Rationale for pertussis booster vaccination throughout life in Europe.

Although the introduction of universal pertussis immunisation in infants has greatly reduced the number of reported cases in infants and young children, disease incidence has been increasing in adolescents and adults in recent years. This changing epidemiological pattern is probably largely attributable to waning immunity after natural infection or vaccination. Furthermore, improved diagnostic testing, active surveillance, changes in disease susceptibility, vaccine characteristics, and increased awareness of the disease might also be contributing factors. Susceptibility to pertussis in adolescents and adults results not only in direct morbidity in these age groups, but also poses a transmission risk to susceptible non-immune infants who are often too young to be vaccinated. Because vaccination schedules vary across Europe, we review the pertussis situation in this region and propose considerations for use of pertussis booster vaccinations at different ages to reduce individual morbidity and transmission from present rates and increase herd protection.

Cost-effectiveness of adolescent pertussis vaccination for the Netherlands: using an individual-based dynamic model.

BACKGROUND: Despite widespread immunization programs, a clear increase in pertussis incidence is apparent in many developed countries during the last decades. Consequently, additional immunization strategies are considered to reduce the burden of disease. The aim of this study is to design an individual-based stochastic dynamic framework to model pertussis transmission in the population in order to predict the epidemiologic and economic consequences of the implementation of universal booster vaccination programs. Using this framework, we estimate the cost-effectiveness of universal adolescent pertussis booster vaccination at the age of 12 years in the Netherlands. METHODS/PRINCIPAL FINDINGS: We designed a discrete event simulation (DES) model to predict the epidemiological and economic consequences of implementing universal adolescent booster vaccination. We used national age-specific notification data over the period 1996-2000--corrected for underreporting--to calibrate the model assuming a steady state situation. Subsequently, booster vaccination was introduced. Input parameters of the model were derived from literature, national data sources (e.g. costing data, incidence and hospitalization data) and expert opinions. As there is no consensus on the duration of immunity acquired by natural infection, we considered two scenarios for this duration of protection (i.e. 8 and 15 years). In both scenarios, total pertussis incidence decreased as a result of adolescent vaccination. From a societal perspective, the cost-effectiveness was estimated at €4418/QALY (range: 3205-6364 € per QALY) and €6371/QALY (range: 4139-9549 € per QALY) for the 8- and 15-year protection scenarios, respectively. Sensitivity analyses revealed that the outcomes are most sensitive to the quality of life weights used for pertussis disease. CONCLUSIONS/SIGNIFICANCE: To our knowledge we designed the first individual-based dynamic framework to model pertussis transmission in the population. This study indicates that adolescent pertussis vaccination is likely to be a cost-effective intervention for The Netherlands. The model is suited to investigate further pertussis booster vaccination strategies.

Conclusions on (cost-)effectiveness of pertussis booster vaccination strategies highly dependent on selections made in evidence review.

This letter reacts on a paper recently published in this journal, reviewing the effectiveness and (cost-)effectiveness of pertussis booster vaccination strategies. We argue that a different selection of (cost-)effectiveness data could validly be made than the one presented in the review as being considered most robust. In particular, we explicitly present an alternative set of (cost-)effectiveness data.

Twenty years of pediatric tuberculous meningitis: a retrospective cohort study in the western cape of South Africa.

OBJECTIVE: Tuberculous meningitis is the most severe extrapulmonary complication of tuberculosis, with high morbidity and mortality rates. The objective of this study was to assess the relationship between presenting clinical characteristics and outcome of pediatric tuberculous meningitis. PATIENTS AND METHODS: We present a retrospective cohort study of all of the children diagnosed with tuberculous meningitis in a large university hospital in South Africa between January 1985 and April 2005. We compared demographic, clinical, and diagnostic characteristics with clinical outcome after 6 months of treatment. RESULTS: We included 554 patients. Common characteristics on admission were young age (82%; <5 years), stage II or III tuberculous meningitis (97%), nonspecific symptoms existing for >1 week (58%), poor weight gain or weight loss (91%), loss of consciousness (96%), motor deficit (63%), meningeal irritation (98%), raised intracranial pressure (23%), brainstem dysfunction (39%), and cranial nerve palsies(27%). Common features of tuberculous meningitis on computed tomography scan of the brain were hydrocephalus (82%), periventricular lucency (57%), infarctions(32%), and basal meningeal enhancement (75%). Clinical outcome after 6 months was as follows: normal (16%), mild sequelae (52%), severe sequelae (19%), and death (13%). All of the patients diagnosed with stage I tuberculous meningitis had normal outcome. Factors associated with poor outcome in univariate analyses were as follows: African ethnicity, young age, HIV coinfection, stage III tuberculous meningitis, absence of headache and vomiting, convulsions, decreased level of consciousness,motor deficits, cranial nerve palsies, raised intracranial pressure, brain stem dysfunction and radiographic evidence of hydrocephalus, periventricular lucency, and infarction. Ethnicity, stage of disease, headache, convulsions, motor function, brainstem dysfunction, and cerebral infarctions were independently associated with poor outcome in multivariate logistic regression analysis. CONCLUSIONS: Tuberculous meningitis starts with nonspecific symptoms and is often only diagnosed when brain damage has already occurred. Earlier diagnosis will improve outcome significantly. We were able to identify presenting variables independently associated with poor clinical outcome.

C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice.

In spite of antibiotic treatment, pneumococcal meningitis continues to be associated with significant morbidity and mortality. The complement system is a key component of innate immunity against invading pathogens. However, activation of complement is also involved in tissue damage, and complement inhibition by C1 inhibitor (C1-inh) is beneficial in animal models of endotoxemia and sepsis. In the present study, we demonstrate classical pathway complement activation during pneumococcal meningitis in rats. We also evaluate the effect of C1-inh treatment on clinical illness, bacterial clearance, and inflammatory responses in rats and mice with pneumococcal meningitis. C1-inh treatment was associated with reduced clinical illness, a less-pronounced inflammatory infiltrate around the meninges, and lower brain levels of proinflammatory cytokines and chemokines. C1-inh treatment increased bacterial clearance, possibly through an up-regulation of CR3. Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis.

A new murine model to study the pathogenesis of tuberculous meningitis.

Tuberculous meningitis (TM) is a severe complication of tuberculosis that mainly occurs during childhood. No murine models are available to study this disease. The purpose of the present study was to develop a murine model to investigate the pathogenesis of TM. Mice were intracerebrally injected with Mycobacterium tuberculosis. Bacilli could be cultured from brain homogenates, and, on histopathological examination, all mice were found to have meningeal cellular infiltration. We found elevated levels of chemoattractants for mononuclear phagocytes and neutrophilic granulocytes. This is the first murine model for TM that can be used for research on the host response to TM, in particular the innate immune response.

Academic and behavioral limitations and health-related quality of life in school-age survivors of bacterial meningitis.

The objectives of this study were to describe health-related quality of life of postmeningitic children and to examine the association between academic and/or behavioral limitations and health-related quality of life. One hundred and eighty-two children (mean age 9.7 years; range 5.3-14.2) were selected randomly from a cohort of 674 school-age children who recovered from non-Haemophilus influenzae type B bacterial meningitis. These children had neither meningitis with 'complex onset', nor prior cognitive or behavioral problems, nor severe disease sequelae. On average 7.4 years after meningitis, they were evaluated using an 'Academic Achievement Test' and their parents filled in the Child Behavior Checklist, the Child Health Questionnaire, and the Health Utilities Index. The long-term incidence of academic and/or behavioral limitations was 32%. Overall health-related quality of life of the postmeningitic children was decreased in comparison with that of a reference population of schoolchildren. The group of postmeningitic children with academic and/or behavioral limitations showed the most marked decrease in quality of life, especially concerning psychosocial health, cognition and family life. The negative effects on quality of life were not significantly influenced by age, gender, causative pathogen, presence of minor neurological impairment, or presence of hearing impairment. In conclusion, health-related quality of life of postmeningitic children is decreased, particularly of those with academic and/or behavioral limitations.

Pubertal development in children born small for gestational age.

UNLABELLED: Reduced fetal growth appears to be associated with precocious adrenarche, early puberty and polycystic ovary syndrome with subsequent fertility problems. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) and children born appropriate for gestational age (AGA). Physical examination was carried out twice. Mean age (+/-SD) at the first visit: SGA group, 9.1+/-1.1 yr; AGA group, 9.0+/-1.1 yr. AT FOLLOW-UP: SGA group, 11.6+/-1.0 yr; AGA group, 11.6 +/-1.1 yr. Pubertal stages of the children were assessed. Pubic hair was recorded as a measure of androgenization. Chronological age (CA) was expressed as a percentage of the age corresponding to the pubertal stage (CA/pubertal age [PA] x 100%). Estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) were measured in all children. FIRST VISIT: All children were prepubertal without signs of pubarche. DHEAS concentrations were higher in SGA children than in AGA children (p = 0.004). FOLLOW UP: Twenty SGA children and 15 AGA children were pubertal. CA/PA x 100% was lower in SGA girls than in AGA girls (p = 0.004). Since 2.5 years earlier all girls had been prepubertal, this means a more rapid progression in the SGA girls. CA/PA x 100% was similar in SGA and AGA boys (p = 0.1). DHEAS levels tended to be higher in SGA children than in AGA children (p = 0.06). These data support that a low birth weight may have long-lasting effects on pubertal development, as observed in a more rapid progression in SGA girls. In prepubertal SGA children, an exaggerated adrenarche is observed compared to AGA children, which tended to persist through puberty.

Neuropsychology of academic and behavioural limitations in school-age survivors of bacterial meningitis.

Neuropsychological impairments possibly underlying academic and/or behavioural limitations were studied in 149 school-age survivors of bacterial meningitis, 68 with and 81 without academic and/or behavioural limitations. Academic limitations affected mathematics, reading, and writing. Behavioural limitations were inferred from scores in the clinical range on the Child Behaviour Checklist. These children had been selected from a cohort of 674 children (57% males) who had recovered from non-Haemophilus influenzae type B bacterial meningitis and who had a mean age at infection of 2 years 4 months (range 1mo to 9y 5mo). They had neither 'complex onset' meningitis, prior cognitive or behavioural problems, nor severe disease sequelae. They were assessed with standardized assessment methods a mean of 7.8 years (range 4 to 10.4) after meningitis. Children with limitations (32% of the cohort) performed generically poorly on measures of cognitive functioning, speed, and motor steadiness, rather than having impairments in specific neuropsychological domains. The presence of two or more minor neurological signs was more frequent in the group with than in the group without limitations (30% versus 9%); this may explain the relatively poor speed and motor steadiness of the group with limitations.

Chemotactic activity of CXCL5 in cerebrospinal fluid of children with bacterial meningitis.

CXCL5 (epithelial-cell-derived neutrophil-activating protein (ENA-)78) is a CXC-chemokine that specifically acts on neutrophils. To obtain insight into the extent of local presence and action of CXCL5 during bacterial meningitis, we measured its concentrations in cerebrospinal fluid (CSF) of patients with culture-proven bacterial meningitis (n=14), aseptic meningitis (n=6), and controls (n=32) and compared these results with levels of other CXC-chemokines, CXCL8- (interleukin-8) and CXCL1-related oncogene (growth-related oncogene (GRO)-alpha). Patients with bacterial meningitis had profoundly elevated CSF concentrations of all three chemokines. CXCL5 was not detectable in patients with aseptic meningitis or control subjects. CSF from patients with bacterial meningitis exerted chemotactic activity towards neutrophils, which was partially inhibited by neutralizing antibodies against CXCL5 and CXCL8, but not CXCL1. CSF from controls exerted minor chemotactic activity, which could be strongly enhanced by the addition of recombinant CXCL5, CXCL8 or CXCL1. During bacterial meningitis, CXCL5 is elevated in CSF, where it is involved in the recruitment of neutrophils to the central nervous system.

Hearing loss at school age in survivors of bacterial meningitis: assessment, incidence, and prediction.

OBJECTIVES: To establish the incidence of sensorineural hearing loss in children who survived non-Haemophilus influenzae type B (Hib) bacterial meningitis, to highlight the actual percentage whose hearing was evaluated, and to develop a prediction rule to identify those who are at risk of hearing loss. METHODS: In 1999, we compiled a cohort of 628 school-aged children who were born between January 1986 and December 1994 and had survived non-Hib bacterial meningitis between January 1990 and December 1995. Presence of sensorineural hearing loss (>25 dB) was determined, based on information from questionnaires and medical records. Potential risk factors for hearing loss were obtained from medical records; independent predictors were identified using multivariate logistic regression analysis, leading to the formulation of a prediction rule. RESULTS: The incidence of hearing loss was 7%. The hearing of 68% of the children was evaluated as part of their routine follow-up after bacterial meningitis, resulting in the detection of 75% of the cases of hearing loss. The remaining 25% were detected after this follow-up had ended. Using a prediction rule based on 5 factors-duration of symptoms before admission >2 days, absence of petechiae, cerebrospinal fluid glucose level

Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis.

To determine the role of endogenous interleukin-18 (IL-18) in pneumococcal meningitis, meningitis was induced in IL-18 gene-deficient (IL-18(-/-)) and wild-type (WT) mice by intranasal inoculation of Streptococcus pneumoniae with hyaluronidase. Induction of meningitis resulted in an upregulation of both pro- and mature IL-18 in brain tissue in WT mice. IL-18(-/-) and WT mice were equally susceptible to develop meningitis after intranasal infection, yet IL-18(-/-) mice showed a prolonged survival and a suppressed inflammatory response, as reflected by a less profound inflammatory infiltrate around the meninges and lower concentrations of cytokines and chemokines in brain tissue. These findings suggest that endogenous IL-18 contributes to a detrimental inflammatory response during pneumococcal meningitis and that elimination of IL-18 may improve the outcome of this disease.

IL-1 receptor type 1 gene-deficient mice demonstrate an impaired host defense against pneumococcal meningitis.

The fatality rate associated with Streptococcus pneumoniae meningitis remains high despite adequate antibiotic treatment. IL-1 is an important proinflammatory cytokine, which is up-regulated in brain tissue after the induction of meningitis. To determine the role of IL-1 in pneumococcal meningitis we induced meningitis by intranasal inoculation with 8 x 10(4) CFU of S. pneumoniae and 180 U of hyaluronidase in IL-1R type I gene-deficient (IL-1R(-/-)) mice and wild-type mice. Meningitis resulted in elevated IL-1alpha and IL-1beta mRNA and protein levels in the brain. The absence of an intact IL-1 signal was associated with a higher susceptibility to develop meningitis. Furthermore, the lack of IL-1 impaired bacterial clearance, as reflected by an increased number of CFU in cerebrospinal fluid of IL-1R(-/-) mice. The characteristic pleocytosis of meningitis was not significantly altered in IL-1R(-/-) mice, but meningitis was associated with lower brain levels of cytokines. The mortality was significantly higher and earlier in the course of the disease in IL-1R(-/-) mice. These results demonstrate that endogenous IL-1 is required for an adequate host defense in pneumococcal meningitis.

Interleukin-10 negatively regulates local cytokine and chemokine production but does not influence antibacterial host defense during murine pneumococcal meningitis.

To determine the role of endogenous interleukin-10 (IL-10) in local host defense during pneumococcal meningitis, the inflammatory responses of IL-10-gene-deficient and wild-type mice after the induction of meningitis were compared. The absence of IL-10 was associated with higher cytokine and chemokine concentrations and a more pronounced infiltrate, but antibacterial defense or survival was not influenced.

CXC-chemokines KC and macrophage inflammatory protein-2 (MIP-2) synergistically induce leukocyte recruitment to the central nervous system in rats.

Intracisternal injection of the CXC-chemokines KC or macrophage inflammatory protein (MIP)-2 induced a pleocytosis in the cerebrospinal fluid (CSF) of rats in a dose dependent way. MIP-2 was much more potent than KC. The concurrent injection of both chemokines revealed a profound synergistic effect on leukocyte recruitment into CSF.