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Aim: To determine the occurrence of educational, behavioural and general health problems in Dutch school-age survivors of bacterial meningitis.Methods: A cohort of 680 school-age survivors of meningitis caused by the most common Gram-positive and Gram-negative bacteria was established approximately 6y after the children's illness. Children with Haemophilus influenzae type b (Hib) meningitis were excluded because this form of the disease has virtually disappeared. Parents completed questionnaires on educational, behavioural and general health problems. The reference group comprised 304 school-age siblings and peers.Results: Postmeningitic children were more likely than controls to under achieve at school: 20% vs 5% (odds ratio 5.6; 95% confidence interval 3.0-10.7). The postmeningitic children repeated a year twice as often as the children in the reference group (16% vs 8%, odds ratio: 2.5, 95% confidence interval 1.5-4.2) and were referred to a special-needs school four times more frequently (8% vs 2%, odds ratio: 5.5; 95% confidence interval 2.0-15.4). Parents also reported more behavioural problems at home. More than half of the postmeningitic children experienced general health problems. The causative pathogen or age at infection had no influence on the relative frequency of educational and behavioural problems, and reduced auditory functioning played only a small part in these problems.Conclusion: Parents perceive educational, behavioural and general health problems in more than 30% of postmeningitic children. Until it is clear which children are at highest risk of developing these problems, it will be necessary to follow postmeningitic children into their school-age years. [ABSTRACT FROM AUTHOR]

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.

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.

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.

Cat-scratch disease (CSD), caused by Bartonella henselae infection, can mimic malignancy and can manifest atypically. Reliable serological testing is therefore of great clinical importance. The diagnostic performance of immunofluorescence assay (IFA) and ELISA was evaluated in a group of Dutch patients with proven CSD (clinical diagnosis confirmed by PCR). Sera of 51 CSD patients and 56 controls (patients with similar symptoms, but who were B. henselae PCR-negative and had an alternative confirmed diagnosis) were tested for anti-B. henselae IgM and IgG by IFA and ELISA. A commercially available IFA test for IgM had a sensitivity of 6%. In-house assays for IgM showed specificities of 93% (IFA) and 91% (ELISA), but with low sensitivities (53% and 65%, respectively). With a specificity of 82% (IFA) and 91% (ELISA), in-house IgG testing showed a significantly higher sensitivity in IFA (67%) than in ELISA (28%, p <0.01). Sensitivity was higher for genotype I (38-75%) than for genotype II (7-67%) infections, but this was only statistically significant for IgG ELISA (p <0.05). In conclusion, detection of IgM against B. henselae by in-house ELISA and IFA was highly specific for the diagnosis of CSD. The high seroprevalence in healthy individuals limits the clinical value of IgG detection for diagnosing CSD. Given the low sensitivity of the serological assays, negative serology does not rule out CSD and warrants further investigation, including PCR. Adding locally isolated (e.g., genotype II) B. henselae strains to future tests might improve the sensitivity.

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.

Aim: In pertussis-like respiratory infections, once pertussis has been laboratory confirmed, other potential causative pathogens will seldom be looked for. Probably most mixed infections are found accidentally and since these mixed infections might cause a more severe disease we performed a retrospective study of their incidence., Methods: We selected from 2 groups of patients with serologically confirmed Bordetella (B.) pertussis infection those in whom serology for other respiratory pathogens had also been performed. Group 1 consisted of 50 pertussis patients with 51 episodes of B. pertussis infection selected from 100 patients with serologically confirmed pertussis. They participated in a long-term follow-up after a B. pertussis infection. In group 2, 31 pertussis patients were selected from 98 consecutive patients with positive pertussis serology from one routine practice., Results: In 23 of 82 pertussis infections (28%) serological evidence of 1 (n = 21) or 2 (n = 2) additional infections were demonstrated. These involved para-influenza virus (n = 6), respiratory syncytial virus (RSV) (n = 6), Mycoplasma pneumoniae (n = 5), adenovirus (n = 4), influenza A virus (n = 3) and influenza B virus (n = 1)., Conclusions: We conclude that in patients with B. pertussis infection, coinfection with another respiratory pathogen is often present.

A 2-year prospective study was performed of children with prolonged coughing to investigate the frequency of different respiratory pathogens, the rate of mixed infections, and possible differences in severity of disease between single and mixed infections. Sera from 135 children (136 episodes of prolonged coughing lasting 1-6 weeks) were tested for antibodies to different viruses and bacteria. Swabs were taken for culture and PCR to detect different viral and bacterial pathogens. One or more pathogens were found in 91 (67%) patients. One infectious agent was found in 49 (36%) patients, two agents in 35 (26%) patients, and more than two agents in seven (5%) patients. The most frequent pathogens encountered were rhinovirus (n = 43; 32%), Bordetella pertussis (n = 23; 17%) and respiratory syncytial virus (n = 15; 11%). The most frequent mixed infection was B. pertussis and rhinovirus (n = 14; 10%). No significant differences in clinical symptoms were observed between patients with or without pathogens; however, patients with mixed infections were significantly older. There was a strong seasonal influence on the number of infections, but not on the number of mixed infections. In children with prolonged coughing, there was a high frequency of mixed infections regardless of the season. However, mixed infection was not associated with increased disease severity. No clinical symptoms were found that allowed discrimination between specific pathogens.

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.

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.

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.

Aim: To develop a prediction rule to identify postmeningitic children at high risk of academic and behavioural limitations., Methods: 182 children (mean age 10 y; range 5-14) were selected from a cohort of 674 school-age survivors of bacterial meningitis. These children had neither meningitis with "complex onset", nor prior cognitive or behavioural problems, nor severe disease sequelae. On average, 7 y after the meningitis, they were evaluated using an "Academic Achievement Test", and their parents filled in the "Child Behaviour Checklist". By reviewing the medical records, potential risk factors for academic and/or behavioural limitations were collected. Independent predictors were identified using multivariate logistic regression analysis, leading to the formulation of a prediction rule., Results: The cumulative incidence of academic and/or behavioural limitations among children who survived bacterial meningitis without severe disease sequelae was 32%. The prediction rule was based on nine independent risk factors: gender, birthweight, educational level of the father, S. pneumoniae, cerebrospinal fluid leukocyte count, delay between admission and start of antibiotics, dexamethasone use, seizures treated with anticonvulsive therapy, and prolonged fever. When 10 was taken as a cut-off point for the risk score computed using this rule, 76% of the children with limitations could be identified, while 38% of the children in the cohort were selected as at risk for these limitations., Conclusion: With a prediction rule based on nine risk factors, postmeningitic children at high risk of developing academic and/or behavioural limitations could be identified. Additional research is required to further validate this prediction rule. In the future, a careful follow-up of high risk children may enhance early detection and treatment of these limitations.

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.

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

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.

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.

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.

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.

A single high dose of inhaled corticosteroid (ICS) can increase airway caliber in children with asthma attacks and laryngitis subglottica. Presumably the effect is due to the vasoconstrictive and antiedematous properties of topical steroids. Enlarged vessels have been suggested to play a role in the pathophysiology of exercise-induced bronchial obstruction (EIB). To investigate this, we evaluated the effect of a single high dose of fluticasone propionate (FP) on EIB in asthmatic children. Nine children aged 8-16 years with mild to moderate asthma were included. All children had a history of EIB, which was confirmed by an exercise test. None was taking ICS maintenance therapy. The children inhaled either a single dose of 1 mg FP or placebo on 2 separate days within 7-14 days. After inhalation, airway caliber (FEV(1)) was assessed for 4 hr before exercise. Then an exercise challenge was performed on a treadmill to assess EIB (% fall FEV(1)). A significant increase in FEV(1) was observed 1 hr after inhalation of FP compared to placebo. Response to exercise was expressed as maximal % fall in FEV(1) from baseline (% fall) and as area under the curve (AUC) of the 30-min time/response curve. The % fall FEV(1) after exercise and the AUC were significantly reduced when FP was inhaled compared to placebo inhalation (% fall 9.7% vs. 19.2%, respectively, P = 0.038 and AUC 92.0%.min vs. 205.7%.min, respectively, P = 0.03). There was considerable individual variability in reduction of EIB, with 5 out of 9 children having a clinically significant response. We conclude that a single high dose of inhaled FP has an acute protective effect on the bronchial response to exercise in a substantial proportion of asthmatic children., (Copyright 2001 Wiley-Liss, Inc.)

Effective laboratory animal models of bacterial meningitis are needed to unravel the pathophysiology of this disease. Previous models have failed to simulate human meningitis by using a directly intracerebral route of infection. Hyaluronidase is a virulence factor of Streptococcus pneumoniae. In this study, a novel model of murine meningitis is described. Intranasal administration of S. pneumoniae with hyaluronidase induced meningitis in 50% of inoculated mice, as defined by a positive cerebrospinal fluid (CSF) culture and an inflammatory infiltrate in the meninges. None of the mice inoculated without hyaluronidase developed meningitis. Hyaluronidase was found to facilitate pneumococcal invasion of the bloodstream after colonization of the upper respiratory tract. Meningitis was characterized by pleocytosis of CSF and the induction of proinflammatory cytokines and CXC chemokines in brain tissue. These results indicate that this murine model mimics important features of human disease and allow for the use of this model for studying issues related to the pathophysiology and the treatment of pneumococcal meningitis.

From December 1999 to March 2000 a nosocomial outbreak of multiresistant Enterobacter cloacae occurred in the neonatal intensive care unit (NICU) at the VU Medical Center, Amsterdam, the Netherlands. Twenty-six patients were infected or colonized with this strain resistant to third generation cephalosporins and with decreased sensitivity for aminoglycosides. Three neonates experienced sepsis with E. cloacae with serious clinical symptoms and two of them died. Comparison of the Enterobacter isolates by amplified-fragment length polymorphism indicated that this outbreak was caused by the spread of a single strain. Infection control precautions were initiated in order to stop further spread; barrier precautions, enforcement of hand disinfection and cohorting of colonized patients. A multidisciplinary crisis team coordinated these infection control precautions and informed all persons involved. Analysis of antibiotic usage in 1999 showed an increase in the use of third generation cephalosporins from November onwards. Due to the resistance pattern of the epidemic strain the use of third generation cephalosporins was discontinued in February 2000. At the end of February the NICU was temporarily closed. The epidemic strain of E. cloacae was isolated from one digital rectal thermometer. Patient use of thermometers and disposable coverings for rectal thermometers were introduced to eliminate this possible means of spread. No spread of multiresistant E. cloacae was found following the introduction of these interventions. Once all the neonates had been transferred, the NICU was disinfected and reopened in March.

Neisseria meningitidis and Streptococcus pneumoniae are the most frequent causes of bacterial meningitis. The incidence of Haemophilus meningitis in the Netherlands is low due to successful Haemophilus influenzae type b vaccination. This implies that there is no need to take account into this microorganism in using initial empiric antimicrobial therapy for bacterial meningitis. Vomiting (especially children), headache, fever, and a stiff neck characterize acute bacterial meningitis. However, even without these signs a patient may still have acute bacterial meningitis. The characteristics in neonates are less specific. An emergency lumbar puncture should be performed in all patients with meningeal irritation or other signs of bacterial meningitis. Examination of the CSF is not indicated for convulsive children (between the ages of 6 months and 6 years) who do not exhibit other clinical signs. In patients who respond adequately to the treatment, it is not necessary to examine the CSF again. Papilloedema or focal neurological symptoms contraindicate a lumbar puncture in patients with bacterial meningitis, until CT results justify that it can be performed safely. Antibiotic treatment should not be delayed until after the CT. General practitioners should treat their patients with suspected meningococcus infection by admitting them to the hospital without first injecting antibiotics. In the Netherlands, patients with suspected pneumococcus meningitis may still be treated with benzylpenicillin. Patients with bacterial meningitis have no fluid restrictions; only in case of the syndrome of inadequate secretion of antidiuretic hormone is fluid reduction indicated. The physician is responsible for prescribing prophylaxis to family members. The Regional Health Services organize chemoprophylaxis for classmates. The latter is only indicated if at least 2 related cases occur in one month.

Background: Gram-negative bacilli are not infrequently encountered as etiologic organisms of pneumonia in children in warm-climate countries., Objectives: To investigate the nasopharyngeal carriage rate and antimicrobial susceptibility patterns of gram-negative bacilli colonizing children with community-acquired pneumonia in Fortaleza, Brazil., Methods: A single nasopharyngeal specimen was collected from children 2 months to 5 years of age presenting at one of the three children's hospitals in Fortaleza and fulfilling the World Health Organization criteria for pneumonia. Randomly recruited healthy children from public daycare centers and immunization clinics served as controls., Results: The study included 912 children, 482 (53%) with pneumonia and 430 (47%) controls. Aerobic gram-negative bacilli were seen in 79 (16%) of the 482 children with pneumonia and 51 (12%) of the 430 healthy controls. Nonfermentative gram-negative bacilli were seen in 85 (18%) of children with pneumonia and 54 (13%) of healthy controls. Neither gender, nutritional status, season, previous hospital admission nor antibiotic use was associated with carriage with gram-negative bacilli. However, pneumonia was associated with increased carriage, whereas concomitant colonization with Streptococcus pneumoniae or Haemophilus influenzae was associated with decreased carriage with gram-negative bacilli. Only 36% of all Escherichia species and 76% of all Klebsiella isolates were susceptible to cotrimoxazole; 90% of all Acinetobacter species were susceptible to gentamicin., Conclusion: Nasopharyngeal carriage with gram-negative bacilli, in particular with Acinetobacter species, is common and associated with a clinical diagnosis of community-acquired pneumonia in children in Fortaleza, Brazil.

To study clonal diversity of penicillin-resistant Streptococcus pneumoniae, 161 randomly selected isolates with reduced susceptibility to penicillin, collected from the nasopharynx of children under 5 years of age with community-acquired pneumonia and healthy controls from public day-care and immunization centres in Fortaleza, Brazil, were characterized by microbiological and serological techniques and automated ribotyping. Also included were 44 randomly selected penicillin-susceptible strains and three international reference strains. With automated ribotyping 75 ribopatterns were observed: 50 ribogroups were unique and 25 ribogroups were represented by two or more isolates. Genetic diversity was extensive but some degree of genetic homogeneity was found in strains from children with pneumonia, strains from children in day-care centres, isolates with reduced susceptibility to penicillin and isolates expressing 'paediatric' serogroups. Fourteen (56%) clusters contained both isolates with reduced penicillin susceptibility and penicillin-susceptible isolates, suggesting emergence of penicillin resistance. In general, there was a good correlation between ribogroups and serogroups, but 12 (48%) clusters contained isolates with alternative serogroups. Isolates with such alternative serogroups were more often encountered in penicillin-susceptible strains (41%) than in strains with reduced susceptibility to penicillin (7%). Thirty-eight (19%) isolates (including seven penicillin-susceptible strains) showed ribotypes indistinguishable from those of two international epidemic clones of S. pneumoniae: ribogroup 54-S-1 (15 isolates) with a ribopattern characteristic of the 23F multiresistant 'Spanish/USA' clone and ribogroup 74-S-3 (23 isolates) with a pattern similar to that of the 6B multiresistant 'Spanish' clone.

Background: It has been reported that intranasal corticosteroids can influence bronchial hyperresponsiveness (BHR) in asthmatic subjects with seasonal rhinitis. The purpose of the present study was to evaluate the effect of intranasal fluticasone propionate and beclomethasone dipropionate on BHR and bronchial calibre (forced expiratory volume in one second, FEV(1)) in children and young adults with seasonal rhinitis and mild asthma during two consecutive grass pollen seasons., Methods: In the first pollen season 25 patients aged 8-28 years were included in a double blind, placebo controlled study. The active treatment group used fluticasone aqueous spray 200 microgram once daily. In the second pollen season 72 patients aged 8-28 years participated in a double blind, placebo controlled study of a similar design to that of the previous year except that an additional treatment group of patients using beclomethasone 200 microg twice daily was included. FEV(1) was measured before and after three and six weeks of treatment; BHR to methacholine (PD(20)) was measured before and after six weeks of treatment., Results: In the first season the mean (SD) logPD(20) of the patients decreased significantly both in the fluticasone group (from 2.43 (0.8) microgram to 1.86 (0.85) microgram) and in the placebo group (from 2.41 (0.42) microgram to 1.87 (0.78) microgram) without any intergroup difference in the change in logPD(20). In the second pollen season the mean logPD(20) in the fluticasone, beclomethasone, and placebo groups did not change significantly., Conclusions: Intranasal steroids did not influence BHR during two grass pollen seasons in children and young adults with seasonal rhinitis and mild asthma.

Respiratory syncytial virus (RSV) is the most prominent pathogen found in respiratory tract infections in children and the most important cause of bronchiolitis in the first two years of life. In the Netherlands approximately 2000 children are admitted each winter season. A serious course is mostly seen in children younger than 3 months, (ex-)prematures, children with bronchopulmonary dysplasia or congenital cardiac anomalies, children with cystic fibrosis younger then 2 years and children with impaired T cell immunity; such cases not rarely require intensive care. Treatment (fluid, nutrition, bronchodilator agents, corticosteroids, oxygen and ventilation) is usually symptomatic. Antiviral therapy is only indicated in immunodeficient patients. For prevention by passive immunization palivizumab was recently registered in the Netherlands, a monoclonal antibody against RSV that has to be administered intramuscularly from the start of the RSV season (15 mg per kg bodyweight once a month during five months). In a number of large-scale American multicenter studies both the number of hospital admissions related to RSV infection and the mean duration of hospital stay showed a statistically significant reduction in high-risk children who had been treated with palivizumab. Palivizumab appears to be indicated in children from the categories with an increased risk for serious RSV disease.

To study the role of surface-associated proteins in the virulence of Streptococcus pneumoniae, we used two serotype 3 strains, ATCC 6303 and WU2, and two PspA-negative mutants of WU2, an encapsulated one, JY1123 (Caps(+)/PspA(-)), and an unencapsulated one, DW3.8 (Caps(-)/PspA(-)). ATCC 6303 and WU2 were highly virulent in mice, while the virulence of JY1123 was slightly decreased (50% lethal doses [LD(50)s], 24, 6, and 147 CFU/mouse, respectively); DW3.8 was avirulent (LD(50), 2 x 10(8) CFU). In vitro, ATCC 6303, WU2, and JY1123 (Caps(+)/PspA(-)) strongly resisted complement activation and complement-dependent opsonophagocytosis, whereas DW3.8 (Caps(-)/PspA(-)) was easily phagocytized in fresh serum. Trypsin treatment of ATCC 6303, WU2, and JY1123 (Caps(+)/PspA(-)) resulted in enhanced complement activation and complement-dependent opsonophagocytosis. Trypsin had no deleterious effect on the polysaccharide capsule. In addition, trypsin pretreatment of ATCC 6303 strongly reduced virulence upon intraperitoneal challenge in mice. This indicated that surface proteins play a role in the resistance to complement activation and opsonophagocytosis and contribute to the virulence of type 3 pneumococci. In subsequent experiments, we could show that the modulation of complement activation was associated with surface components that bind complement regulator factor H; binding is trypsin sensitive and independent of prior complement activation. Immunoblotting of cell wall proteins of the virulent strain ATCC 6303 with anti-human factor H antibody revealed three factor H-binding proteins of 88, 150, and 196 kDa. Immunogold electron microscopy showed a close association of factor H-binding components with the outer surface of the cell wall. The role of these factor H-binding surface proteins in the virulence of pneumococci is interesting and warrants further investigation.

Five patients, 4 boys and 1 girl aged 13-41 months, developed invasive Haemophilus influenzae type b (Hib) disease (2 epiglottitis, 3 meningitis) despite full (or at least 3 times) vaccination. At admission as well during convalescence, 3 out of 5 had IgG anti Hib antibody levels < or = 5 U/ml. Serum immunoglobulin levels, including IgG subclasses, as well as complement were normal in all cases. In 2 of the 3, booster vaccinations with Hib conjugate vaccine elicited adequate antibody titres. Since the incorporation of the conjugated Hib polysaccharide tetanus toxoid vaccine (HibTT) in the National Vaccination Programme in the Netherlands, the number of invasive infections caused by Hib has dropped significantly. Causes of Hib conjugate vaccine failures are mostly unknown. In about one-third of the cases serum immunoglobulin levels are deficient, most often IgG2 or IgM. Susceptibility to Hib infection is in part also genetically determined. In the follow-up of Hib vaccine failures, anti Hib antibody titres should be determined. Booster vaccinations may be necessary.

The efficacies and safeties of a 3-day, 3-dose course of azithromycin (10 mg/kg of body weight per day) and a 10-day, 30-dose course of erythromycin (40 mg/kg/day) for the treatment of acute lower respiratory tract infections in children were compared in an open randomized multicenter study. Sixty-eight of 85 evaluable patients (80%) had radiologically proven pneumonia, and 20% had bronchitis. Treatment success defined as cure or major improvement was achieved in 42 of 45 (93%) azithromycin recipients versus 36 of 40 (90%) erythromycin recipients. Adverse events were reported in 12 of 45 and 6 of 40 of the patients treated with azithromycin and erythromycin, respectively, a difference which was not statistically significant. In conclusion, a 3-day course of azithromycin is as effective as a 10-day course of erythromycin in the treatment of community-acquired lower respiratory tract infections in children, with comparable safety and acceptability profiles. This shorter treatment course might have a beneficial effect on compliance, especially in the pediatric age group.