Severe meningococcal disease in childhood

British Journal of Anaesthesia 90 (1): 72±83 (2003)

DOI: 10.1093/bja/aeg005

REVIEW ARTICLE Severe meningococcal disease in childhood P. B. Baines1²* and C. A. Hart2 1

Paediatric Intensive Care Unit, Royal Liverpool Children's Hospital, Eaton Road, Liverpool L12 2AP, UK. 2 Department of Medical Microbiology and Genitourinary Medicine, Duncan Building, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK

Meningococcal disease remains an important cause of illness in the UK (Commun Dis Rep CDR Suppl 1999; 9: S5), and is the commonest infective cause of death in children outwith the neonatal period. Although most common in children, adults are also affected. Meningococcal vaccines offer long-term protection only against Group C disease, which causes less than half of invasive meningococcal disease (Commun Dis Rep CDR Wkly 1998; 8: 2) in the UK. Br J Anaesth 2003; 90: 72±83 Keywords: children; critical care; infection, meningococcal

The meningococcus

Epidemiology

Neisseria meningitidis (the meningococcus) is an encapsulated, oxidase positive, Gram-negative coccus. Up to onehalf of the mass of the outer cell membrane is lipooligosaccharide.48 During growth, endotoxin-rich outer membrane is released by blebbing (Fig. 1). Meningococci are separated by their capsular polysaccharide antigens into several groups (A, B, C, 29-E, H, I, K, L, W-135, X, Y, Z). In the UK, Group B disease is most common.4 The incidence of Group C disease, ~30% of all cases, is increasing in Britain.63 Meningococci are then further subdivided by outer membrane proteins into serotypes and serosubtypes.

Meningococcal disease occurs extensively throughout the world. A broad `meningitis belt' extends across sub-Saharan Africa, with recurrent epidemics of Group A disease.72 In the UK, meningococcal disease occurs throughout the year, but with a winter predominance. Invasive meningococcal disease is most common in infants. The annual attack rate for infants of 5.9 per 100 000 far exceeds the adult rate of 0.4 per 100 000. There is also a much smaller secondary peak incidence around 18 years of age.58

History

Vieusseux23 ®rst described meningococcal infections in reporting an outbreak during 1805 in Geneva. In 1887, Weichselbaum isolated meningococci from six of eight patients with meningitis. Immune serum was the ®rst effective therapy, with large case series demonstrating a reduction in mortality from ~70% of cases, to ~30%.34 Sulphonamides were then used, initially in combination with serum therapy.23 Meningococci have developed widespread resistance to sulphonamides, and more recently penicillin resistance has also been reported. Currently, initial hospital management of meningococcal infections is usually with cefotaxime or ceftriaxone.83

Meningococcal carriage, spectrum of disease and natural history Meningococci may cause different clinical syndromes: meningitis, septicaemia, conjunctivitis, pericarditis, epiglottitis, pneumonia and arthritis.102 In clinical practice, meningitis or septicaemia, or more often a combination of both, are the most commonly encountered problems.89 96 In population-based studies, mortality of meningococcal disease, both sepsis and meningitis together, ranges from 6 to 9%,96 117 with a rate of neurological sequelae ranging from 8 to 29%.31 74 96 The reported mortality rate of children who are admitted to intensive care units with ²

Declaration of interest. Paul Baines was supported by the Johanne Holly Meningitis Fund for part of the time that this review was in preparation.

Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003

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*Corresponding author. E-mail: [email protected]

Severe meningococcal disease

Invasive disease

Fig 1 Electron microscopy of a pair of meningococci surrounded by `blebs' of membrane, which contain endotoxin. One of the many blebs is indicated by an arrow. Radiating from the meningococci are pili, found more commonly in pathogenic meningococci.

Risk factors for carriage and invasive disease Household overcrowding is a risk factor for carrying meningococci and for invasive disease.9 73 103 Control of meningococcal epidemics in military recruits was achieved by adequate bed spacing.23 Meningococcal disease is more commonly seen in those with socioeconomic deprivation,103 or with material deprivation.60 High rates of nasal carriage occur in military recruits. In studies of recruits to the armed forces, the carriage rate on admission was 30% which increased to >70% after 9 months.6 Nasopharyngeal carriage of meningococci is more common in smokers, with a higher carriage rate in heavier smokers. Passive smoking is a risk factor for invasive disease.33 60 103 Bactericidal antibody prevents meningococcal disease. This is demonstrated by the inverse relationship between the rate of carriage of antimeningococcal antibodies and rate of disease with age, and by the protective effect of anti-meningococcal antibodies in military recruits.43 Complement de®ciency, though rare, predisposes individuals to recurrent invasive meningococcal disease.93 Meningococcal infections caused by the less common serotypes (that is neither A, B nor C), in older people or recurrent meningococcal disease are more likely to be a consequence of complement de®ciencies. The mortality rate, ~6%, is lower than the overall rate for meningococcal disease.93 Heritable factors determine the outcome of

meningococcal disease varies between 9 and 35%, with a reduction in overall mortality to 9% in the latest series.108 The reduction in mortality rate is not a consequence of admitting fewer ill children. When the actual mortality of children with meningococcal disease is compared with the mortality predicted by the Paediatric Risk of Mortality Score (PRISM),82 to give a standardized mortality rate (SMR), it may be seen that the SMR has progressively fallen over time.108 As meningococci have no natural reservoir other than humans, nasopharyngeal carriage is the reservoir of pathogenic meningococci and is a necessary ®rst step in invasive disease. Nasal carriage generates antibodies to the strain of meningococcus carried, often with crossreactivity to other meningococcal groups.43 Swabbing underestimates nasopharyngeal carriage of meningococci.98 Adults commonly carry apparently pathogenic meningococci in the nasopharynx, whereas children are more likely to harbour the non-pathogenic Neisseria lactamica,43 which engenders an immune response, cross-reacting with N. meningitidis. The rate of meningococcal infection is better related to the rate of acquisition of carriage than to the absolute rate of meningococcal carriage.114 73

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After nasopharyngeal colonization, translocation across the nasopharyngeal mucosa occurs.101 In some children, a self-limiting bacteraemia will result.106 In others, bloodstream spread to the meninges may occur with clinical features of meningitis. In other children, the predominant feature is cardiovascular collapseÐseptic shock. The most common presentation in Europe is with features of both meningitis and septicaemia (~60%). One-®fth present with features of meningitis alone, and one-quarter present with septicaemia alone.96 The mortality of meningococcal septicaemia is consistently higher than the mortality from meningococcal meningitis. When features of both septicaemia and meningitis are present, the mortality rate is intermediate. In a retrospective study between 1977 and 1993, mortality from meningococcal meningitis alone was 1.2%, for children with both sepsis and meningitis 11%, and for children with meningococcal septicaemia, the mortality rate was 19%.89 Spontaneous recovery after meningococcal bacteraemia may occur, though rarely.26 106 In children who have predominantly either sepsis or meningitis separately, infection and in¯ammation can be demonstrated to be predominantly within either the meninges, or the bloodstream.18

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infection. In Lancashire, UK, the rate of invasive meningococcal disease in children of Indian subcontinent origin was one-quarter the rate of other children. Whether this re¯ects genetic or cultural factors is not clear.92 A polymorphism of the tumour necrosis factor-a (TNFa) promoter region, which may increase TNF-a production, is related to more severe infections and outcome. The evidence for the importance of the TNF-a polymorphism in meningococcal disease is con¯icting.75 86 115 Polymorphisms of interleukin-1 (IL-1) and its receptor (IL1R),86 of the plasminogen-activator-inhibitor-1 (PAI-1) gene,52 and of the mannose binding lectin (MBL) variable gene,54 have been related to the outcome of invasive meningococcal disease. Prior or concurrent respiratory tract infections are associated with invasive meningococcal disease.6 118

Pathophysiology Cardiac function in meningococcal disease

Diagnosis of meningococcal disease Although the classical petechial rash in a child with evidence of infection is pathognomic of meningococcal disease, up to one-®fth of children have no rash or no petechiae on presentation.65 Lumbar puncture may be considered in meningitis but is contraindicated in meningococcal sepsis. Deterioration may follow either positioning for lumbar puncture or as a consequence of coning.88 Antibiotics should not be withheld pending the results of cerebrospinal ¯uid (CSF) analysis. Children may deteriorate dramatically from mild or non-speci®c symptoms to overwhelming collapse over only a few hours. Extensive rash usually predicts severe disease, though children may be severely unwell, with only a limited rash. The overwhelmingly most frequent cause of fever and petechiae or purpura is meningococcal infection.28 Bacterial con®rmation may be sought by blood or CSF antigen detection, but in the CSF, antigen detection may be no more sensitive than microscopy and culture.25 Antigen detection remains useful even after the administration of antibiotics. Other antigens (including Escherichia coli K1 in the case of Group B meningococci) cross-react producing false positives.25 Meningococci may be cultured from invasive sites, though given the exquisite sensitivity of meningococci to antibiotics, cultures of blood or CSF are rarely positive after antibiotic treatment. Infection may be con®rmed by an increase in antibody titre. More recently, a polymerase chain reaction (PCR) test for meningococcal DNA has been developed, with the advantage that meningococci need not be alive at the time the sample is obtained, and the test may be performed relatively rapidly (in time to inform outbreak management). PCR is reliable and has become the gold standard for speci®c diagnosis of meningococcal disease.21 74

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The primary cause of cardiovascular collapse from sepsis is peripheral circulatory failure, although myocardial performance may also be impaired. In a volume resuscitated septic patient, the cardiac output is at least normal and often high.80 In volunteers receiving endotoxin i.v., arterial pressure falls as a result of lowered systemic vascular resistance.105 Several studies have assessed cardiac function in patients with meningococcal disease. Echocardiography of 12 children with meningococcal disease found impairment of ventricular function in seven, three of whom died. Children with normal cardiac function survived.14 In a study of critically ill patients, those with meningococcal disease had lower cardiac outputs despite higher cardiac ®lling pressures than patients with other forms of Gram-negative sepsis. An increase in ®lling pressure produced an increase in cardiac output in Gram-negative sepsis, but no increase in cardiac output was seen in those with meningococcal disease.71 These results suggest that cardiac dysfunction is more prominent in meningococcal disease. This is supported by other work showing that in meningococcal disease, the cardiac stroke volume was lower than in other forms of Gram-negative sepsis, though the cardiac output was maintained to a similar level by a higher heart rate.41 Earlier work, describing measurements of central venous pressure in 11 hypotensive patients, found that the pressure was high (22±33 cm H2O) in seven of them. These measurements were before ¯uid resuscitation and suggest cardiac dysfunction rather than vasodilation, which would lower the central venous pressure.62 In children who died from meningococcal septicaemia, again with pulmonary arterial catheters placed, the cardiac ®lling pressures were lower, with lower cardiac output and a higher systemic vascular resistance than in those who survived, despite similar amounts of ¯uid resuscitation and inotrope therapy.70 Raised cardiac troponin concentrations were shown in children found to have worse myocardial function on echocardiography.107 In two extensive post-mortem series of meningococcal disease, one including 200 patients of all ages and the other of 86 children from South Africa, the reported incidence of myocarditis was high at 57 and 27% respectively.47 77 These studies suggest the pathophysiology of meningococcal disease may be different from other forms of septic shock, with myocardial failure playing a more prominent role. Pericardial effusions have been described in meningococcal disease. They may follow severe sepsis, or present as primary pericardial effusions, whose aetiology is de®ned only after drainage.55

Severe meningococcal disease

Many mediators are involved in severe sepsis. The importance of some mediators is beyond dispute, most particularly TNF-a, which is a key cytokine in the modulation of in¯ammation. Nitric oxide, too has attracted considerable attention recently.7 11 29 44 81

Endotoxin Endotoxin, released by meningococci, is fundamental in the pathology of meningococcal disease. Brandtzaeg15 demonstrated a graded relationship between the bloodstream concentration of endotoxin and disease severity. Higher endotoxin concentrations were associated with shock, renal failure and respiratory distress. Groups separated on initial plasma endotoxin concentrations had progressively higher mortality rates [culminating in a mortality of 100% for those with lipooligosaccharide (LOS) concentrations of 10 000 ng litre±1]. A good relationship was found between endotoxin concentrations and other mediators of in¯ammation.16 In animal models, meningococcal endotoxin will reproduce the pathophysiological features of meningococcal disease.19 Disease severity is also related to the meningococcal bacterial DNA load in blood.45

Cytokines A cascade of cytokines is produced in response to endotoxin. TNF-a is the ®rst cytokine to be produced. After a rapid increase, systemic concentrations of TNF-a fall rapidly to low concentrations.111 Inhibitors of TNF-a improve the outcome of animal models of meningococcal disease,76 but have been ineffective in critically ill adults with sepsis.85 The importance of TNF-a in the pathogenesis of meningococcal disease is well recognized.113 TNF-a acts by binding to cell surface receptors, which may be released. Circulating soluble TNF receptors may either inhibit or prolong the action of TNF. Elevations of TNF-a and of both TNF receptors have been described in patients with meningococcal disease.40 110 In severely ill patients, TNF-a increased more than the TNF receptors. Further evidence for the importance of TNF-a in meningococcal disease originates from studies of TNF-a genotypes. In a study conducted in London, children with meningococcal disease and a particular TNF-a promoter polymorphism (NcoI TNF2 allele), which causes higher transcription of TNF mRNA, had a higher incidence of severe disease (relative risk 1.6, 95% CI 1.1±2.3) and of death (relative risk 2.5, 95% CI 1.1±5.7).75 This was not con®rmed by two other studies, which found no relationship of the same TNF promoter polymorphism (-308) to outcome.86 115 IL-1 concentrations are raised in meningococcal disease and are higher in those who die.110 IL-1 is modulated by

Endothelial cell activation Cytokines, including TNF and IL-1, activate endothelial cells, altering function in several ways: cells round up, have increased permeability, change from anti-coagulant to procoagulant, and display increased adhesiveness for white cells. Nitric oxide and cytokines are produced.56 These responses are described as endothelial cell activation. Endothelial cell surface glycosaminoglycans (GAG) are important in restricting the permeability of the endothelium for negatively charged proteins, including albumin. Binding of the leucocytes to endothelial cells may cause dysfunction of the endothelial cells directly.59 Urinary excretion of GAGs relates to urinary protein leak and re¯ects the tissue leak of serum.78 On skin biopsy of maculopapular lesions, meningococci are found ingested by neutrophils, and intracellularly in the endothelial cells, with surrounding complement and immunoglobulin deposition.100 Ingestion of meningococci by endothelial cells is demonstrable in culture. 75

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interleukin-1 receptor antagonist (IL-1ra). Circulating IL1ra may block the activity of IL-1.37 In studying an IL-1 polymorphism, it was shown that heterozygotes survived best, with an odds ratio of 4.1. Both homozygotes had a higher mortality.86 Interestingly, when the heterozygote was present in common with homozygosity for the common allele for the IL-1 receptor, the odds ratio for survival was still higher (7.8-fold). High concentrations of IL-6, which correlate with disease severity have been described in meningococcal disease.36 51 110 IL-6 and IL-6 receptor (IL-6R) concentrations are inversely related, where iller patients with higher IL-6 concentrations have lower IL-6R concentrations.36 Whereas TNF-a concentrations decline rapidly in patients with sepsis,111 IL-6 concentrations are more sustained, remaining high until clinical recovery.37 IL-8, a chemoattractant cytokine, concentrations are higher in those with meningococcal shock and higher still in those who die.36 110 IL-10 is an anti-in¯ammatory cytokine, amongst whose actions is inhibition of the release of TNF-a and IL-1. Concentrations were higher in those who died from meningococcal disease.110 IL-12 is also found in higher concentrations in those with more severe disease. Of the two components of IL-12, p40 is more elevated than p75.50 Increased serum concentrations of most of the cytokines are shortlived,110 with the exception of IL-6, IL-1ra, and the soluble TNF receptors, whose half-life is relatively prolonged.37 After a proin¯ammatory state at the outset of meningococcal disease, the prolonged expression of IL-1ra and the TNF receptors, as well as a down regulation of TNF production, suggests a transition to an anti-in¯ammatory state.109

Mediators of sepsis

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Blood clotting depends not just on the blood components, but also on the endothelium and circulating cells.79 A profound disturbance of clotting factors and modulators, and ®brinolytic components and their modulators is seen clearly in meningococcal disease.17 32 67 116 The usual balance between coagulation and ®brinolysis is disturbed, so that although formal coagulation tests may be markedly prolonged, there is a tendency to thrombosis. Activated protein C, which inhibits activated clotting factors, is antithrombotic. Lower concentrations of protein C activity were shown in those who died when contrasted with those who survived meningococcal disease (5% of normal compared with 23% of normal). Protein C concentrations are markedly lower than those seen in other forms of sepsis,12 and activation of protein C is impaired in meningococcal disease.30 The reduction of protein S and antithrombin III is neither as marked nor as prolonged as the depression of protein C.32 Higher concentrations of plasminogen activator inhibitor 1 (PAI-1) were demonstrated in children with meningococcal disease.17 A promoter polymorphism of the PAI-1 gene increases concentrations of PAI-1, and is found more frequently in more severe meningococcal disease.52 This ®nding suggests that impairment of plasminogen activation and clot lysis may be relevant in meningococcal disease. These disturbances have signi®cance because of interactions between in¯ammation and clotting pathways, and after a recent adult study demonstrating that activated protein C reduced the mortality in adults with severe sepsis.12

Prevention of meningococcal disease Disease may be prevented directly in two ways: by vaccination, and by the administration of antibiotics to groups at high risk of meningococcal disease (chemoprophylaxis). Public health measures to reduce overcrowding,9 and smoking,33 may indirectly reduce mortality.

Vaccination

Nitric oxide

Meningococcal polysaccharide vaccines have been available for some years, but are ineffective in younger children, and in older children produce only short-term protection and hyporesponsiveness to subsequent doses of vaccine.63 A recently developed conjugated Group C vaccine overcomes these concerns.63 Conjugated Group C vaccination started in selected age groups in the UK in 1999 with a marked reduction in Group C disease in the vaccinated groups, and an increase in Group C disease in the unvaccinated population.84 Currently, Group C vaccination starts at 2 months, with a `catch up' programme for older children.

Nitric oxide, identi®ed as the endothelial derived relaxant factor, is produced constitutively by endothelial cells where it controls resting vascular tone. Inducible nitric oxide synthase (iNOS), produced in response to in¯ammation, produces 1000-fold as much nitric oxide as does the usual endothelial form. Overproduction of large amounts of nitric oxide lowers arterial pressure as a consequence of vasodilation and will also impair cardiac contractility.11 High nitric oxide metabolite concentrations have been reported in children with sepsis.29 High concentrations of nitric oxide metabolites, which are related to disease severity, have been demonstrated in meningococcal disease.7 Although initial human studies of nitric oxide synthesis inhibition had shown an improvement in cardiovascular stability,81 a subsequent placebo controlled trial in critically ill adults found that those treated with NOS inhibitors have higher mortality than controls.44

Chemoprophylaxis Meningococcal disease is more common in close contacts of patients with invasive meningococcal disease, with a secondary attack rate several thousandfold higher than the general population.69 Antibiotic prophylaxis of contacts of cases of invasive meningococcal disease with rifampicin is recommended.3 49 Another group, who may be at higher risk, the subject of recent controversy,39 are health care workers exposed to

Calcium Calcium is of fundamental importance in intracellular regulation. Intracellular concentrations of calcium are 76

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tightly controlled, and calcium ¯uxes are important in motility, secretion and in enzyme regulation.95 Extracellular concentrations of calcium are 1000-fold intracellular concentrations, and again are tightly controlled. Low calcium concentrations are found in meningococcal disease with three-quarters of severely affected children having ionized or total hypocalcaemia.8 This is related to disease severity and seems not to be a consequence of calcium chelation. Parathormone concentrations are not altered consistently. The most likely cause of hypocalcaemia is intracellular redistribution.8 Although calcium infusions are often used to increase calcium concentration, information supporting the correction of hypocalcaemia in critically ill patients is limited. In critically ill adults, correction of hypocalcaemia increased the arterial pressure, without increasing the cardiac output.112 In animal models, administration of calcium increased mortality and administration of calcium antagonists lowered mortality.64 Given these ®ndings, it may be appropriate to use calcium infusions for refractory hypotension, though not for the correction of asymptomatic hypocalcaemia.

Coagulation

Severe meningococcal disease Table 1 Initial management of meningococcal disease 1 Initial assessment Airway Breathing Circulation (APLS), speci®cally: Cardiovascular instability: (i) Hypotension: systolic pressure <75 mm Hg under 4 years or <85 mm Hg if over 4 years (ii) Capillary re®ll time of >2 s Neurological instability: (i) Reduced consciousness (Glasgow Coma Scale <8 or deteriorating level of consciousness) (ii) Airway protection

2 I.V. access

STEPS 2±5 PROCEED SIMULTANEOUSLY

Intraosseous line if any delay

4 Resuscitation If cardiovascular instability (hypotensive or poor peripheral perfusion): Human albumin solution (HAS) 20 ml kg±1 4.5% or saline 0.9%, rapid infusion, which may be repeated immediately If more than 40 ml kg±1 of 4.5% HAS needed quickly (<1 h) consider: Tracheal intubation with ventilation Central venous access, initially aiming to maintain a central venous pressure (CVP) 8±10 cm H2O and for reliable delivery of inotropes Initial inotrope dobutamine (5 mg kg±1 min±1 increasing to 20 mg kg±1 min±1). At more than dobutamine 10 mg kg±1 min±1 add epinephrine (initially 0.01 mg kg±1 min±1). Consider norepinephrine at the same initial dose as epinephrine if 1.0 mg kg±1 min±1 epinephrine insuf®cient. Inotropes may be given peripherally Continuing ¯uid resuscitation (4.5% HAS) based on CVP If depressed or ¯uctuating level of consciousness or unable to protect airway: Intubation and ventilation to a normal PaCO2 With evidence of meningitis (neck stiffness) give dexamethasone 0.4 mg kg±1 twice daily for four doses 5 Antibiotics Cefotaxime i.v. 50 mg kg±1 four times a day for 5 days 6 Further management Appropriate support, usually attempted correction of clotting with fresh frozen plasma, transfusion of packed red cells to maintain a haemoglobin >9.0 g dl±1 Consider the need for haemo®ltration Maintain cardiovascular and ventilatory support Early institution of enteral feeds Oropharyngeal swab for N. meningitidis culture Enteral rifampicin to eliminate nasopharyngeal carriage of N. meningitidis

control studies, from the UK and a case-series from Scandinavia, compared the outcome of patients receiving pre-hospital antibiotics (parenteral penicillin is recommended in both countries) with those who did not, drawing opposite conclusions.22 99

infected oropharyngeal secretions at times of airway manipulation. They are not usually advised to take prophylactic antibiotics unless mouth to mouth resuscitation is given,3 though recently it has been proposed that face masks should be worn and that chemoprophylaxis should be given to those who are exposed to respiratory secretions directly.104

Standard therapy Standard treatment relies on good general paediatric care. Most children with meningococcal disease are cared for on general paediatric wards. With good clinical care, children with severe meningitis, with resulting complications for example of reduced consciousness or ®ts, are recognized and treated appropriately. Children who develop septic shock are also recognized and resuscitated appropriately. An approach to the resuscitation of children with severe meningococcal disease is given in Table 1. Recognition of the more ill children so that they may receive more aggressive therapy is important. Shock is more commonly a cause of deterioration than are the complications of meningitis. Shock may be recognized by poor peripheral perfusion, with grey clammy skin. The more

Improving the outcome of invasive disease Awareness Campaigns to increase the awareness of the importance of the classical petechial or purpuric rash are likely to accelerate presentation of patients with meningococcal disease.

Pre-emptive antibiotics Antibiotics should be administered as soon as the diagnosis of meningococcal disease is made,3 although they are administered unreliably before admission to hospital. Case77

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3 Sampling Blood for `gas' glucose measurement (BM Stix), routine biochemical investigations, blood count, clotting tests and cross-match or group and save Blood for culture, antigen testing and PCR

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Antibiotics should not be delayed pending a lumbar puncture. Scores have been developed to aid in the assessment of children with meningococcal disease. The Glasgow meningococcal score (GMS)97 has been much used, and as it relies only on the base de®cit, clinical assessment and simple addition, is a clinically applicable score. Although the GMS recognizes how ill children are, it does not predict how ill children may become. Children may present with a low score and subsequently deteriorate. Notwithstanding this, the GMS, with repeated rescoring, may aid in the management of children with meningococcal disease.

Novel therapies Steroids Steroids may be considered in two separate situations: in meningitis and in septicaemia. Steroids have improved the outcome of children with meningitis.68 A reduction in sequelae of meningococcal meningitis is more dif®cult to demonstrate. Currently, expert advice in the UK remains that steroids should not be used in meningococcal meningitis.68 In septicaemic meningococcal shock, steroids have been considered for some time. The adrenal haemorrhage of the Waterhouse±Friedrichsen syndrome led to concerns that steroid release may be inadequate. Longstanding evidence of adrenal insuf®ciency in meningococcal disease is supported by more recent work.90 In sepsis in general, two large trials of critically ill adults with infections failed to show a bene®t from steroid therapy. Latterly, two trials of critically ill adults requiring catecholamine infusions, found that the duration of catecholamine dependence was reduced by steroid therapy,35 though as yet no improvement in survival has been shown. In practice, children requiring higher doses of epinephrine or norepinephrine often receive supplemental steroids.

Haemo®ltration As endotoxin, and mediators released by endotoxin, drive meningococcal disease, haemo®ltration or plasmaphoresis have been used to `wash out' the endotoxins and proin¯ammatory cytokines. Although endotoxin clearance was not accelerated by plasma or whole blood exchange, the balance of cytokines may be favourably affected.36 Since the original reports, many case reports and case series have described technically successful haemodialysis, haemo®ltration, blood exchange or leucoplasmaphoresis in children. Furthermore, many of the series report impressively lower mortality in children treated with these strategies compared with historical controls.13 A single randomized trial has studied plasma®ltration in septic shock. In a small study of 30 patients, including only eight children, the mortality rate was unchanged by plasma®ltration.87 78

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extensive the rash, the more ill the child will be, though some children have severe illness despite only minimal rash. Up to 20% of children will not have the classical petechial or purpuric rash on presentation, so meningococcal disease cannot be excluded on the absence of the typical rash.65 The arterial pressure may be relatively well maintained, but more severely ill children are almost always impressively tachycardic. Shocked children are often obtunded and so are more amenable to interventions such as venepuncture than less ill children, which is a worrying sign. Ill children are usually tachypnoeic, whether as a consequence of acidosis or of ¯uid leak into the lungs. Very high or, more particularly, a low core temperature indicates an ill child. In laboratory investigations, a raised base de®cit, or lactate both suggest more severe disease, though capillary samples may not always be reliable and an arterial or well¯owing venous sample should be obtained to con®rm the ®ndings. Very ill children will have a low rather than a high white cell or neutrophil count, indicating overwhelming sepsis. Bacteria may be seen on the blood ®lm, though these numbers of bacteria usually indicate imminent death. A greater depression of platelet count or prolongation of clotting times usually indicates a more ill child. The platelet count is usually relatively well sustained on admission, falling 12±24 h later. The response to treatment is also important. Children with shock who respond rapidly to small volume ¯uid resuscitation are obviously less worrying than those in whom tachycardia and hypotension persist after treatment. The need for larger volumes of ¯uid indicates more severe disease. For example, if >40 ml kg±1 of colloid (a volume equivalent to half of the circulating volume) is given over a short time, intubation, central venous access and inotropes should be considered.83 Aggressive ¯uid resuscitation is of prime importance in paediatric septic shock.20 As large volumes of ¯uid may be used,70 this is best guided by central venous pressure measurements. Inotropes may be needed, and in severely ill children, may be needed before a central line has been placed. Often dobutamine or dopamine is the initial choice of inotrope, with progression to epinephrine, or norepinephrine, if needed. If the child remains hypotensive and poorly perfused in the face of epinephrine and norepinephrine and an adequate central venous pressure, the further management may involve steroids or a calcium infusion. These are considered further below. Inodilators (including the phosphodiesterase inhibitors) have been used, but published experience is limited. Children with meningitis are less likely to die than are children with sepsis, but should be monitored for a deterioration in level of consciousness or for ®ts. Lumbar puncture is contraindicated if the intracranial pressure is raised. Normal appearances on cerebral computed tomography do not mean that lumbar puncture will be safe.88 Lumbar puncture is to be avoided in the child who is cardiovascularly unstable or has clotting impairment.

Severe meningococcal disease Table 2 Randomized controlled trials of anti-endotoxin treatment in meningococcal disease Intervention Pentaglobin and polymyxin

Mortality Active treatment 7/23 (30%) mortality Controls 5/17 (29%) mortality P=0.94, difference in proportions 0.01 95% CI 0.03±0.27

J5 study group,57 France and Switzerland, 1992

Anti-endotoxin polyclonal antibody (J5)

Active treatment 10/40 (25%) mortality Controls 12/33 (36%) mortality P=0.317, difference in proportions 0.11 95% CI 0.32±0.09

Derkx,27 pan-European, 1999

Anti-endotoxin monoclonal antibody (HA-1A)

Active treatment 24/130 (18.5%) mortality Controls 37/137 (27%) mortality P=0.08, difference in proportions 0.09 95% CI 0.18±0.02

Levin,61 UK and USA, 2000

rBPI

Active treatment 14/190 (7.4%) mortality Controls 20/203 (9.9%) mortality P=0.48, difference in proportions 0.025 95% CI 0.08±0.03

Although the role of haemo®ltration as a speci®c therapy to aid clearance of in¯ammatory mediators is unclear, its importance in general management for supporting renal function and allowing the clearance of the large volumes of ¯uid which may need to be given in resuscitation, or in clotting factor support and drug treatment, is invaluable.

With evidence of improved survival from meningococcal shock after pretreatment with activated protein C in an animal model of meningococcal shock,91 aggressive correction of disturbance of coagulation modulators (protein C, protein S and antithrombin III) has been described in a small case series of meningococcal disease or septic purpura fulminans. In general, relatively good outcomes are reported despite a selection of severely ill patients.116 Often, as well as aggressive correction of modulators of coagulation, haemo®ltration or plasma®ltration was used. After the recent demonstration of reduced mortality in critically ill adults by using activated protein C treatment,12 and given the more marked depression of protein C in meningococcal disease, it may be argued that protein C replacement should be more widely used. Protein C replacement is not without complications, as was shown by the rate of serious bleeding after protein C replacement that was double that of controls. Protein C reduced in¯ammation as shown by a reduction of IL-6 concentrations. Plasminogen activator inhibitor-1 (PAI-1), an anti®brinolytic, is markedly elevated on presentation in meningococcal disease. The signi®cance of this is reinforced by the genetic studies of PAI-1. Several case reports describe the use of tissue plasminogen activator (t-PA).119 t-PA is described to improve perfusion to compromised limbs, and to improve the general condition of the patient. Again, there is a risk of serious bleeding. Seven of 70 patients treated with t-PA had signi®cant intracranial haemorrhages.119

Extracorporeal membrane oxygenation Extracorporeal membrane oxygenation (ECMO) has been used as rescue therapy for severely ill children with meningococcal disease. In a case series drawing together the experience of several centres, seven children were treated for intractable shock and ®ve for severe respiratory failure (which was later in the course of the disease). Survival to hospital discharge occurred in eight of the 12 (75% survival) in a group with a predicted mortality of 72%.42 ECMO is available in only a restricted number of sites. Children with intractable shock are too unstable for transfer, though if they present to a unit with ECMO, it may be an appropriate intervention. ECMO is feasible for severe respiratory failure, developing more slowly, later in the course of disease.

Modulators of coagulation There is good evidence of a disturbance of coagulation in severe meningococcal disease. Initially, heparin was used to reduce the morbidity and mortality of meningococcal disease. However, heparin infusion did not reduce the mortality rate in a study of a rabbit model of meningococcal disease.38 Although several case series have reported the use of heparin infusions in meningococcal disease, only one small randomized trial has been reported, in which no difference was seen between the heparin treated and control groups.46

Anti-endotoxin strategies As endotoxin plays a pivotal role in the development of meningococcal disease, attempts to inactive or clear endotoxin have been developed, including haemo®ltration. Speci®c anti-endotoxin strategies have been developed 79

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including: endotoxin binding chemicals such as polymyxin; antibodies to conserved components of endotoxin, both polyclonal (J5) and monoclonal (HA-1A); and bactericidal/ permeability-increasing protein (BPI), a natural compound which acts to bind and inactivate endotoxin. As yet, none of the anti-endotoxin treatments (Table 2) have been shown to reduce mortality. In the most recent trial, rBPI21 (a recombinant form of the N-terminal fragment of BPI) did not lower mortality signi®cantly.61 However, mortality was signi®cantly lower amongst the group who survived to receive all of the rBPI21 infusion. Amongst the reasons why anti-endotoxin strategies have been ineffective may be the fact that endotoxin releases a host of other mediators. Removing endotoxin leaving the other mediators is to `close the stable door after the horse has bolted'. However, animal work demonstrates that although anti-endotoxin treatments work best when given before endotoxin challenge, they still reduce in¯ammation and mortality when given after endotoxin administration.1 In addition, some of the anti-endotoxin treatments used have been ineffective. For example, polymyxin pretreatment does not alter either the in¯ammatory response or the mortality of rabbits in response to meningococcal LOS, though it does reduce the in¯ammatory response and mortality rate to E. coli lipopolysaccharide.10 Nor did the monoclonal antibody to endotoxin (HA-1A) reduce the in¯ammatory response to meningococcal endotoxin in an in vitro experiment.24 Interestingly, rabbits treated with i.v. immunoglobulin had lower endotoxin concentrations, but an unchanged mortality rate.94

Summary Meningococcal disease remains an important cause of severe illness in children and adults. The recent introduction of Group C conjugated vaccine is reducing the incidence of Group C disease, but invasive disease caused by other groups continues unabated.84 Clinical care of children with severe meningococcal disease relies on aggressive resuscitation and stabilization. There is as yet no speci®c treatment for meningococcal disease, though, hearteningly, the mortality of children with severe meningococcal disease is declining.108

1 Alpert G, Baldwin G, Thompson C, et al. Limulus antilipopolysaccharide factor protects rabbits from meningococcal endotoxin shock. J Infect Dis 1992; 165: 494±500 2 Anderson CTM, Berde CB, Sethna NF, Pribaz JJ. Meningococcal purpura fulminans: treatment of vascular insuf®ciency in a twoyear-old child with lumbar epidural sympathetic blockade. Anesthesiology 1989; 71: 463±4 3 Anonymous. Control of meningococcal disease: guidance for consultants in communicable disease. Commun Dis Rep CDR Rev 1995; 13: R189±95 4 Anonymous. Invasive meningococcal disease. Commun Dis Rep CDR Wkly 1998; 8: 2 5 Anonymous. Infectious disease in England and Wales: October to December 1998. Commun Dis Rep CDR Suppl 1999; 9: S5 6 Artenstein MS, Rust JH, Hunter DH, Lamson TH, Buescher EL. Acute respiratory disease and meningococcal infection in army recruits. JAMA 1967; 201: 1004±8 7 Baines PB, Stanford S, Bishop-Bailey D, et al. Nitric oxide production in meningococcal disease is directly related to disease severity. Crit Care Med 1999; 27: 1187±90 8 Baines PB, Thomson AP, Fraser WD, Hart CA. Hypocalcaemia in severe meningococcal infections. Arch Dis Child 2000; 83: 510±13 9 Baker M, McNicholas A, Garrett N, et al. Household crowding a major risk factor for epidemic meningococcal disease in Auckland children. Pediatr Infect Dis J 2000; 19: 983±90 10 Baldwin G, Alpert G, Caputo GL, et al. Effect of polymyxin B on experimental shock from meningococcal and Escherichia coli endotoxins. J Infect Dis 1991; 164: 542±9 11 Balligand J-L, Ungureanu D, Kelly RA, et al. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocyte follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993; 91: 2314±19 12 Bernard GR, Vincent J-L, Laterre P-F, et al. Ef®cacy and safety of recombinant human activated protein C for severe sepsis. New Engl J Med 2001; 344: 699±709 13 Bjorvatn B, Bjertnaes L, Fadnes HO, et al. Meningococcal septicaemia treated with combined plasmaphoresis and leucaphoresis or with blood exchange. Br Med J 1984; 288: 439±41 14 Boucek MM, Boerth RC, Artman M, Graham TP, Boucek RJ. Myocardial dysfunction in children with acute meningoccemia. J Pediatr 1984; 105: 538±42 15 Brandtzaeg P, Kierulf P, Gaustad P, et al. Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis 1989; 159: 195±204 16 Brandtzaeg P, Sandset PM, Joo GB, Ovstebo R, Abildgaard U, Kierulf P. The quantitative association of plasma endotoxin,

Prostacyclin After evidence that production of prostacyclin by endothelial cells is reduced by incubation with sera from children with meningococcal disease,53 prostacyclin has been used for its vasodilatory and anti-platelet activity to improve perfusion in severely ill children with meningococcal disease. There is no clinical information to support the use of prostacyclin speci®cally in meningococcal disease, though prostacyclin seems to have cytoprotective activity in many other situations, and has theoretical advantages. Use of prostacyclin may be limited by hypotension.

Strategies to maintain limb perfusion Topical nitrates have been reported to improve perfusion of children with focal ischaemia. Local sympathetic block by epidural and caudal techniques have been described,2 though would be contraindicated in most patients by the active sepsis, coagulopathy and cardiovascular instability. Distal limb perfusion may be compromised by the compartment syndrome. Measurement of compartment pressures may be useful, with surgical decompression where necessary. 80

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