Gelatinase B [matrix metalloproteinase (MMP)-9] and collagenases (MMP-8/-13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children.

We investigated the protein expression of gelatinases [matrix metalloproteinase (MMP)-2 and -9] and collagenases (MMP-8 and -13) in cerebrospinal fluid (CSF) from patients with bacterial (BM, n = 17) and aseptic (AM, n = 14) meningitis. In both, MMP-8 and -9 were increased in 100% of patients, whereas MMP-13 was detectable in 53% and 82% respectively. Three patients with clinical signs of meningitis, without CSF pleocytosis, scored positive for all three MMPs. MMP-8 appeared in two isoforms, granulocyte-type [polymorphonuclear cell (PMN)] and fibroblast/macrophage (F/M) MMP-8. Analysis of kinetic changes from serial lumbar punctures showed that these MMPs are independently regulated, and correlate only partly with CSF cytosis or levels of the endogenous inhibitor, tissue inhibitor of matrix metalloproteinase-1. In vitro, T cells, peripheral blood mononuclear cells (PBMCs) and granulocytes (PMN) release MMP-8 and -9, whereas MMP-13 could be found only in the former two cell types. Using models of exogenous (n-formyl-Met-Leu-Phe, T cell receptor cross-linking) and host-derived stimuli (interleukin-2), the kinetics and the release of the MMP-8, -9 and -13 showed strong variation between these immune cells and suggest release from preformed stocks. In addition, MMP-9 is also synthesized de novo in PBMCs and T cells. In conclusion, invading immune cells contribute only partially to MMPs in CSF during meningitis, and parenchymal cells are an equally relevant source. In this context, in patients with clinical signs of meningitis, but without CSF pleocytosis, MMPs seem to be a highly sensitive marker for intrathecal inflammation. The present data support the concept that broad-spectrum enzyme inhibition targeting gelatinases and collagenases is a potential strategy for adjunctive therapy in infectious meningitis.

Acute streptococcal tonsillopharyngitis: a review of clinical efficacy and bacteriological eradication.

This review evaluates studies published between January 1997 and August 2003 comparing clinical outcome and bacteriological eradication rates for patients with acute streptococcal tonsillopharyngitis treated with penicillin or other antimicrobial agents. Studies were identified using MEDLINE, and clinical outcome and bacteriological eradication at end of treatment and 2 weeks after end of treatment were ascertained. Any longer-term follow-up was also noted, along with treatment-related adverse events and compliance. Clinical efficacy rates between penicillin and comparator antibiotics were generally high and similar. Bacterial eradication rates were more variable and, 2 weeks after treatment, ranged from 64% to 93% for penicillin and 31% to 98% for comparators. Simpler dosing schedules and shorter therapy durations produced higher compliance rates. This review highlights the similarities and differences between treatment with penicillin and a wide range of comparator antibiotics. Therapy for acute group A streptococcal pharyngitis should combine excellent clinical efficacy, high bacteriological eradication rates, good tolerance and a simple, convenient dosing regimen.

Role of Chlamydia pneumoniae and Mycoplasma pneumoniae as causative agents of community-acquired pneumonia in hospitalised children and adolescents.

The aim of the study presented here was to determine the prevalence of Chlamydia pneumoniae versus Mycoplasma pneumoniae infections in paediatric patients with community-acquired pneumonia. A total of 50 patients (mean age, 5.5 years; median, 3.9 years) with community-acquired pneumonia were enrolled. Four patients were found to have Chlamydia pneumoniae infection (1 culture positive, 1 PCR positive and 2 serology positive) and 16 patients had Mycoplasma pneumoniae infection (2 PCR positive, 4 PCR and serology positive, 10 serology positive), including three patients with coinfection. The rates of Mycoplasma pneumoniae infection were 22%, 35% and 40% in children aged 1-3, >3-7 and >7 years, respectively. Acute Chlamydia pneumoniae infection was substantially less common than Mycoplasma pneumoniae infection in our study cohort.

Seroprevalence of varicella-zoster virus immunoglobulin G antibodies in Swiss adolescents and risk factor analysis for seronegativity.

BACKGROUND: Little is known about the seroprevalence of anti-varicella-zoster virus (VZV) serum antibodies in adolescents in Switzerland as in most other European countries. METHODS: Serum specimens from 13- to 15-year-old students from eight urban and rural areas in Switzerland, obtained as part of an allergy risk assessment study project (SCARPOL), were available for analysis of IgG antibodies against VZV by enzyme-linked immunosorbent assay (ELISA) and confirmation by fluorescent antibody staining of membrane antigen in a subcohort. Serum specimens and comprehensive sociodemographic data had been collected during two study periods between 1992 and 1995. RESULTS: Data and serum specimens were available from 1709 and 1788 subjects, respectively. Seroprevalence of anti-VZV antibodies as measured by ELISA was 95.5% (95% confidence interval, 94.5 to 96.4). When serum specimens that were indeterminate by ELISA were tested by FAMA, seroprevalence was 96.5% (95% confidence interval, 95.7 to 97.4). After logistic regression analysis, the number of siblings was the only factor that significantly influenced the presence of VZV antibodies (90.1% in those with no siblings, >96% with 1 or more siblings), whereas residence (urban vs. rural), parental education, nationality and gender did not. CONCLUSIONS: Seroprevalence of anti-VZV serum antibodies is comparatively high among Swiss adolescents. Individuals who grow up without siblings have a significant risk of evading natural VZV infection in childhood, and they therefore form a potential target group for varicella immunization in Switzerland.

Multiple herpetic whitlow lesions in a 4-year-old girl: case report and review of the literature.

UNLABELLED: Herpetic whitlow is a herpes simplex virus type 1 or 2 infection of the fingers characterised by erythema and painful, non-purulent vesicles. In children it typically occurs after auto-inoculation from herpes stomatitis, herpes labialis or genitalis. Occasionally, person-to-person transmission occurs from family members with herpes labialis. We report a 4-year-old girl with multiple herpetic whitlows secondary to herpetic stomatitis and present a review of the medical literature based on a systematic MEDLINE search of published paediatric patients (English, French and German language). Of 42 identified patients, 72% were younger than 2 years, most had endogenous or exogenous inoculation of herpes simplex virus type 1 and 65% were initially misdiagnosed as having "bacterial felon". Recurrences were reported in 23%. CONCLUSION: herpetic whitlow should be suspected based on clinical signs. Specific diagnosis can be made by polymerase chain reaction or culture. The high rate of misdiagnosed cases indicates that this entity is not sufficiently known. Lesions are self-limited; surgical interventions can be harmful and should be avoided. Recurrences occur as frequently as in adults.

Diagnosis of acute haematogenous osteomyelitis and septic arthritis: 20 years experience at the University Children's Hospital Basel.

OBJECTIVE: To review the diagnostic experience with acute haematogenous osteomyelitis (AHOM) and/or septic arthritis at our institution. METHODS: Retrospective review of the medical records of those patients with a bacteriologically and/or radiologically confirmed diagnosis, hospitalised in the University Children's Hospital Basel, Switzerland between January 1980 and July 2000. RESULTS: 90 patients (61% males), 4 weeks to 14 years of age, met the inclusion criteria. Median duration of disease prior to hospitalisation was 3 days (range 0-14); 88% were admitted during the first week after onset of complaints. 81 patients received no antimicrobial therapy prior to hospitalisation and are the subject of this presentation. ESR (1st hour in mm; median 36; range 11-124), CRP (mg/l; median 64; range 0-221) and WBC (x 10(9)/l; median 13; range 5-34) were elevated in 100%, 82% and 58% of patients, respectively. Blood cultures (BC) and/or tissue cultures (TC) were performed in 79 (98%) patients. Overall, bacteria were isolated from 53 patients (65%) with Staph. aureus as the most frequent organism (n = 31; 50%). BC were performed in 67 patients and yielded 35 (52%) positive cultures; TC (n = 47) yielded 27 (57%) isolates. In 34 patients with both BC and TC performed, only 12 (35%) were positive in both tests. Diagnostic findings were observed in 23 (59%) of 39 plain radiographs, 31 (56%) of 55 sonograms, 39 (89%) of 44 99mTc-labeled bone scans and 4 (100%) of 4 MRI. 41 patients with diagnostic radiological findings had consecutive TC yielding 30 (73%) bacteriological isolates. Median duration of hospitalisation was 15 days (range 2-66). CONCLUSION: Our data indicate that the diagnostic procedures of choice should be 1) early bone scan or MRI, 2) BC and 3) TC. Of supportive laboratory parameters, ESR and CRP were most valuable in our hands.

[Seroprevalence of IgG antibodies against measles, mumps and rubella in Swiss children during the first 16 months of life]. / Seroprävalenz von IgG-Antikörpern gegen Masern, Mumps und Röteln bei Schweizer Kindern in den ersten 16 Lebensmonaten.

OBJECTIVE: To study the question of how long maternal IgG antibodies against measles, mumps and rubella persist in infants. METHODS: Sera of children aged 0-16 months who had been hospitalised in our institution between 1994 and 1999 were identified from our routine serum collection. Exclusion criteria were: preterm delivery; suspected measles, mumps or rubella illness or exanthema of unknown aetiology; transfusion of blood products in the 6 months preceding serum collection; foreign-born mother; previous MMR immunisation. IgG antibodies were measured by use of commercially available ELISA kits. RESULTS: 254 serum specimens were analysed. Age distribution of patients was as follows: 0-3 months n = 58; > 3-6 months n = 48; > 6-9 months n = 52; > 9-12 months n = 42; > 12-16 months n = 54. The following seroprevalence rates for IgG antibodies were found (measles/mumps/rubella): 0-3 months 97%/62%/91%; > 3-6 months 40%/2%/42%; > 6-9 months 4%/2%/10%; > 9-12 months 2%/0%/12%; > 12-16 months 0%/7%/7%. CONCLUSIONS: Our results demonstrate high levels of passive immunity against measles and rubella in Swiss infants during the first months of life, whereas immunity against mumps appears to be considerably less reliable. Beyond the first 3 months of life, IgG antibodies against all 3 illnesses are lacking in the majority of patients; beyond 12 months of age they are only rarely detectable. These results raise the question whether the first MMR immunisation, currently recommended at the age of 15 months in Switzerland, should be brought forward.

Brevibacterium casei sepsis in an 18-year-old female with AIDS.

Brevibacterium sp. was isolated from the blood of an acutely ill 18-year-old female with AIDS. The isolate was identified as Brevibacterium casei by use of carbohydrate assimilation tests. Treatment was successful with intravenously administered ciprofloxacin. To our knowledge, this is the first report of sepsis caused by B. casei in a human immunodeficiency virus-infected patient.

Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae.

To evaluate the spectrum and regulation of matrix metalloproteinases (MMPs) in bacterial meningitis (BM), concentrations of MMP-2, MMP-3, MMP-8, and MMP-9 and endogenous inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were measured in the cerebrospinal fluid (CSF) of 27 children with BM. MMP-8 and MMP-9 were detected in 91% and 97%, respectively, of CSF specimens from patients but were not detected in control patients. CSF levels of MMP-9 were higher (P<.05) in 5 patients who developed hearing impairment or secondary epilepsy than in those who recovered without neurological deficits. Levels of MMP-9 correlated with concentrations of TIMP-1 (P<.001) and tumor necrosis factor-alpha (P=.03). Repeated lumbar punctures showed that levels of MMP-8 and MMP-9 were regulated independently and did not correlate with the CSF cell count. Therefore, MMPs may derive not only from granulocytes infiltrating the CSF space but also from parenchymal cells of the meninges and brain. High concentrations of MMP-9 are a risk factor for the development of postmeningitidal neurological sequelae.

Acute community-acquired diarrhea requiring hospital admission in Swiss children.

In order to ascertain the prevalence of agents that cause childhood diarrheal illness, stool specimens of 312 consecutive children with community-acquired diarrhea requiring admission were evaluated. Pathogens were detected in 166 (53%) of the 312 children (>/=2 pathogens in 28 children): Rotavirus (n=75), Salmonella spp. (n=37), Campylobacter spp. (n=24), Shigella spp. (n=5), Giardia spp. (n=4), Yersinia spp. (n=2), Aeromonas spp. (n=15), Cryptosporidium (n=15), enteropathogenic Escherichia coli (n=13), enterotoxigenic E. coli (n=7), and enterohemorrhagic E. coli (n=5). In conclusion, acute childhood diarrheal illness pathogens, such as Aeromonas, Cryptosporidium, and diarrheagenic E. coli, account for a large proportion of patients with a microbiologically positive stool specimen.

Comparison of immunogenicity and safety of a virosome influenza vaccine with those of a subunit influenza vaccine in pediatric patients with cystic fibrosis.

The objective of this study was to compare the immunogenicity and safety of a single-dose regimen and a two-dose regimen of a trivalent virosome influenza vaccine (Inflexal Berna V) with those of a trivalent subunit influenza vaccine (Influvac) in children and adolescents with cystic fibrosis (CF). In an open, randomized, multicenter study with parallel groups, 11 young children with CF (1 to 6 years old) and 53 older children and adolescents with CF (>6 years old) were randomly assigned to one of the following immunization regimens: virosome vaccine at 0.5 ml on study day 0 or 0.25 ml on days 0 and 28 or a standard regimen of subunit vaccine, i. e., 0.5 ml on day 0 for older children and 0.25 ml on days 0 and 28 for younger children. Safety assessments, i.e., recording of systemic and local adverse events (AEs) and vital signs, were made for a 5-day observation period after each immunization. Hemagglutination inhibition (HI) titers were determined at baseline and 4 weeks after the single-dose and the two-dose immunizations, respectively. Immunogenicity was assessed according to the criteria of the European Agency for the Evaluation of Medicinal Products (EMEA). Both vaccines induced comparable HI antibody titers. Seroconversion (> or =4-fold rise in HI antibody titers, reaching a titer of > or =1:40) was achieved in 41 to 100% of the participants. Seroprotection (HI titer, > or =1:40) and a >2.5-fold increase in geometric mean titers were achieved in 100% of the participants. Thus, all three EMEA requirements for influenza vaccine efficacy were met by all treatment groups and for both vaccines. The virosome vaccine, when administered as a single dose, seemed to induce superior immunogenicity compared with the standard pediatric two-dose regimen. Totals of 42 and 57% of vaccinees receiving virosome and subunit vaccines, respectively, reported at least one local AE (predominantly pain). Totals of 84 and 71% of subjects receiving virosome and subunit vaccines, respectively, complained in response to questions of at least one systemic AE (mainly cough, fatigue, coryza, or headache). The majority of events were mild or moderate and lasted 1 or 2 days only. No obvious relationship was found between AE reporting rate and vaccine formulation, age group, or dose regimen. The relatively high AE reporting rate seemed to be partly related to the symptomatology of the underlying CF disease. In summary, the virosome and subunit vaccines induced in both age groups and against all three influenza strains an efficient immune response and were well tolerated by the children and adolescents with CF.

[Herpes simplex virus type 1 and 2 in Switzerland]. / Herpes-simplex-Virus Typ 1 und 2 in der Schweiz.

A worldwide increase in the incidence of genital herpes infections has been described in recent years. Transmission of the herpes simplex virus type 2 (HSV-2) by asymptomatic seropositive subjects is considered to be a relevant mode of infection. The seroprevalence of HSV-2 varies considerably between different populations. In Europe, data are scarce and the epidemiological situation in Switzerland is unknown. In 1997 we performed serological examinations in 151 adult volunteers (87% between 20 and 49 years of age) of a low-risk population from the region of Basel with no history of genital herpes or any other sexually transmitted disease. The overall seroprevalence of HSV-1 was 77% and an annual seroconversion rate of 4.6% (95% CI: 3.8-5.6) was estimated for both sexes. Of the 51 subjects with no symptoms of orolabial herpes, 25 (49%) proved to be HSV-1 seropositive. In contrast, of 91 patients with symptoms of orolabial herpes, 90 (97%) had serum antibodies against HSV-1. The seroprevalence of HSV-2 was 14.6% for women (n = 89) and 8.1% for men (n = 62). The annual seroconversion rate was estimated to be 0.61% (95% CI: 0.14-1.4) for women and 0.49% (95% CI: 0.09-1.4) for men for the period after 1985 (when "safer sex" and the use of condoms were promoted). Our results indicate the significance of herpes simplex virus type 2 infections in Switzerland. More detailed studies are needed to describe the epidemiology of HSV-2 infections more reliably, especially in view of progress in the development of vaccines against HSV infections.

[Rotavirus gastroenteritis in infants and children. Results of a prospective study in the area of Geneva and Basel 1997/1998 (RoMoS). RoMoS Study Group]. / Rotavirus-Gastroenteritis im Säuglings- und Kleinkindesalter Ergebnisse einer prospektiven Erfassung in den Regionen Genf und Basel 1997/1998 (RoMoS). RoMoS-Studiengruppe.

BACKGROUND: In Europe information is scarce about the impact of rotavirus, probably the most important cause of acute gastroenteritis in children up to the age of 4 years. The aim of this study was to collect data on the frequency and symptoms of community-acquired rotavirus-positive acute gastroenteritis in Switzerland. PATIENTS AND METHODS: In 6 paediatric practices, 3 each in the Geneva and Basle areas, every child up to the age of 48 months presenting with acute gastroenteritis between December 1997 and May 1998 was eligible for inclusion in the study. The symptoms, course of the disease and treatment were recorded in a standardized fashion after informed consent had been obtained. Stool specimens were screened for rotavirus by ELISA, and PCR was performed for serotyping in ELISA-positive samples. RESULTS: 294 of 6672 children under observation were taken to their paediatrician because of acute gastroenteritis during the study period. Informed consent was obtained in 256 cases (mean age 19.2 months). 234 stool specimens were available of which 96 (41%) were rotavirus-positive. The incidence of rotavirus-positive acute gastroenteritis was 1.6 per 100 children and winter season. Acute gastroenteritis due to rotavirus was more severe than rotavirus-negative acute gastroenteritis, with diarrhoea and vomiting in 84% versus 54%, and dehydration in 42% versus 28%, 5% of the acute gastroenteritis cases compared to 11% of the rotavirus-positive cases were hospitalized. In the Geneva and Basle areas the predominant rotavirus types, as identified by PCR in ELISA-positive stool specimens, were G4 P[8] and G1 P[8] respectively (67% each). CONCLUSION: Rotavirus infection was a relevant cause of acute gastroenteritis in our study population, resulting in more severe symptoms than rotavirus-negative acute gastroenteritis. All G-types identified in our study are included in the recently developed tetravalent vaccine. Cost-benefit analysis and ethical issues will need to be considered in evaluating the impact of the vaccine in Switzerland.

[Childhood meningitis]. / Meningitis im Kindesalter.

Early and reliable diagnosis, prompt and adequate treatment, and intensive monitoring are the mainstays for normal outcome of patients with meningitis. Major progress has been achieved during the last 5-10 years. The successful implementation of the active immunization against Haemophilus influenzae type b has dramatically changed the epidemiology of bacterial meningitis: total incidence has been cut in half and approximately half of the cases now occur in adults. Important new insights into the pathogenesis and the pathophysiology have been gained resulting in specific supportive and antiinflammatory measures. Emergence of antibiotic-resistance in meningitis pathogens have lead to modified antimicrobial therapies. Knowledge about factors associated with a poor prognosis is important in selecting patients for more intensive surveillance and treatment, and in identifying candidates for new preventive or therapeutic strategies.

Properdin deficiency in a large Swiss family: identification of a stop codon in the properdin gene, and association of meningococcal disease with lack of the IgG2 allotype marker G2m(n).

Properdin deficiency was demonstrated in three generations of a large Swiss family. The concentration of circulating properdin in affected males was < 0.1 mg/l, indicating properdin deficiency type I. Two of the nine properdin-deficient males in the family had survived meningitis caused by Neisseria meningitidis serogroup B without sequel. Two point mutations were identified when the properdin gene in one of the properdin-deficient individuals was investigated by direct solid-phase sequencing of overlapping polymerase chain reaction (PCR) products. The critical mutation was found at base 2061 in exon 4, where the change of cytosine to thymine had generated the stop codon TGA. The other mutation was positioned at base 827 in intron 3. The stop codon in exon 4 was also demonstrated by standard dideoxy sequencing in three additional family members. The question was asked if genetic factors such as partial C4 deficiency and IgG allotypes could have influenced susceptibility to meningococcal disease in the family. No relationship was found between C4 phenotypes and infection. Interestingly, the two properdin-deficient males with meningitis differed from the other properdin-deficient persons in that they lacked the G2m(n) allotype, a marker known to be associated with poor antibody responses to T-independent antigens. This implies that the consequences of properdin deficiency might partly be determined by independent factors influencing the immune response.