningococcal disease appear late in the illness. Recognising early symptoms of sepsis could increase the proportion of children identified by primary-care clinicians and shorten the time to hospital admission. The framework within which meningococcal disease is diagnosed should be changed to emphasise identification of these early symptoms by parents and clinicians.

The role of healthcare delivery in the outcome of meningococcal disease in children: case-control study of fatal and non-fatal cases

Abstract Objective To determine whether suboptimal management in hospital could contribute to poor outcome in children admitted with meningococcal disease. Design Case-control study of childhood deaths from meningococcal disease, comparing hospital care in fatal and non-fatal cases. Setting National statistics and hospital records. Subjects All children under 17 years who died from meningococcal disease (cases) matched by age with three survivors (controls) from the same region of the country. Main outcome measures Predefined criteria defined optimal management. A panel of paediatricians blinded to the outcome assessed case records using a standardised form and scored patients for suboptimal management. Results We identified 143 cases and 355 controls. Departures from optimal (per protocol) management occurred more frequently in the fatal cases than in the survivors. Multivariate analysis identified three factors independently associated with an increased risk of death: failure to be looked after by a paediatrician, failure of sufficient supervision of junior staff, and failure of staff to administer adequate inotropes. Failure to recognise complications of the disease was a significant risk factor for death, although not independently of absence of paediatric care (P = 0.002). The odds ratio for death was 8.7 (95% confidence interval 2.3 to 33) with two failures, increasing with multiple failures. Conclusions Suboptimal healthcare delivery significantly reduces the likelihood of survival in children with meningococcal disease. Improved training of medical and nursing staff, adherence to published protocols, and increased supervision by consultants may improve the outcome for these children and also those with other life threatening illnesses.

Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children

ObjectiveMeningococcal sepsis invariably is associated with coagulopathy. We have previously reported an association between mortality rate in meningococcal disease and the functional 4G/5G promoter polymorphism of the plasminogen-activator-inhibitor (PAI)-1 gene in a small patient cohort. In a much larger cohort, we aimed to confirm these results and further investigate the role of the 4G/5G polymorphism in determining susceptibility, outcome, and complications of disease. DesignSusceptibility was investigated in two separate studies, a case-control study and a family-based transmission study, each test using a separate patient cohort. Severity was investigated using clinical diagnosis, the presence of vascular complications, Pediatric Risk of Mortality (PRISM)-predicted morality, and actual mortality. SettingUniversity hospital and laboratories. SubjectsSubjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls. InterventionsDNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques. Measurements and Main ResultsPredicted mortality distribution differed significantly between genotypes (p = .05) with a significantly higher median PRISM in the 4G/4G (41.1%) than the 4G/5G (23.4%) and 5G/5G (19.0%) genotyped patients combined (p = .02). Actual mortality rate was significantly associated with both genotype (chi-square = 14.8, p = .001) and allele frequencies (chi-square = 14.0, p < .0001), with more deaths in the 4G/4G (28.4%) than the 4G/5G and 5G/5G genotyped patients combined (14.9%; chi-square = 7.9; p = .005; risk ratio, 1.9; 95% confidence interval, 1.2–3.0). Logistic regression indicated a 40% and 91% reduction in the odds of dying if a patient was either 4G/5G or 5G/5G, respectively, in comparison to a 4G homozygous patient. When analyzed by clinical diagnosis, the association with death was found only in the sepsis group (chi-square = 18.7, p < .0001; risk ratio, 2.7; 95% confidence interval, 1.6–4.6). In survivors of disease, a significantly higher proportion of 4G/4G patients suffered from vascular complications (chi-square = 6.7, p = .03; risk ratio, 2.4; 95% confidence interval, 1.1–5.0). The 4G/5G polymorphism was not associated or linked with susceptibility (case-control result, p = .6; family-based transmission study results, p = .2). ConclusionsThis study confirms that Caucasian pediatric patients carrying the functional PAI-1 4G/4G genotype are at an increased risk of developing vascular complications and dying from meningococcal disease.

The new system of review by multicentre research ethics committees: prospective study

Abstract Objective: To assess the function of the new system of review by multicentre research ethics committees and to highlight areas where improvement is still needed. Design: Prospectively collected data from a multicentre study was examined with respect to the ethics review process. Administrative, financial, and time elements of the review process were audited. Setting: A single multicentre research ethics committee and 125 local ethics committees from six regions of England. Main outcome measures: Time to reply, time to approval, and number of non-local changes to the application requested. Results: Only 40% of local ethics committees considered our study in the manner specified in the 1998 directive. Less than a third of committees replied within the 21 day period stipulated, although committees acting by executive subcommittee replied more quickly than those not acting by executive subcommittee. There was a tendency for executive subcommittees to approve studies in a shorter time. Local ethics committees asked for a large number of non-local changes to the application. The financial cost of applying to multiple ethics committees remains high, mainly because multiple copies of research applications are being requested. Conclusions: The new system of approval by multicentre research ethics committee for multicentre studies was introduced to reduce administrative costs, speed up the process of reviews by multiple research ethics committees, and standardise the conclusions of the local research ethics committees. Since its introduction an improvement has been seen, but the system is not yet universally functioning as intended. Ethics review still remains a hindrance to the financial resources and commencement of national studies. We strongly support the structure of review by multicentre research ethics committees but suggest that the system has yet to achieve its aims.

Parenteral penicillin for children with meningococcal disease before hospital admission: case-control study

Abstract Objective To explore the impact on mortality and morbidity of parenteral penicillin given to children before admission to hospital with suspected meningococcal disease. Design Retrospective comparison of fatal and non-fatal cases. Setting England, Wales, and Northern Ireland; December 1997 to February 1999. Participants 158 children aged 0-16 years (26 died, 132 survived) in whom a general practitioner had made the diagnosis of meningococcal disease before hospital admission. Results Administration of parenteral penicillin by general practitioners was associated with increased odds ratios for death (7.4, 95% confidence interval 1.5 to 37.7) and complications in survivors (5.0, 1.7 to 15.0). Children who received penicillin had more severe disease on admission (median Glasgow meningococcal septicaemia prognostic score (GMSPS) 6.5 v 4.0, P = 0.002). Severity on admission did not differ significantly with time taken to reach hospital. Conclusions Children who were given parenteral penicillin by a general practitioner had more severe disease on reaching hospital than those who were not given penicillin before admission. The association with poor outcome may be because children who are more severely ill are being given penicillin before admission.

Emergency management of meningococcal disease: eight years on

Application of the new edition of the meningococcal treatment algorithm may help in the early management of critically ill patients In 1999, our personal practice article, “Emergency management of meningococcal disease” was printed in this journal1 and, although the journal considered publishing such personal practice statements to be unfashionable,2 it was mostly well received and has since been cited over 60 times. In the original article, we proposed an algorithm for identifying management priorities in treating patients with meningococcal disease, on the basis of our experiences of 425 cases and on the available published evidence wherever possible. During, the past 8 years, over 51 000 copies of the algorithm have been disseminated to accident and emergency departments, intensive care units and paediatric units in the UK and elsewhere by the charity Meningitis Research Foundation. The algorithm has also appeared in several other articles, book chapters and a handbook for junior doctors (35 000 copies distributed and now available at http://www.meningitis.org). It has now been revised for the fifth time and the updated version is included with this perspective (fig 1⇓). Furthermore, a version of the algorithm modified for the management of adults with meningococcal disease has been published3 and an interactive tool designed for education of junior doctors (see http://www.meningitis.org). Figure 1  Algorithm: Early Management of Meningococcal Disease n Children, 5th edition. Copies of the algorithm are available from the Meningitis Research Foundation (http://www.meningitis.org). Several changes have been made since the 1999 edition of the algorithm was published. We still advocate the use of 4.5% human albumin solution as the fluid for volume resuscitation in meningococcal disease in view of the low mortality that we have observed when using this fluid.4 The safety of the use of albumin solution in adults has been confirmed in …

Risk score to stratify children with suspected serious bacterial infection: observational cohort study

Objectives To derive and validate a clinical score to risk stratify children presenting with acute infection. Study design and participants Observational cohort study of children presenting with suspected infection to an emergency department in England. Detailed data were collected prospectively on presenting clinical features, laboratory investigations and outcome. Clinical predictors of serious bacterial infection (SBI) were explored in multivariate logistic regression models using part of the dataset, each model was then validated in an independent part of the dataset, and the best model was chosen for derivation of a clinical risk score for SBI. The ability of this score to risk stratify children with SBI was then assessed in the entire dataset. Main outcome measure Final diagnosis of SBI according to criteria defined by the Royal College of Paediatrics and Child Health working group on Recognising Acute Illness in Children. Results Data from 1951 children were analysed. 74 (3.8%) had SBI. The sensitivity of individual clinical signs was poor, although some were highly specific for SBI. A score was derived with reasonable ability to discriminate SBI (area under the receiver operator characteristics curve 0.77, 95% CI 0.71 to 0.83) and risk stratify children with suspected SBI. Conclusions This study demonstrates the potential utility of a clinical score in risk stratifying children with suspected SBI. Further work should aim to validate the score and its impact on clinical decision making in different settings, and ideally incorporate it into a broader management algorithm including additional investigations to further stratify a childs risk.

Evaluation of temperature–pulse centile charts in identifying serious bacterial illness: observational cohort study

Background Distinguishing serious bacterial infection (SBI) from milder/self-limiting infections is often difficult. Interpretation of vital signs is confounded by the effect of temperature on pulse and respiratory rate. Temperature–pulse centile charts have been proposed to improve the predictive value of pulse rate in the clinical assessment of children with suspected SBI. Objectives To assess the utility of proposed temperature–pulse centile charts in the clinical assessment of children with suspected SBI. Study design and participants The predictive value for SBI of temperature–pulse centile categories, pulse centile categories and Advanced Paediatric Life Support (APLS) defined tachycardia were compared among 1360 children aged 3 months to 10 years presenting with suspected infection to a hospital emergency department (ED) in England; and among 325 children who presented to hospitals in the UK with meningococcal disease. Main outcome measure SBI. Results Among children presenting to the ED, 55 (4.0%) had SBI. Pulse centile category, but not temperature–pulse centile category, was strongly associated with risk of SBI (p=0.0005 and 0.288, respectively). APLS defined tachycardia was also strongly associated with SBI (OR 2.90 (95% CI 1.60 to 5.26), p=0.0002). Among children with meningococcal disease, higher pulse and temperature–pulse centile categories were both associated with more severe disease (p=0.004 and 0.041, respectively). Conclusions Increased pulse rate is an important predictor of SBI, supporting National Institute for Health and Clinical Excellence recommendations that pulse rate be routinely measured in the assessment of febrile children. Temperature–pulse centile charts performed more poorly than pulse alone in this study. Further studies are required to evaluate their utility in monitoring the clinical progress of sick children over time.

G101(P) The 0.12 Formula For the Management of Hypoglycaemia and Hyperglycaemia in Children with Type 1 Diabetes Mellitus: Validation and Safety Data

Background The life of patients with diabetes mellitus is populated with hypo- and hyperglycaemias, both of which are associated with inherent dangers. Existing formulas attempting to quantify patients’ insulin requirements have proved ineffective and rather arbitrary1; they are based on estimations of 24 hour consumptions of insulin and carbohydrates in the average person. Objective This paper tests the effectiveness of the 0.12 formula that is based on patient’s weight and carbohydrates consumption. It calculates glucose and insulin sensitivity and guides the treatment of hypo- and hyperglycaemia, specifically for each patient. Method Data from the Continuous Glucose monitoring system (CGMS) applications and the associated food diary were used to assess the blood sugar achieved after hypo- and hyperglycaemia treatment. This was compared to that expected via the 0.12 formula using the Wilcoxon statistical analysis. Results 20 and 42 patients were assessed for hypoglycaemia and hyperglycaemia respectively. In either treatment, there was no statistically significant difference between expected and achieved blood sugar; p-values were 0.53 and 0.072 respectively. Furthermore, insulin sensitivity derived using the 0.12 formula was compared to that calculated through the historically popular 100 rule1. Wilcoxon statistical analysis showed significant statistical difference between the two formulas; p-value 0.0025, (confidence interval +/- 0.000484). Conclusion This data demonstrates that the proposed formula is safe, reliable and effective for the management of hypo- and hyperglycaemia in children with type I diabetes mellitus and should be implemented widely to improve safe practise. As it is patient specific and user-friendly, it allows patients/parents to feel in control over their diabetes and contributes to overall patient safety. Reference Hanas, R. Type 1 Diabetes in Children, adolescents and young adults. Class Publishing, London 2007.