RESUMEN
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Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Artritis Infecciosa/diagnóstico , Artritis Infecciosa/tratamiento farmacológico , Artritis Infecciosa/fisiopatología , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/complicaciones , Infecciones Meningocócicas/tratamiento farmacológico , Neisseria meningitidis Serogrupo W-135 , Neisseria meningitidis Serogrupo W-135/aislamiento & purificación , Ceftriaxona/uso terapéutico , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Hemartrosis/complicaciones , Hemartrosis/tratamiento farmacológicoRESUMEN
BACKGROUND: In England and Wales, the incidence of invasive meningococcal disease has been declining for more than a decade, but meningococcal group W (MenW) cases have been increasing since 2009. METHODS: Public Health England conducts enhanced national surveillance of invasive meningococcal disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed MenW cases diagnosed during 3 epidemiologic years (2010-2011 to 2012-2013), alongside whole-genome sequencing analysis of the clinical isolates. RESULTS: The year-on-year increase in invasive MenW disease across all age groups since 2009-2010 was due to rapid endemic expansion of a single clone belonging to the sequence type 11 complex (cc11). In 2013-2014, MenW was responsible for 15% of all invasive meningococcal disease. All but 1 of the recent MenW:cc11 isolates were very closely related, consistent with recent clonal expansion. Clinical follow-up of all 129 MenW cases diagnosed during 2010-2011 to 2012-2013 revealed that most patients were previously healthy (n = 105 [81%]), had not travelled abroad prior to illness and the majority presented with septicemia (n = 63 [49%]), meningitis (n = 16 [12%]) or both (n = 21 [16%]); however, one-quarter had atypical presentations including pneumonia (n = 15 [12%]), septic arthritis (n = 9 [7%]), and epiglottitis/supraglottitis (n = 5 [4%]). Forty-eight (37%) required intensive care and 15 (12%) died. There was no association between infecting strain, clinical disease, or outcome. CONCLUSIONS: The recent increase in invasive MenW disease in England and Wales is due to rapid endemic expansion of a single clone belonging to cc11 and is associated with severe disease with unusual clinical presentations. This increase will require careful monitoring in the coming years.
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Enfermedades Endémicas , Meningitis Meningocócica/epidemiología , Meningitis Meningocócica/microbiología , Infecciones Meningocócicas/epidemiología , Infecciones Meningocócicas/microbiología , Neisseria meningitidis/clasificación , Adolescente , Adulto , Anciano , Artritis Infecciosa/epidemiología , Artritis Infecciosa/microbiología , Cápsulas Bacterianas/clasificación , Niño , Preescolar , Inglaterra/epidemiología , Monitoreo Epidemiológico , Femenino , Estudios de Seguimiento , Genoma Bacteriano , Humanos , Lactante , Masculino , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/mortalidad , Persona de Mediana Edad , Neisseria meningitidis/genética , Neisseria meningitidis/aislamiento & purificación , Fenotipo , Filogenia , Neumonía Bacteriana/epidemiología , Neumonía Bacteriana/microbiología , Estudios Prospectivos , Estudios Retrospectivos , Sepsis/epidemiología , Sepsis/microbiología , Análisis de Secuencia de ADN , Supraglotitis/epidemiología , Supraglotitis/microbiología , Gales/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The serogroup A conjugate meningococcal vaccine, MenAfriVac, was introduced in mass vaccination campaigns in December 2010 in Burkina Faso, Mali and Niger. In the coming years, vaccination will be extended to other African countries at risk of epidemics. To document the molecular characteristics of disease-causing meningococcal strains circulating in the meningitis belt of Africa before vaccine introduction, the World Health Organization Collaborating Centers on Meningococci in Europe and United States established a common strain collection of 773 isolates from cases of invasive meningococcal disease collected between 2004 and 2010 from 13 sub-Saharan countries. METHODOLOGY: All isolates were characterized by multilocus sequence typing, and 487 (62%) were also analyzed for genetic variation in the surface antigens PorA and FetA. Antibiotic susceptibility was tested for part of the collection. PRINCIPAL FINDINGS: Only 19 sequence types (STs) belonging to 6 clonal complexes were revealed. ST-5 clonal complex dominated with 578 (74.8%) isolates. All ST-5 complex isolates were remarkably homogeneous in their PorA (P1.20,9) and FetA (F3-1) and characterized the serogroup A strains which have been responsible for most epidemics during this time period. Sixty-eight (8.8%) of the 773 isolates belonged to the ST-11 clonal complex which was mainly represented by serogroup W135, while an additional 38 (4.9%) W135 isolates belonged to the ST-175 complex. Forty-eight (6.2%) serogroup X isolates from West Africa belonged to the ST-181 complex, while serogroup X cases in Kenya and Uganda were caused by an unrelated clone, ST-5403. Serogroup X, ST-181, emerged in Burkina Faso before vaccine introduction. CONCLUSIONS: In the seven years preceding introduction of a new serogroup A conjugate vaccine, serogroup A of the ST-5 clonal complex was identified as the predominant disease-causing strain.
Asunto(s)
Infecciones Meningocócicas/microbiología , Neisseria meningitidis/genética , África del Sur del Sahara , Antibacterianos/farmacología , Variación Genética , Humanos , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/tratamiento farmacológico , Neisseria meningitidis/clasificación , Neisseria meningitidis/efectos de los fármacos , Neisseria meningitidis/aislamiento & purificación , Porinas/genética , SerotipificaciónRESUMEN
The clinical symptoms induced by Neisseria meningitidis reflect compartmentalized intravascular and intracranial bacterial growth and inflammation. In this chapter, we describe a classification system for meningococcal disease based on the nature of the clinical symptoms. Meningococci invade the subarachnoid space and cause meningitis in as many as 50-70% of patients. The bacteremic phase is moderate in patients with meningitis and mild systemic meningococcemia but graded high in patients with septic shock. Three landmark studies using this classification system and comprising 862 patients showed that 37-49% developed meningitis without shock, 10-18% shock without meningitis, 7-12% shock and meningitis, and 18-33% had mild meningococcemia without shock or meningitis. N. meningitidis lipopolysaccharide (LPS) is the principal trigger of the innate immune system via activation of the Toll-like receptor 4-MD2 cell surface receptor complex on myeloid and nonmyeloid human cells. The intracellular signals are conveyed via MyD88-dependent and -independent pathways altering the expression of >4,600 genes in target cells such as monocytes. However, non-LPS molecules contribute to inflammation, but 10-100-fold higher concentrations are required to reach the same responses as induced by LPS. Activation of the complement and coagulation systems is related to the bacterial load in the circulation and contributes to the development of shock, organ dysfunction, thrombus formation, bleeding, and long-term complications in patients. Despite rapid intervention and advances in patient intensive care, why as many as 30% of patients with systemic meningococcal disease develop massive meningococcemia leading to shock and death is still not understood.
Asunto(s)
Inmunidad Innata/inmunología , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/fisiopatología , Modelos Animales , Neisseria meningitidis/inmunología , Investigación , Choque Séptico/fisiopatología , Síndrome de Waterhouse-Friderichsen/fisiopatología , Animales , Activación de Complemento/inmunología , ADN Bacteriano/sangre , Humanos , Lipopolisacáridos/química , Infecciones Meningocócicas/microbiología , PorcinosRESUMEN
In order to asses the clinical forms of meningococcal disease, we reviewed 201 cases diagnosed as meningococcal disease in the University Hospital of the Fluminense Federal University in Rio de Janeiro, 185 of which met the inclusion criteria. Clinical and laboratorial characterization allowed for grouping of the cases as follows: meningococcal meningitis, 18%; meningitis with septicemia, 62%; and septicemia, 20%. Available epidemiological data did not differentiate clinical forms. The following were significantly greater in meningococcal meningitis: duration of clinical history; frequency of neurological manifestations; positive bacterioscopy; culture and latex test in cerebrospinal fluid. The following were significantly predominant in septicemia: shock; fatal outcome and higher partial thromboplastin time. Septicemia and meningitis with septicemia were differentiated from meningococcal meningitis in the following: duration of clinical history; occurrence of focal neurological signs; disseminated intravascular coagulation; and arthritis. Clinical and laboratory data lead us to admit meningococcal meningitis as a localized form of Meningococcal disease, and meningitis with septicemia and septicemia as variations in severity of the systemic form of the disease.
Asunto(s)
Infecciones Meningocócicas/clasificación , Sepsis/microbiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Meningitis Meningocócica/complicaciones , Meningitis Meningocócica/diagnóstico , Infecciones Meningocócicas/complicaciones , Infecciones Meningocócicas/diagnóstico , Persona de Mediana Edad , Estudios Retrospectivos , Sepsis/complicaciones , Sepsis/diagnósticoAsunto(s)
Artritis Infecciosa/inmunología , Complemento C2/deficiencia , Enfermedades Genéticas Congénitas/inmunología , Infecciones Meningocócicas/inmunología , Neisseria meningitidis , Artritis Infecciosa/microbiología , Cefotaxima/uso terapéutico , Niño , Complemento C2/genética , Femenino , Humanos , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Neisseria meningitidis/clasificación , Neisseria meningitidis/efectos de los fármacos , Neisseria meningitidis/patogenicidad , Rifampin/uso terapéutico , SerotipificaciónRESUMEN
Visando avaliar formas clínicas da doença meningocócica, foram revistos 201 casos diagnosticados como doença meningocócica, em Hospital Universitário da Universidade Federal Fluminense; durante o período de 1971 a 1996, dos quais 185 preencheram os critérios de inclusão. A caracterização clínico-laboratorial permitiu reagrupá-los nas formas de doença meningocócica com meningite, 18 por cento, meningite e septicemia, 62 por cento, e septicemia, 20 por cento. Dados epidemiológicos disponíveis não diferenciaram formas clínicas. Na meningite meningocócica foi significativamente maior: tempo de história clínica; freqüência de manifestações neurológicas; e positividade da bacterioscopia, cultura e teste do látex no líquor. Na septicemia menigocócica, houve predomínio significativamente de: choque; letalidade e níveis maiores de tempo parcial de tromboplastina. Septicemia meningogócica e septicemia com meningite se diferenciaram da meningite meningocócica quanto a: tempo de história clínica; ocorrência de sinais neurológicos focais; coagulação intravascular disseminada e artrite. Dados clínico-laboratoriais levam a admitir meningite como forma localizada de doença meningocócica, e septicemia com meningite e septicemia como variações de gravidade da forma sistêmica da doença.
In order to asses the clinical forms of meningococcal disease, we reviewed 201 cases diagnosed as meningococcal disease in the University Hospital of the Fluminense Federal University in Rio de Janeiro, 185 of which met the inclusion criteria. Clinical and laboratorial characterization allowed for grouping of the cases as follows: meningococcal meningitis, 18 percent; meningitis with septicemia, 62 percent; and septicemia, 20 percent. Available epidemiological data did not differentiate clinical forms. The following were significantly greater in meningococcal meningitis: duration of clinical history; frequency of neurological manifestations; positive bacterioscopy; culture and latex test in cerebrospinal fluid. The following were significantly predominant in septicemia: shock; fatal outcome and higher partial thromboplastin time. Septicemia and meningitis with septicemia were differentiated from meningococcal meningitis in the following: duration of clinical history; occurrence of focal neurological signs; disseminated intravascular coagulation; and arthritis. Clinical and laboratory data lead us to admit meningococcal meningitis as a localized form of Meningococcal disease, and meningitis with septicemia and septicemia as variations in severity of the systemic form of the disease.
Asunto(s)
Humanos , Masculino , Femenino , Lactante , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Infecciones Meningocócicas/clasificación , Sepsis/microbiología , Meningitis Meningocócica/complicaciones , Meningitis Meningocócica/diagnóstico , Infecciones Meningocócicas/complicaciones , Infecciones Meningocócicas/diagnóstico , Estudios Retrospectivos , Sepsis/complicaciones , Sepsis/diagnósticoRESUMEN
OBJECTIVE: To investigate the levels of human neutrophil elastase and lymphocyte-derived granzymes A and B in relation to disease severity in children with meningococcal disease. DESIGN: Clinical observational cohort study. SETTING: Paediatric intensive care unit. PATIENTS: All patients with meningococcal disease during the study period were included. MEASUREMENTS AND RESULTS: Blood sampling was done on the day of admission and on days 3 and 7. Assays for elastase and granzymes were done with ELISA. Sixty-one patients were included: 19 having distinct meningitis; 17 meningitis and shock; and 25 fulminant septicaemia. On admission levels of elastase were increased in all patients, being highest in those with fulminant septicaemia and lowest in those with distinct meningitis. Granzyme A (although marginally) and granzyme B levels were only increased in patients with shock. In 20 of the 28 patients admitted for > or = 3 days elastase decreased from admission ("rapid-decrease" group). In the remaining 8 patients, elastase started to decrease after 2 days ("slow-decrease" group). Patients of the "slow-decrease" group had a higher temperature up to day 4, needed more respiratory support (mean airway pressure in cm H2O on days 3 and 4: p=0.02 and p<0.01, respectively), and more circulatory support (>2 inotropic agents on day 3; p=0.04) compared with the "rapid-decrease" group. CONCLUSIONS: Human neutrophil elastase and granzyme B are related with disease severity during the initial phase of meningococcal disease and prolonged neutrophil activation is associated with the extent of organ dysfunction during the period thereafter.
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Elastasa de Leucocito/sangre , Infecciones Meningocócicas/enzimología , Serina Endopeptidasas/sangre , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Granzimas , Humanos , Unidades de Cuidado Intensivo Pediátrico , Masculino , Infecciones Meningocócicas/clasificación , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
To determine the case fatality rate and risk factors for death in children with invasive meningococcal infection, 163 children admitted with meningococcal disease to the Instituto Materno Infantil de Pernambuco, a tertiary paediatric teaching hospital in Recife, Brazil, were included in this retrospective cohort study. Cases were categorised as meningitis, septicaemia and septicaemia with meningitis. Forty-six (28.2 per cent) children had meningitis alone, 88 (54 per cent) septicaemia and meningitis and 29 (17.8 per cent) only septicaemia. Four of the patients with meningitis died (8.7 per cent), compared to 31 out of the 88 (35.2 per cent) with septicaemia and meningitis and 18 of the 29 (62.1 per cent) with septicaemia alone (p < 0.001). Symptoms <24 h (AOR 3.8, 95 per cent CI 1.1-13.1), platelet count <100 000 mm(3) (AOR 13.8, 95 per cent CI 3.1-60.9) and acidosis (AOR 6.0, 95 per cent CI 1.7-21) were the significant risk factors for death. Invasive meningococcal infection has a high case-fatality rate in this tertiary centre in Recife, especially in the septic forms. The identification of risk factors for death could contribute to the early recognition of patients with higher risk on admission in a middle-income country population.
Asunto(s)
Infecciones Meningocócicas/mortalidad , Neisseria meningitidis/aislamiento & purificación , Adolescente , Brasil , Niño , Preescolar , Femenino , Hospitalización , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico , Masculino , Registros Médicos , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/complicaciones , Neisseria meningitidis/patogenicidad , Estudios Retrospectivos , Factores de Riesgo , Sepsis/complicacionesRESUMEN
Due to a high complication and case fatality rate, meningococcal diseases are important health problems both in tropical countries experiencing severe epidemics as well as in countries of moderate climate zones. Worldwide N. meningitidis of sero-groups A, B, and C are predominant and to a lesser extent serogroups W (135) and Y play a role, whereas in Europe more than 90 % of meningococcal diseases are caused by serogroups B and C of N. meningitidis. In Germany and other developed countries the majority of cases occur in very young children and adolescents. Since many years, meningococcal polysaccharide vaccines against diseases due to N.meningitidis serogroup A, C, Y and W (135) are commercially available. Unfortunately, a vaccine against diseases caused by N. meningitidis serogroup B is still under development. The recently developed and licensed conjugated meningococcal vaccines against N. meningitidis serogroup C are also protective against disease in very young children. Eight countries in Western Europe as well as Australia have already established country-wide immunization programs for children and adolescents. Within only 2 to 3 years, well managed programs have achieved far-reaching control of meningococcal C disease in UK and the Netherlands. In Germany, the Advisory Committee on Immunization (STIKO recommends immunization for selected risk groups. The current increase of the percentage of meningococcal C diseases to 28 - 30 % gives reason for further discussion regarding immunization strategies. How-ever, the STIKO expressively declares, that in addition to the recommendation for risk groups, the physician can use all vaccines licensed in Germany without any restriction. It is his/her responsibility to advice the patients regarding immunization possibilities against the life-threatening meningococcal disease, particularly if cases are occurring.
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Infecciones Meningocócicas/epidemiología , Infecciones Meningocócicas/terapia , Inglaterra/epidemiología , Geografía , Humanos , Incidencia , Infecciones Meningocócicas/clasificación , Gales/epidemiologíaAsunto(s)
Infecciones Meningocócicas/clasificación , Modelos Estadísticos , Índice de Severidad de la Enfermedad , Choque Séptico/clasificación , Niño , Mortalidad Hospitalaria , Humanos , Infecciones Meningocócicas/mortalidad , Valor Predictivo de las Pruebas , Pronóstico , Proyectos de Investigación/normas , Choque Séptico/mortalidadRESUMEN
The polymerase chain reaction (PCR) can be used to investigate suspected meningococcal infection, with rapid results. We became aware that Birmingham Health Authority was not being informed about certain patients on whom meningococcal PCR had been performed. To establish whether notification was overlooked in some patients with suspected meningococcal disease, or whether PCR was performed on patients in whom it was thought meningococcal disease was unlikely, we compared numbers of patients notified to us over six months who had PCR with numbers of patients not notified who had PCR. Between 1st August 1999 and 31st January 2000, 54 PCR requests were made on seventy-seven notified patients; 51 PCR requests were made on non-notified patients and none were positive. Median age and length of stay were shorter in the non-notified patients. We conclude: (i) PCR may be being used inappropriately on younger patients who have shorter admissions and are unlikely to have meningococcal disease; (ii) in a number of patients initially admitted and notified with meningococcal disease the diagnosis is subsequently reconsidered. A 'denotification' procedure for such patients could make information on meningococcal disease more reliable.
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Notificación de Enfermedades , Infecciones Meningocócicas/epidemiología , Reacción en Cadena de la Polimerasa , Adolescente , Adulto , Anciano , Niño , Preescolar , Inglaterra/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Tiempo de Internación/estadística & datos numéricos , Masculino , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/diagnóstico , Persona de Mediana Edad , Estadísticas no ParamétricasRESUMEN
We examined the use of polymerase chain reaction (PCR) in investigating suspected cases of meningococcal infection in Birmingham. Data held by Birmingham Health Authority were interrogated to determine cases of suspected or confirmed meningococcal infection for a 3-year period from April 1996. The microbiology departments of five local hospitals completed a standard proforma about the microbiological investigation of cases and included details of patient age, clinical presentation and method of confirmation of the clinical diagnosis. Of 273 cases, 123 had PCR performed on either cerebrospinal fluid and/or blood. Groups more likely to have a PCR done were those presenting with septicaemia alone, and those in the 5-14 year age group. In 33 cases. PCR was the only positive microbiological result. Over the study period there was increasing but variable use of PCR in the investigation of meningococcal infection and PCR increased the yield of confirmed cases.
Asunto(s)
Infecciones Meningocócicas/epidemiología , Neisseria meningitidis/aislamiento & purificación , Adolescente , Adulto , Distribución por Edad , Niño , Preescolar , Inglaterra/epidemiología , Humanos , Lactante , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/complicaciones , Infecciones Meningocócicas/diagnóstico , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Sepsis/complicaciones , Sepsis/epidemiologíaRESUMEN
OBJECTIVES: To review the scientific rationale for the clinical use of recombinant bactericidal permeability-increasing protein (rBPI21) and to discuss the results, implications, and lessons learned during the clinical development of rBPI21 for adjunctive treatment of children with severe meningococcemia. DATA SOURCES: The published medical literature. STUDY SELECTION: Of the phase I/II and phase III trials in humans, preclinical experimental studies were selected. Data from these sources are presented in the context of the authors' experiences as principal investigators in the phase I/II and/or phase III clinical trials. DATA EXTRACTION AND DATA SYNTHESIS: Bactericidal permeability-increasing protein and N-terminal fragments of bactericidal permeability-increasing protein, such as rBPI21, bind and neutralize endotoxin and are potently bactericidal against both smooth and rough forms of Gram-negative bacteria, including Neisseria meningitidis. Based on these properties and compelling preclinical data indicating that administration of rBPI21 reduced mortality in several models of sepsis, we initiated clinical trials by using rBPI21 as adjunctive therapy for children with severe meningococcemia. Data from the phase III, randomized, placebo-controlled trial indicate that rBPI21 reduces clinically significant morbidities and improves the functional outcome of children with severe meningococcemia. No statistically significant benefit in mortality was demonstrated; however, because of the rare incidence of disease and the rapidity of death in this study, the trial was substantially underpowered to detect a statistically significant mortality advantage. Before the completion of the trial, the probability that the study might have been underpowered to detect a significant reduction in mortality was recognized. An attempt at selecting a previously unvalidated composite end point to increase the meaningful event rate for the primary end point proved unsuccessful. Significant improvements were seen in other prospectively defined outcome variables that suggest an overall substantial benefit of therapy with rBPI21 in children with severe meningococcemia. CONCLUSIONS: As the largest therapeutic trial conducted in pediatric critical care, the phase III trial of rBPI21 demonstrates important principles that can influence the design of future trials targeting rare, life-threatening diseases.
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Bacteriemia/tratamiento farmacológico , Proteínas de la Membrana/uso terapéutico , Infecciones Meningocócicas/tratamiento farmacológico , Actividades Cotidianas , Animales , Bacteriemia/clasificación , Bacteriemia/complicaciones , Bacteriemia/mortalidad , Niño , Ensayos Clínicos Fase III como Asunto , Personas con Discapacidad , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Proteínas de la Membrana/farmacología , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/complicaciones , Infecciones Meningocócicas/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis. METHODS: We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat. FINDINGS: Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019). INTERPRETATION: Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.
Asunto(s)
Bacteriemia/tratamiento farmacológico , Proteínas de la Membrana/uso terapéutico , Infecciones Meningocócicas/tratamiento farmacológico , Adolescente , Amputación Quirúrgica/estadística & datos numéricos , Bacteriemia/clasificación , Bacteriemia/mortalidad , Quimioterapia Adyuvante , Niño , Preescolar , Método Doble Ciego , Endotoxinas , Femenino , Escala de Coma de Glasgow , Humanos , Lactante , Masculino , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/mortalidad , Resultado del Tratamiento , Reino Unido , Estados UnidosRESUMEN
OBJECTIVES: Meningococcal disease is a homogeneous and well-characterized form of sepsis. Cardiovascular collapse is prominent in severe meningococcal disease. Nitric oxide overproduction may be a mediator of cardiovascular collapse. We relate the level of nitric oxide metabolites, nitrates and nitrites, to disease severity in meningococcal disease. DESIGN: Prospective, nonrandomized study. SETTING: Tertiary referral pediatric intensive care unit. PATIENTS: Children admitted with a clinical diagnosis of meningococcal disease. INTERVENTIONS: Blood was sampled from children with meningococcal disease. Disease severity was scored using the Glasgow meningococcal septicemia prognostic score and pediatric risk of mortality score. Plasma nitrates and nitrites were measured in stored plasma using the Greiss reaction after conversion of all the nitrate to nitrite. MEASUREMENTS AND MAIN RESULTS: Twenty-two children were studied. In 19, the final diagnosis was meningococcal disease. Of the 19 children with meningococcal disease, 7 had a Glasgow meningococcal septicemia prognostic score of <8 (mild) and 12 had a Glasgow meningococcal septicemia prognostic score > or = 8 (severe). Three children died, all of these being in the severely affected group. Higher levels of nitrates and nitrites were seen in the more severely affected children (median admission nitrates and nitrites, 27.5 vs. 59.7 nmol/mL; p = 0.063; median peak nitrates and nitrites, 49.9 vs. 114 nmol/mL; p = .01) or those with an increased predicted mortality using pediatric risk of mortality (Spearman's p 0.742; p = .0003). CONCLUSIONS: Higher levels of nitrates and nitrites are seen in sicker children with meningococcal disease.
Asunto(s)
Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/metabolismo , Óxido Nítrico/biosíntesis , Niño , Escala de Coma de Glasgow , Humanos , Unidades de Cuidado Intensivo Pediátrico , Infecciones Meningocócicas/mortalidad , Nitratos/sangre , Óxido Nítrico/metabolismo , Nitritos/sangre , Pronóstico , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
Neisseria meningitidis serogroup C bactericidal titers and class-specific enzyme-linked immunosorbent assay (ELISA) antibody concentrations were measured in sera from 173 children (1 to 5 years old) before and 6 weeks and 7 months following vaccination with a quadrivalent (A/C/Y/W-135) polysaccharide vaccine. The immune responses of the children were compared with those of 40 adults 6 weeks postvaccination. Both bactericidal titers and ELISA antibody concentrations were significantly higher in the adults than in the children (P < 0.05). In addition, the ratio of immunoglobulin G (IgG) to IgM was higher in the children than in the adults. With an ELISA total antibody concentration of >/=2 microg/ml used as a measure of seroconversion, >/=84% of the individuals from each age group responded to the serogroup C polysaccharide. However, with a >/=4-fold-increase in bactericidal titer used, only 18% of 1-year-olds, 32% of 2-year-olds, and 50 to 60% of 3-, 4-, and 5-year-olds seroconverted. The ELISA results suggest that >50% of all children retained >/=2 microg of total antibody per ml at 7 months postimmunization. However, the bactericidal titers suggest that <10% of children <4 years old retained a >/=4-fold increase at 7 months following vaccination. Of particular note, 59 of 79 sera (75%) from the 1- and 2-year-olds had high ELISA antibody concentrations (2 to 20 microg/ml) with no associated bactericidal titer (<1:8). Discordant results between bactericidal titers and ELISA antibody concentrations were not explained by the presence of IgA blocking antibody or relative levels of IgG and IgM. The bactericidal results show age-dependent differences in the production and retention of antibody in young children immunized with serogroup C polysaccharide; these differences are not evident with the ELISA data.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Vacunas Bacterianas/uso terapéutico , Infecciones Meningocócicas/prevención & control , Polisacáridos Bacterianos/uso terapéutico , Vacunación , Adulto , Factores de Edad , Especificidad de Anticuerpos , Vacunas Bacterianas/inmunología , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas Inmunológicas , Lactante , Infecciones Meningocócicas/clasificación , Infecciones Meningocócicas/inmunología , Montana , Polisacáridos Bacterianos/inmunología , SerotipificaciónRESUMEN
Meningococcal arthritis is a recognized manifestation of Neisseria meningitidis infection, the presentation of which may be confusing. Although arthritis occurs in the setting of meningococcal meningitis, it may also be seen as a primary event without neurological involvement and with or without cutaneous manifestations. We describe a patient with primary meningococcal arthritis and review the literature relating to the clinical types and pathogenic mechanisms. Comparisons of patient series from 1980 to the present with those reported before 1980 are described.