Day two abstracts

NICE commissioned the National Collaborating Centre for Women’s and Children’s Health (NCC-WCH) to develop a guideline to make recommendations about the management of bacterial meningitis and meningococcal septicaemia in children in 2007. Stakeholders helped in developing a scope for the project and, after the appointment of a guideline development group (GDG) at the end of 2007, a series of questions of clinical importance were formulated to cover the following topics listed in the guideline scope (see http://www.nice.org.uk/guidance/index.jsp?action=folder&o=45010):

• diagnosis of bacterial meningitis and meningococcal septicaemia
• management of suspected bacterial meningitis and meningococcal septicaemia in primary care and the in the pre-hospital setting
• management of bacterial meningitis and meningococcal septicaemia in secondary care
• retrieval and transfer to secondary and tertiary care
• choice and timing of investigations
• information that should be given to parents and carers

Papers of potential relevance were identified from database searches by NCC-WCH information scientists and sorted for closer inspection by NCC-WCH research fellows. Using criteria set out in the NICE guidelines manual, the research fellows identified approximately 200 papers for data extraction to provide an evidence base for the questions. At a series of 10 meetings during 2008/09 the GDG examined this evidence and formulated recommendations to be incorporated into the guideline. Key recommendations were selected by the GDG and will be presented.

The draft guideline will be available for public consultation from 22 October to 17 December and publication is anticipated in June 2010.

AJP acknowledges the huge efforts of the staff of NCC-WCH and the GDG in preparing the guideline.

This work was undertaken by the GDG convened by the NCC-WCH which received funding from NICE. The views expressed in this publication are those of the authors and not necessarily those of the Institute.

The outcome of neonatal meningitis in both developed and developing countries remains unacceptable. Despite declines in mortality over the last 2 decades, the most recent data on neurodevelopmental outcome suggest little change has occurred and up to 50% of infants with neonatal meningitis may have some form of disability at 5 years of age. Strategies for prevention are relatively few but should be prioritized and vaccination, especially with an effective Group B Streptococcal vaccine holds much promise. Using recent developments in the management of meningococcal disease in children as a model, it seems likely that a number of aspects of the current management of neonatal meningitis could be improved or modified with potential for better outcomes. These might include earlier recognition of signs and symptoms by parents and healthcare workers, earlier identification of the causative pathogen, earlier initiation of appropriate antimicrobial therapy, improvements in supportive care and better antimicrobial agents. Potentially effective adjunctive therapies such as corticosteroids and glycerol have not been adequately assessed in this population. More data are needed to quantify these issues, formulate new strategies of intervention and ultimately demonstrate their efficacy.

Download the presentation

Objective: To audit current UK practice of the management of severe sepsis in children against the 2002 American College of Critical Care Medicine/Pediatric Advanced Life Support (ACCM-PALS) guideline.

Design: Prospective observational study with data collected by 17 PICUs and two PICU retrieval services over a 6-month period between December 2006 and May 2007.

Participants: 200 children accepted for PICU admission within 12 h of arrival in hospital, whether or not successfully transported to a PICU, with a discharge diagnosis of sepsis or suspected sepsis.

Main outcome measures: Medical interventions, physiological and laboratory data to determine the presence or absence of shock, inter-hospital transfer times, predicted mortality using the Paediatric Index of Mortality, version 2 (PIM2) scoring system, and observed mortality.

Results: 34/200 (17%) children died following referral. Although children defined as being in shock received significantly more fluid (p<0.001) than those who were not in shock, overall fluid and inotrope management suggested by the 2002 ACCM-PALS guideline was not followed in 62% of shocked children. Binary logistic regression analysis demonstrated that the odds ratio for death, if shock was present at PICU admission, was 3.8 (95% CI 1.4 to 10.2, p = 0.008).

Conclusions: The presence of shock at PICU admission is associated with an increased risk of death. Despite clear consensus guidelines for the emergency management of children with severe sepsis and septic shock, most children received inadequate fluid resuscitation and inotropic support in the crucial few hours following presentation.

Reference: Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit. Inwald DP, Tasker RC, Peters MJ, Nadel S on behalf of the Paediatric Intensive Care Society Study Group (PICS-SG). Archives of Disease in Childhood 2009;94:348-353

Download the presentation

Aims: Sidestream Darkfield Imaging (SDF) non-invasively visualises the microcirculation in real time. Studies using SDF in adults with severe sepsis show microcirculatory abnormalities. This has not previously been studied in children. Disturbances in the microcirculation result from endothelial activation mediated through adhesion molecules. We aimed to ascertain whether microcirculatory disturbances are present in children with meningococcal disease (MCD) and whether these disturbances correlate with plasma levels of adhesion molecules.

Methods: Twenty children admitted to the paediatric intensive care unit with MCD were recruited. The sublingual microcirculation was visualised using SDF at admission and at timed intervals until extubation. All SDF images were obtained by the same investigator. Images were analysed by two blinded investigators, by assessment of the Microvascular Flow Index (MFI), Capillary Density (CD), Proportion of Perfused Vessels (PPV) and Perfused Vessel Density (PVD) – as detailed in previous studies. Plasma ICAM-1, VCAM-1, E-selectin and P-Selectin were measured at admission.

Results: All children survived. Significant reductions in MFI, CD, PPV and PVD were found in children with MCD at admission compared to controls (p<0.005). These differences were no longer significant prior to extubation. There were strong correlations between MFI and PPV and adhesion molecules;

A correlation was found between CD and P-Selectin (r=-0.53, p<0.05). Correlations were also found between the amount of resuscitation volume required and MFI (r=-0.52, p<0.05) and PPV (r=-0.47, p<0.05). MFI at admission also correlated with total length of inotropic support required (r=-0.56, p<0.05) and total length of ventilatory requirement (r=-0.48, p<0.05).

Conclusion:These results confirm microcirculatory dysfunction in children with severe MCD and microcirculatory recovery alongside clinical recovery. Microcirculatory variables correlate with markers of endothelial activation and may predict the need for inotropic and ventilatory support. SDF could be a useful adjunct in guiding resuscitation in severe sepsis in children.

Read Dr Paize's biography here

Download the presentation

Mortality from pediatric sepsis / septic shock has improved markedly in our lifetime. In 1968, the University of Minnesota reported 97% mortality with gram negative bacteria sepsis. In 2007, the US KIDS database reported a 4% mortality, 2% in previously healthy children and 8% in chronically ill children. These heartening outcomes have also been reported in the United Kingdom and the Netherlands with meningococcal disease (St Mary’s and Erasmus hospitals), in severe malaria in Kenya, and in dengue shock in Vietnam and Thailand. This marked improvement has come with recognition of age specific differences in the pathophysiology and management of infants and children compared to adult septic shock. Bang and colleagues have demonstrated that administration of a five day course of IM gentamycin and oral co-trimoxazole by village health workers to newborns with septic symptoms reduced all cause mortality by 6 fold. Ten percent of infants received antibiotics in this study, the same percent who receive antibiotics antenatally or perinatally in the developed world. Investigators from the Wellcome Trust have demonstrated in London, Kilifi, and Vietnam that fluid resuscitation in the emergency setting can powerfully reduce mortality. In London, the linkage of early albumin resuscitation with peripheral inotropic support and intubation in the referral center, followed by transfer to the PICU was associated with a reduced mortality from 22-2%. In Kilifi, fluid resuscitation with albumin in the emergency setting reduced severe malaria mortality to 4%. In Vietnam, fluid resuscitation of children with mostly Stage III but some Stage IV shock resulted in 0% mortality. These fabulous ‘study’ results demonstrate that early recognition and treatment is very powerful. Unfortunately, the most recent PICS study shows that these therapies, and perhaps early recognition, are not being successfully accomplished in the emergency or general practitioner settings with a not unexpected near 20% mortality rate. In the US we have reported that children increase their odds of death from multiple organ failure by 40% for each hour which goes by without these therapies. The Canadians have remarkably demonstrated that adults receive antibiotics for septic shock on average 6 hours after presentation, with an associated 7 percent increase in mortality with each hour that ensues without antibiotics. The adult activated protein C trial found that surgical sepsis patients had a 4% mortality when the nidus of infection was removed compared to a 98% mortality when it was not, regardless of whether they received the drug or placebo. Hence our greatest challenge today is to put together the educational and organizational structures needed to accomplish our wonderful ‘study’ results in ‘general practice’.

The first step in this quest is recognition of barriers to implementation. Immunisations can avert these barriers, if one agrees that barriers to immunisation are trivial, but unfortunately they are not. My bias is that immunisations will someday be the complete answer, but until then many babies and children will die or be devastated unless we address education, recognition, and treatment barriers. The Bang study shows us that parent or non-parent health workers are essential to early recognition and antibiotic treatment. The St. Mary’s study shows us that community wide public health and hospital education programs are critical to outcome when antibiotics are not enough. Being from the United States, a quite vast country, I think that all these efforts will be difficult and certainly could use some help from medical breakthroughs as well. On the early, low tech, recognition and treatment end, the Finns have reported that oral glycerol reduces morbidity and mortality by 50% in infants with meningitis. Many say that prolonged capillary refill has a fair amount of false positives but not in children whose parents know they are sick. Parents are easily trained in this technique and it is very helpful for early recognition of shock. Hyaluronidase can be safely given sub cutaneously allowing 20 mL/kg of fluid to be given (clysis) in much the same way as your veterinarian resuscitates your cat. Fluid resuscitation can now be administered in the office where there are no IV capabiltiies. Inotropes can be given peripherally as well. Two exciting inotropes which have yet to be tested systematically include enoximone and levosimendan. What of the patients who come after late recognition and even later treatment? Titration of therapies to superior vena cava oxygen saturations > 70% can reduce mortality 4-fold. Non invasive cardiac output monitoring has not been tested, but there is little reason to think it would not be helpful as well. Extracorporeal therapies are needed in the very delayed resuscitation scenario. Complex coagulopathy and even purpura fulminans can be reversed with plasma exchange or, if you like, plasma infusion with continuous hemofiltration. ECMO is life saving, particulary in newborn septic shock. For the fastest growing population of sepsis, children with chronic illness, immune deficiency syndromes both congenital and acquired are the cause of unending sepsis and multiple organ failure. These children can be treated with immune modulation therapies that were not available a short ten years ago. The present and the future are bright, the work ahead is great!

Download the presentation

Malaria and other infectious diseases pose a major health burden for children in sub-Saharan Africa (SSA), accounting for millions of deaths annually. Little progress has been made towards reducing current mortality rates of 15-30% for children admitted to hospitals in SSA with life-threatening infection. Currently, anti-malarial and anti-microbial drugs are the mainstay of treatment for severe infections, and little consideration is given to the use of adjunctive supportive therapies. Child survival programmes have largely ignored the role of triage and emergency care in reducing child mortality, despite the fact that these interventions may be highly cost-effective.

Globally, the consensus view of paediatricians delivering care to critically sick children is that emergency clinical management should be standardised, and should target key aspects of deranged physiology, irrespective of the underlying disease process. Adherence to guideline management of paediatric septic shock has, in countries with neonatal and paediatric intensive care facilities, been associated with a marked improvement in outcome over the past 20 years. The situation is markedly different in poorly-resourced hospitals in SSA, where sophisticated point-of-care tests, intensive care monitoring and specialist clinical care are rarely available. Over 50% of childhood deaths in African hospitals occur within 24 hours of admission, and shock complicates many of these cases. Adoption of simple treatment algorithms for the treatment of hypovolaemia and prevention of shock (irrespective of aetiology) could be of great benefit, but their effectiveness and safety have not been rigorously evaluated.

The FEAST trial is an on-going multi-centre randomised clinical trial designed to evaluate different fluid resuscitation strategies in children presenting to hospital with severe febrile illness and shock, with the intention of generating data of practical value to clinicians working in resource-poor settings in Africa. The trial addresses the question of whether fluid resuscitation results in improved survival compared to standard case management (no fluid resuscitation). More specifically, the trial has been designed with the aim of resolving the current debate over whether rapid correction of intravascular volume, using colloidal or crystalloidal solutions improves both survival and neurological outcome in children with neurological presentations of severe illness (cerebral malaria and meningo-encephalitis).

Download the presentation

Developing countries carry the greatest burden of bacterial meningitis and the highest fatality rate. Although several countries in sub-Saharan Africa have rapidly advancing health care systems, clinicians continue to face exceptional challenges in the management of bacterial meningitis especially where resources are limited.

Reasons underlying the differences in the outcome between developed and developing countries probably include delayed access to health care facilities, limitations in diagnostic facilities and failure of appropriate medical care. Host factors such a HIV co-infection, malnutrition, anaemia and genetic susceptibility may also contribute to poor outcome.

In many areas, diagnosis relies heavily on clinical examination as even simple laboratory tests are not universally available. Although several algorithms have been developed, diagnostic accuracy remains an important hurdle; distinguishing between bacterial, viral, TB and cryptococcal meningitides and cerebral malaria are significant priorities. Several low cost laboratory tests are available; these include the use of urine-analysis reagent strips to provide semi-quantitative estimates of glucose and protein and the use of rapid antigen detection kits. Nonetheless, microscopy and culture of CSF remain the gold standard although even these have significant limitations.

Although the availability of appropriate antibiotic therapy continues to improve, it is far from universal. In addition there is growing evidence of widespread marketing of sub-standard or counterfeit therapy. This in turn promotes the emergence of drug resistant organisms which poses particular problems in developing countries. Route of antibiotic administration is an important consideration in resource poor settings as skills and equipment necessary for intravenous therapy are often scarce. Similarly, duration of therapy needs careful definition within the context of the setting.

Supportive therapies such as fluid resuscitation, nutritional support, seizure control and the use of adjunctive steroids or glycerol have been subject to recent debate. The utility of such interventions cannot necessarily be generalized from experience in wealthy countries, although there is much to gain from relatively simple interventions aimed at optimising basic medical care.

In the broader context of development in Africa, it is as likely that further improvement in the outcome from bacterial meningitis will be achieved through education and socio-political advance as from improvements in individual patient management. By far the greatest effect is likely to be derived through the widespread deployment of vaccine technology.

Download the presentation

Epidemic Group A meningococcal meningitis continues to be a major public health problem in Sub-Saharan Africa. Waves of epidemic Group A meningococcal meningitis occur periodically in Africa and are superimposed on high endemic rates of disease. Reactive vaccination campaigns using meningococcal PS vaccines have not eliminated these epidemics.

The Meningitis Vaccine Project (MVP), a partnership between WHO and PATH, was established in 2001 with Gates Foundation support with the goal of eliminating epidemic meningitis through the development and widespread introduction of an affordable Group A meningococcal (Men A) conjugate vaccine. Using an innovative partnership model (Serum Institute of India; CBER/FDA, Bethesda and SynCoBioPartners, Amsterdam) MVP has developed a Men A conjugate vaccine (MenAfriVacTM) with a target price of less than $US 0.50 per dose.

Preclinical development finished in 2004 and the vaccine has been successfully tested in Phase I and Phase II and II/III clinical trials in India and Africa (1-29 years). The vaccine has been shown to be safe, highly immunogenic and able to prime immunological memory when compared to polysaccharide vaccine. Widespread use of the vaccine is expected to generate broad herd immunity.

MVP has successfully developed and managed a “push” strategy for the development of an affordable new vaccine product that was of little interest to major vaccine manufacturers. Introduction of the vaccine at public health scale is planned for 2009/2010 and widespread use of the vaccine is expected to eliminate Group A meningococcal meningitis epidemics from Sub Saharan Africa.

Download the presentation

Public health management of invasive meningococcal disease varies in Europe. We performed a systematic literature review to identify evidence-based measures for prevention of subsequent disease in contacts of sporadic cases. Recommendations were based on quality of evidence and balance of benefits and harms, and classified as weak or strong according to GRADE methodology.

We strongly recommended chemoprophylaxis for household contacts based on an estimated 85% reduction in risk in treated versus untreated contacts derived from five observational studies. No direct evidence was available in other settings. However, the risk of a subsequent case of meningococcal disease after one case in pre-school settings was relatively high. We made a weak recommendation to provide chemoprophylaxis to children in the same preschool as a case, depending on risk assessment.

We found low quality evidence that exposure to saliva as might occur with sharing of drinks with a case was not a risk factor. The same applied to sharing the same transport vehicle. Weak recommendations were made not to give chemoprophylaxis based on such contact alone.

Moderate or high quality evidence exists that besides antibiotics most commonly used for chemoprophylaxis (rifampicin, ciprofloxacin, ceftriaxone), minocycline, azithromycin and ce-fixime also effectively eradicate meningococci. All but minocycline were strongly recom-mended for chemoprophylaxis. Surveillance of susceptibility of pathogenic meningococcal strains to these drugs is important.

We found weak evidence for persistent carriage of meningococci in the nasopharynx after inpatient therapy of a case with non-eradicating antibiotics. As carriage in the case is likely to pose a continuing risk to close contacts, consensus was for a strong recommendation to pro-vide chemoprophylaxis to such patients before hospital discharge.

Indirect evidence showed that the risk of disease among household contacts remained elevated (1.1/1000) during the 12 months following a case, even after receiving chemoprophylaxis. We made a strong recommendation to offer an appropriate vaccine to household con-tacts if a case was caused by a vaccine preventable strain.

This review permitted some clear evidence and consensus based recommendations, but areas of uncertainty with only weak recommendations remain. This may reasonably lead to different policies between countries. Yet if potential for confusion is high, e.g. in managing airplane contacts, consensus across Europe is desirable.

Read Dr Stuart's biography here

Download the presentation

A quadrivalent meningococcal conjugate vaccine (serogroups A,C,Y, W, MCV4) is licensed for use in the United States for persons aged 2-55 years and was recommended for routine use in adolescents by the Advisory Committee on Immunization Practices in 2005. Because a substantial proportion of disease in the U.S. is caused by serogroup Y, introduction of MCV4 was an important step in prevention of meningococcal disease. Prior and during vaccine introduction, rates of meningococcal disease decreased to historic lows and have remained low. This decrease in disease incidence is unlikely attributable to MCV4 since vaccine coverage was approximately 40% among 13-17 year-olds in 2008. The impact of quadrivalent conjugate vaccine in the United States is difficult to measure in the setting of low disease incidence, but early estimates suggest MCV4 effectiveness may not be as high as MenC vaccine effectiveness in adolescents. Reasons for lower effectiveness of MCV4 may include vaccine composition, slower uptake of vaccine among a targeted age group with no catch-up campaigns, and increased heterogeneity of circulating invasive organisms. The duration of protection of a single dose of MCV4 and the potential for herd immunity with high vaccine coverage has not been established.

New meningococcal conjugate vaccines are in the late stages of development in the U.S. for adolescents and adults as well as for infants, for whom there are currently no vaccines licensed in the United States. Considering recommending routine infant meningococcal vaccination is challenging in the setting of historic low disease incidence, the high proportion of cases caused by serogroup B in this age group, and a crowded immunization schedule. However, the need for meningococcal conjugate vaccines exists in the United States as well as other countries where disease is caused by a combination of serogroups A,C,Y or W-135.

Download the presentation

Neisseria meningitidis group B (MenB) causes most meningococcal disease in industrialised countries and is the leading cause of bacterial meningitis in the UK. In 2008, 1229 cases of MenB were confirmed in the UK, representing approximately 90 percent of all laboratory confirmed meningococcal cases.

The virtual disappearance of meningococcal group C disease in the UK since the introduction of the MenC vaccine demonstrates the impact an effective vaccine can have on meningococcal disease, but the development of a vaccine against all variants of MenB bacteria in circulation remains a difficult challenge.

This session will include a presentation of recent epidemiological data from England and Wales, including information on the prevalence of antigens that will be key to assessing the potential coverage of MenB vaccines in development.

A number of prospective MenB vaccines have progressed well into clinical trials. These are based on different approaches, including reverse vaccinology, recombinant outer membrane proteins, and up-regulation of minor conserved antigens. During this session, scientists involved in the development of four prospective MenB vaccines will summarise current progress.

This will be followed by a question and answer session and round-table discussion of wide-ranging issues. Please come prepared to ask questions!

• Download Prof Ray Borrow's presentation
• Download Dr Jan Poolman's presentation
• Download Dr Paul Keiser's presentation