The Diverse Spectrum of Invasive Meningococcal Disease in Pediatric and Adolescent Patients: Narrative Review of Cases and Case Series.

INTRODUCTION: Invasive meningococcal disease (IMD) is a potentially life-threatening disease caused by Neisseria meningitidis infection. We reviewed case reports of IMD from newborns, infants, children, and adolescents, and described the real-life clinical presentations, diagnoses, treatment paradigms, and clinical outcomes. METHODS: PubMed and Embase were searched for IMD case reports on patients aged ≤ 19 years published from January 2011 to March 2023 (search terms "Neisseria meningitidis" or "invasive meningococcal disease", and "infant", "children", "paediatric", pediatric", or "adolescent"). RESULTS: We identified 97 publications reporting 184 cases of IMD, including 25 cases with a fatal outcome. Most cases were in adolescents aged 13-19 years (34.2%), followed by children aged 1-5 years (27.6%), children aged 6-12 years (17.1%), infants aged 1-12 months (17.1%), and neonates (3.9%). The most common disease-causing serogroups were W (40.2%), B (31.7%), and C (10.4%). Serogroup W was the most common serogroup in adolescents (17.2%), and serogroup B was the most common in the other age groups, including children aged 1-5 years (11.5%). The most common clinical presentations were meningitis (46.6%) and sepsis (36.8%). CONCLUSIONS: IMD continues to pose a threat to the health of children and adolescents. While this review was limited to case reports and is not reflective of global epidemiology, adolescents represented the largest group with IMD. Additionally, nearly half of the patients who died were adolescents, emphasizing the importance of monitoring and vaccination in this age group. Different infecting serogroups were predominant in different age groups, highlighting the usefulness of multivalent vaccines to provide the broadest possible protection against IMD. Overall, this review provides useful insights into real-life clinical presentations, treatment paradigms, diagnoses, and clinical outcomes to help clinicians diagnose, treat, and, ultimately, protect patients from this devastating disease.

Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial.

BACKGROUND: Fluid resuscitation is the recommended management of shock, but increased mortality in febrile African children in the FEAST trial. We hypothesised that fluid bolus-induced deaths in FEAST would be associated with detectable changes in cardiovascular, neurological, or respiratory function, oxygen carrying capacity, and blood biochemistry. METHODS: We developed composite scores for respiratory, cardiovascular, and neurological function using vital sign data from the FEAST trial, and used them to compare participants from FEAST with those from four other cohorts and to identify differences between the bolus (n=2097) and no bolus (n=1044) groups of FEAST. We calculated the odds of adverse outcome for each ten-unit increase in baseline score using logistic regression for each cohort. Within FEAST participants, we also compared haemoglobin and plasma biochemistry between bolus and non-bolus patients, assessed the effects of these factors along with the vital sign scores on the contribution of bolus to mortality using Cox proportional hazard models, and used Bayesian clustering to identify subgroups that differed in response to bolus. The FEAST trial is registered with ISRCTN, number ISRCTN69856593. FINDINGS: Increasing respiratory (odds ratio 1·09, 95% CI 1·07-1·11), neurological (1·26, 1·21-1·31), and cardiovascular scores (1·09, 1·05-1·14) were associated with death in FEAST (all p<0·0001), and with adverse outcomes for specific scores in the four other cohorts. In FEAST, fluid bolus increased respiratory and neurological scores and decreased cardiovascular score at 1 h after commencement of the infusion. Fluid bolus recipients had mean 0·33 g/dL (95% CI 0·20-0·46) reduction in haemoglobin concentration after 8 h (p<0·0001), and at 24 h had a decrease of 1·41 mEq/L (95% CI 0·76-2·06; p=0·0002) in mean base excess and increase of 1·65 mmol/L (0·47-2·8; p=0·0070) in mean chloride, and a decrease of 0·96 mmol/L (0·45 to 1·47; p=0·0003) in bicarbonate. There were similar effects of fluid bolus in three patient subgroups, identified on the basis of their baseline characteristics. Hyperchloraemic acidosis and respiratory and neurological dysfunction induced by saline or albumin bolus explained the excess mortality due to bolus in Cox survival models. INTERPRETATION: In the resuscitation of febrile children, albumin and saline boluses can cause respiratory and neurological dysfunction, hyperchloraemic acidosis, and reduction in haemoglobin concentration. The findings support the notion that fluid resuscitation with unbuffered electrolyte solutions may cause harm and their use should be cautioned. The effects of lower volumes of buffered solutions should be evaluated further. FUNDING: Medical Research Council, Department for International Development, National Institute for Health Research, Imperial College Biomedical Research Centre.

Exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type.

PURPOSE: To explore exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type and to explore patient experiences of physiotherapy. METHODS: A cross sectional questionnaire survey design was used to collect quantitative and qualitative data from adult members of the Hypermobility Syndromes Association and Ehlers-Danlos Syndrome Support UK. Descriptive and inferential statistics were used to analyse the data. Qualitative data was analysed thematically. RESULTS: 946 questionnaires were returned and analysed. Participants who received exercise advice from a physiotherapist were 1.75 more likely to report high volumes of weekly exercise (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.30-2.36, p < 0.001) than those with no advice. Participants who believed that exercise is important for long-term management were 2.76 times more likely to report a high volume of weekly exercise compared to the participants who did not hold this belief (OR = 2.76, 95% CI = 1.38-5.50, p = 0.004). Three themes emerged regarding experience of physiotherapy; physiotherapist as a partner, communication - knowledge, experience and safety. CONCLUSION: Pain, fatigue and fear are common barriers to exercise. Advice from a physiotherapist and beliefs about the benefits of exercise influenced the reported exercise behaviours of individuals with Ehlers-Danlos syndrome - hypermobility type in this survey. Implications for rehabilitation Exercise is a cornerstone of treatment for Ehlers-Danlos syndrome/Ehlers-Danlos syndrome - hypermobility type. Pain, fatigue and fear of injury are frequently reported barriers to exercise. Advice from physiotherapists may significantly influence exercise behaviour. Physiotherapists with condition specific knowledge and good verbal and non-verbal communication facilitate a positive therapeutic experience.

Invasive Meningococcal Disease in the Vaccine Era.

Infection with the meningococcus is one of the main causes of meningitis and septicaemia worldwide. Humans are the only natural reservoir for the meningococcus which is found primarily as a commensal inhabitant in the nasopharynx in ~10% of adults, and may be found in over 25% of individuals during adolescence. Prompt recognition of meningococcal infection and early aggressive treatment are essential in order to reduce mortality, which occurs in up to 10% of those with invasive meningococcal disease (IMD). This figure may be significantly higher in those with inadequate or delayed treatment. Early administration of effective parenteral antimicrobial therapy and prompt recognition and appropriate management of the complications of IMD, including circulatory shock and raised intracranial pressure (ICP), are critical to help improve patient outcome. This review summarizes clinical features of IMD and current treatment recommendations. We will discuss the evidence for immunization and effects of vaccine strategies, particularly following implementation of effective vaccines against Group B meningococcus.

Effect of a Pediatric Early Warning System on All-Cause Mortality in Hospitalized Pediatric Patients: The EPOCH Randomized Clinical Trial.

Importance: There is limited evidence that the use of severity of illness scores in pediatric patients can facilitate timely admission to the intensive care unit or improve patient outcomes. Objective: To determine the effect of the Bedside Paediatric Early Warning System (BedsidePEWS) on all-cause hospital mortality and late admission to the intensive care unit (ICU), cardiac arrest, and ICU resource use. Design, Setting, and Participants: A multicenter cluster randomized trial of 21 hospitals located in 7 countries (Belgium, Canada, England, Ireland, Italy, New Zealand, and the Netherlands) that provided inpatient pediatric care for infants (gestational age ≥37 weeks) to teenagers (aged ≤18 years). Participating hospitals had continuous physician staffing and subspecialized pediatric services. Patient enrollment began on February 28, 2011, and ended on June 21, 2015. Follow-up ended on July 19, 2015. Interventions: The BedsidePEWS intervention (10 hospitals) was compared with usual care (no severity of illness score; 11 hospitals). Main Outcomes and Measures: The primary outcome was all-cause hospital mortality. The secondary outcome was a significant clinical deterioration event, which was defined as a composite outcome reflecting late ICU admission. Regression analyses accounted for hospital-level clustering and baseline rates. Results: Among 144 539 patient discharges at 21 randomized hospitals, there were 559 443 patient-days and 144 539 patients (100%) completed the trial. All-cause hospital mortality was 1.93 per 1000 patient discharges at hospitals with BedsidePEWS and 1.56 per 1000 patient discharges at hospitals with usual care (adjusted between-group rate difference, 0.01 [95% CI, -0.80 to 0.81 per 1000 patient discharges]; adjusted odds ratio, 1.01 [95% CI, 0.61 to 1.69]; P = .96). Significant clinical deterioration events occurred during 0.50 per 1000 patient-days at hospitals with BedsidePEWS vs 0.84 per 1000 patient-days at hospitals with usual care (adjusted between-group rate difference, -0.34 [95% CI, -0.73 to 0.05 per 1000 patient-days]; adjusted rate ratio, 0.77 [95% CI, 0.61 to 0.97]; P = .03). Conclusions and Relevance: Implementation of the Bedside Paediatric Early Warning System compared with usual care did not significantly decrease all-cause mortality among hospitalized pediatric patients. These findings do not support the use of this system to reduce mortality. Trial Registration: clinicaltrials.gov Identifier: NCT01260831.

Clinical Characteristics and Risk Factors for Poor Outcome in Infants Less Than 90 Days of Age With Bacterial Meningitis in the United Kingdom and Ireland.

BACKGROUND: To describe the clinical characteristics and risk factors associated with poor outcome in infants <90 days of age with bacterial meningitis. METHODS: Prospective, enhanced, national population-based active surveillance for infants <90 days of age with bacterial meningitis in the United Kingdom and Ireland between July 2010 and July 2011. Infants were identified through the British Paediatric Surveillance Unit, laboratory surveillance and meningitis charities. RESULTS: Clinical details was available for 263 of 298 (88%) infants where a bacterium was identified, 184 (70%) were born at term. Fever was reported in 143 (54%), seizures in 73 (28%), bulging fontanelle in 58 (22%), coma in 15 (6%) and neck stiffness in 7 (3%). Twenty-three (9%) died and 56/240 (23%) of the survivors had serious central nervous system complications at discharge. Temperature instability [odds ratio (OR), 2.99; 95% confidence interval (CI): 1.21-7.41], seizures (OR, 7.06; 95% CI: 2.80-17.81), cerebrospinal fluid protein greater than the median concentration (2275 mg/dL; OR, 2.62; 95% CI: 1.13-6.10) and pneumococcal meningitis (OR, 4.83; 95% CI: 1.33-17.58) were independently associated with serious central nervous system complications while prematurity (OR, 5.84; 95% CI: 2.02-16.85), low birthweight (OR, 8.48; 95% CI: 2.60-27.69), coma at presentation (OR, 31.85; 95% CI: 8.46-119.81) and pneumococcal meningitis (OR, 4.62; 95% CI: 1.19-17.91) were independently associated with death. CONCLUSIONS: The classic features of meningitis were uncommon. The presentation in young infants is often nonspecific, and only half of cases presented with fever. A number of clinical and laboratory factors were associated with poor outcomes; further research is required to determine how knowledge of these risk factors might improve clinical management and outcomes.

Assessment of healthcare delivery in the early management of bacterial meningitis in UK young infants: an observational study.

OBJECTIVE: To define early presenting features of bacterial meningitis in young infants in England and to review the adequacy of individual case management as compared with relevant national guidelines and an expert panel review. DESIGN: Retrospective medical case note review and parental recall using standardised questionnaires. SETTING: England and Wales. PARTICIPANTS: Infants aged <90 days with bacterial meningitis diagnosed between July 2010 and July 2013. RESULTS: Of the 97 cases recruited across England and Wales, 66 (68%) were admitted from home and 31 (32%) were in hospital prior to disease onset. Almost all symptoms reported by parents appeared at the onset of the illness, with very few new symptoms appearing subsequently. Overall, 20/66 (30%) infants were assessed to have received inappropriate prehospital management. The median time from onset of first symptoms to first help was 5 hours (IQR: 2-12) and from triage to receipt of first antibiotic dose was 2.0 hours (IQR: 1.0-3.3), significantly shorter in infants with fever or seizures at presentation compared with those without (1.7 (IQR: 1.0-3.0) vs 4.2 (IQR: 1.8-6.3) hours, p=0.02). Overall, 26 (39%) infants had a poor outcome in terms of death or neurological complication; seizures at presentation was the only significant independent risk factor (OR, 7.9; 95% CI 2.3 to 207.0). For cases in hospital already, the median time from onset to first dose of antibiotics was 2.6 (IQR: 1.3-9.8) hours, and 12/31 (39%) of infants had serious neurological sequelae at hospital discharge. Hearing test was not performed in 23% and when performed delayed by ≥4 weeks in 41%. CONCLUSIONS: In young infants, the non-specific features associated with bacterial meningitis appear to show no progression from onset to admission, whereas there were small but significant differences in the proportion of infants with more specific symptoms at hospital admission compared with at the onset of the illness, highlighting the difficulties in early recognition by parents and healthcare professionals alike. A substantial proportion of infants received inappropriate prehospital and posthospital management. We propose a targeted campaign for education and harmonisation of practice with evidence-based management algorithms.

The influence of joint hypermobility on functional movement control in an elite netball population: A preliminary cohort study.

OBJECTIVES: To ascertain the prevalence of General Joint Hypermobility (GJH) and Joint Hypermobility Syndrome (JHS) in elite level netballers. To investigate whether GJH influences functional movement control and explore whether symptoms of dysautonomia are reported in this population. DESIGN: Observational within-subject cross-sectional design. SETTING: Field based study. PARTICIPANTS: 27 elite level netballers (14-26 years). MAIN OUTCOME MEASURES: GJH and JHS were assessed using the Beighton scale, 5 point questionnaire and the Brighton Criteria. Functional movement control was measured using posturography on a force platform and the Star Excursion Balance Test (SEBT). RESULTS: The prevalence of GJH was 63% (n = 17) (Beighton score ≥4/9) and JHS was 15% (n = 4). Symptoms of dysautonomia were minimally prevalent. A trend was observed in which participants with GJH demonstrated increased postural instability on the functional tests. Following Bonferroni adjustment, this was statistically significant only when comparing posturographic data between the distinctly hypermobile participants and the rest of the group for path area (p = 0.002) and velocity (p = 0.002) on the left side. CONCLUSIONS: A high prevalence of GJH was observed. A trend towards impairment of functional movement control was observed in the netballers with GJH. This observation did not reach statistical significance except for posturographic path area and velocity.

Incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United kingdom and Republic of Ireland: prospective, enhanced, national population-based surveillance.

BACKGROUND: Bacterial meningitis remains a major cause of morbidity and mortality in young infants. Understanding the epidemiology and burden of disease is important. METHODS: Prospective, enhanced, national population-based active surveillance was undertaken to determine the incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United Kingdom and Ireland. RESULTS: During July 2010-July 2011, 364 cases were identified (annual incidence, 0.38/1000 live births; 95% confidence interval [CI], .35-.42). In England and Wales, the incidence of confirmed neonatal bacterial meningitis was 0.21 (n = 167; 95% CI, .18-.25). A total of 302 bacteria were isolated in 298 (82%) of the cases. The pathogens responsible varied by route of admission, gestation at birth, and age at infection. Group B Streptococcus (GBS) (150/302 [50%]; incidence, 0.16/1000 live births; 95% CI, .13-.18) and Escherichia coli (41/302 [14%]; incidence, 0.04/1000; 95% CI, .03-.06) were responsible for approximately two-thirds of identified bacteria. Pneumococcal (28/302 [9%]) and meningococcal (23/302 [8%]) meningitis were rare in the first month, whereas Listeria meningitis was seen only in the first month of life (11/302 [4%]). In hospitalized preterm infants, the etiology of both early- and late-onset meningitis was more varied. Overall case fatality was 8% (25/329) and was higher for pneumococcal meningitis (5/26 [19%]) than GBS meningitis (7/135 [5%]; P = .04) and for preterm (15/90 [17%]) compared with term (10/235 [4%]; P = .0002) infants. CONCLUSIONS: The incidence of bacterial meningitis in young infants remains unchanged since the 1980s and is associated with significant case fatality. Prevention strategies and guidelines to improve the early management of cases should be prioritized.

Adolescent fatigue, POTS, and recovery: a guide for clinicians.

Many teenagers who struggle with chronic fatigue have symptoms suggestive of autonomic dysfunction that may include lightheadedness, headaches, palpitations, nausea, and abdominal pain. Inadequate sleep habits and psychological conditions can contribute to fatigue, as can concurrent medical conditions. One type of autonomic dysfunction, postural orthostatic tachycardia syndrome, is increasingly being identified in adolescents with its constellation of fatigue, orthostatic intolerance, and excessive postural tachycardia (more than 40 beats/min). A family-based approach to care with support from a multidisciplinary team can diagnose, treat, educate, and encourage patients. Full recovery is possible with multi-faceted treatment. The daily treatment plan should consist of increased fluid and salt intake, aerobic exercise, and regular sleep and meal schedules; some medications can be helpful. Psychological support is critical and often includes biobehavioral strategies and cognitive-behavioral therapy to help with symptom management. More intensive recovery plans can be implemented when necessary.

Early diagnosis model for meningitis supports public health decision making.

OBJECTIVE: To develop a predictive model for rapid differential diagnosis of meningitis and meningococcal septicaemia to support public health decisions on chemoprophylaxis for contacts. METHODS: Prospective study of suspected cases of acute meningitis and meningococcal septicaemia admitted to hospitals in the South West, West Midlands and London Regions of England from July 2008 to June 2009. Epidemiological, clinical and laboratory variables on admission were recorded. Logistic regression was used to derive a predictive model. RESULTS: Of the 719 suspect cases reported, 385 confirmed cases were included in analysis. Peripheral blood polymorphonuclear count of >16 × 10(9)/l, serum C-reactive protein of >100 mg/l and haemorrhagic rash were strongly and independently associated with diagnosis of bacterial meningitis and meningococcal septicaemia. Using a simple scoring system, the presence of any one of these factors gave a probability of >95% in predicting the final diagnosis. CONCLUSION: We have developed a model using laboratory and clinical factors, but not dependent on availability of CSF, for differentiating acute bacterial from viral meningitis within a few hours of admission to hospital. This scoring system is recommended in public health management of suspected cases of meningitis and meningococcal septicaemia to inform decisions on chemoprophylaxis.

Which early 'red flag' symptoms identify children with meningococcal disease in primary care?

BACKGROUND: Symptoms are part of the initial evaluation of children with acute illness, and are often used to help identify those who may have serious infections. Meningococcal disease is a rapidly progressive infection that needs to be recognised early among children presenting to primary care. AIM: To determine the diagnostic value of presenting symptoms in primary care for meningococcal disease. DESIGN OF STUDY: Data on a series of presenting symptoms were collected using a parental symptoms checklist at point of care for children presenting to a GP with acute infection. Symptom frequencies were compared with existing data on the pre-hospital features of 345 children with meningococcal disease. SETTING: UK primary care. METHOD: The study recruited a total of 1212 children aged under 16 years presenting to their GP with an acute illness, of whom 924 had an acute self-limiting infection, including 407 who were reported by parents to be febrile. Symptom frequencies were compared with those reported by parents of 345 children with meningococcal disease. Main outcome measures were diagnostic characteristics of individual symptoms for meningococcal disease. RESULTS: Five symptoms have clinically useful positive likelihood ratios (LR+) for meningococcal disease: confusion (LR+ = 24.2, 95% confidence interval [CI] = 11.5 to 51.3), leg pain (LR+ = 7.6, 95% CI = 4.9 to 11.9), photophobia (LR+ = 6.5, 95% CI = 3.8 to 11.0), rash (LR+ = 5.5, 95% CI = 4.3 to 7.1), and neck pain/stiffness (LR+ = 5.3, 95% CI = 3.5 to 8.3). Cold hands and feet had limited diagnostic value (LR+ = 2.3, 95% CI = 1.9 to 3.0), while headache (LR+ = 1.0, 95% CI = 0.8 to 1.3), and pale colour (LR+ = 0.3, 95% CI = 0.2 to 0.5) did not discriminate meningococcal disease in children. CONCLUSION: This study confirms the diagnostic value of classic 'red flag' symptoms of neck stiffness, rash, and photophobia, but also suggests that the presence of confusion or leg pain in a child with an unexplained acute febrile illness should also usually prompt a face-to-face assessment to exclude meningococcal disease. Telephone triage systems and primary care clinicians should consider these as 'red flags' for serious infection.

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 child's 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.

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

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.

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.

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.

OBJECTIVE: Meningococcal 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.DESIGN Susceptibility 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. SETTING: University hospital and laboratories. SUBJECTS: Subjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls. INTERVENTIONS: DNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques. MEASUREMENTS AND MAIN RESULTS: Predicted 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). CONCLUSIONS: This 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.