Trends in primary-care consultations, comorbidities, and antibiotic prescriptions for respiratory infections in The Netherlands before implementation of pneumococcal vaccines for infants.

The burden of respiratory infections is mainly seen in primary healthcare. To evaluate the potential impact of new preventive strategies against respiratory infections, such as the implementation of pneumococcal conjugate vaccines for infants in 2006 in The Netherlands, we conducted a baseline retrospective cohort study of electronic primary-care patient records to assess consultation rates, comorbidities and antibiotic prescription rates for respiratory infections in primary care. We found that between 1995 and 2005, overall registered consultation rates for lower respiratory tract infections had increased by 42·4%, upper respiratory infections declined by 4·9%, and otitis media remained unchanged. Concomitantly, there was a steady rise in overall comorbidity (75·7%) and antibiotic prescription rates (67·7%). Since Dutch primary-care rates for respiratory infections changed considerably between 1995 and 2005, these changes must be taken into account to properly evaluate the effect of population-based preventive strategies on primary-care utilization.

[Limping in toddlers due to disorders of the spine and spinal cord]. / Mank lopen bij peuters door afwijkingen aan de wervelkolom en het ruggenmerg.

Limping is a frequent symptom during childhood and can be caused by a variety ofdiseases, the most common causes being trauma and infections of the bones or joints. The authors describe three cases of limping in toddlers caused by infrequent spinal diseases. The toddlers presented with limping without a preceding trauma. In the first patient, an 18-month-old girl, the limping was caused by spondylodiscitis. She recovered completely after antibiotics. The second patient, a 13-month-old boy, presented with limping caused by neuroblastoma with extensive bone metastasis. Despite chemotherapy and partial resection of the neuroblastoma, the boy did not survive. In the last patient, a 19-month-old girl, the limping was caused by an intraspinal intramedullary astrocytoma. She recovered after partial resection of the tumour. In young children presenting with limping, diagnoses involving the spine should also be considered because early intervention can influence the prognosis favourably.

Association of CD14 promoter polymorphism with otitis media and pneumococcal vaccine responses.

Innate immunity is of particular importance for protection against infection during early life, when adaptive immune responses are immature. CD14 plays key roles in innate immunity, including in defense against pathogens associated with otitis media, a major pediatric health care issue. The T allele of the CD14 C-159T polymorphism has been associated with increased serum CD14 levels. Our objective was to investigate the hypothesis that the CD14 C-159T allele is protective against recurrent acute otitis media in children. The association between the CD14 promoter genotype and the number of acute otitis media episodes was evaluated both retrospectively and prospectively in a cohort of 300 children. Serotype-specific immunoglobulin G (IgG) antibody responses after pneumococcal vaccinations were examined according to CD14 genotype to compare immune responsiveness across genotypes. An age-dependent association was found: compared with that for CC homozygotes aged between 12 to 24 months, TT homozygotes had fewer episodes of acute otitis media (79 versus 41%, respectively; P = 0.004); this relationship was absent in older children. Additionally, TT homozygotes showed higher serotype-specific anti-pneumococcal IgG antibody levels. Our data suggest that genetic variation in CD14, a molecule at the interface of innate and adaptive immune responses, plays a key role in the defense against middle ear disease in childhood and in pneumococcal vaccine responsiveness. These findings are likely to be important to these and other immune-mediated outcomes in early life.

The impact of recurrent acute otitis media on the quality of life of children and their caregivers.

OBJECTIVE: To assess the quality of life of 384 Dutch children aged 1-7 years with recurrent acute otitis media (AOM), and compare it with that of children from four reference populations: (i) children from a general population; (ii) children with mild-to-moderate asthma, (iii) children with mild-to-moderately severe chronic illness, and (iv) US children with persistent or recurrent otitis media. DESIGN: Survey. SETTING: A general and an academic hospital (study population of children with recurrent AOM, n = 384); general population (n = 225 and 117); primary care (children with asthma, n = 64); community care (children with chronic illness, n = 82); and a general hospital (children with persistent or recurrent otitis media, n = 169). PARTICIPANTS: A total of 384 children aged 1-7 years who had experienced at least two episodes of AOM in the preceding year and their caregivers. MAIN OUTCOME MEASURES: Generic and disease-specific quality of life as judged by the children's caregivers. Age-adjusted total and subscale scores were compared with those of the reference populations. RESULTS: For all generic questionnaires, children with recurrent AOM had poorer scores than children from the general population. Quality of life of children with four or more episodes of AOM in the preceding year was poorer than that of children with two to three episodes. Children with recurrent AOM scored lower on the health-related questionnaire than children with mild-to-moderately severe chronic illness. Quality of life of the present study population was similar to those of children with asthma and US children with chronic otitis media with effusion or recurrent AOM. CONCLUSION: Recurrent AOM has a considerable negative impact on the quality of life of children and causes concern to their caregivers. These effects are proportional to the severity of the condition. Professionals involved in the care of children with OM should be aware that OM not only affects physical functioning but also general well-being of the child and its family. These outcomes should therefore be included in the evaluation of the child with otitis media both in the clinical and research setting.

Pneumococcal conjugate vaccination does not induce a persisting mucosal IgA response in children with recurrent acute otitis media.

AIM: In a prospective controlled study in young children with a history of recurrent acute otitis media, we analyzed the salivary IgA and IgG antibody titers upon vaccination with a 7-valent pneumococcal conjugate vaccine (PCV) given once or twice, followed by a 23-valent polysaccharide booster vaccination. METHODS: Salivary IgA and IgG antibody concentrations to vaccine serotype 6B, 14, 18C and 19F were measured by enzyme immunoassay in 38 samples of children vaccinated with PCV and 45 control samples. In the PCV group, 12 samples were taken prior to vaccination, 12 samples 4 weeks after the polysaccharide booster (8 months after the first conjugate vaccination) and 14 samples 7 months after the last vaccination (14 months after the first conjugate vaccination). In the control group 15 children were sampled at each of these three time points. RESULTS: We observed an increase in salivary IgG antibody concentrations against serotype 6B, 14, and 18C 14 months after the primary vaccination in children vaccinated with PCV twice, although this was significant for serotype 14 only. There was no increase in salivary IgG antibody in children vaccinate with PCV once nor in control children. IgA antibody titers increased significantly after 8 and after 14 months in both the pneumococcal vaccine recipients and the controls. However, the observed increase in mean antibody titers was significantly higher in control children compared to the PCV group. CONCLUSION: We suggest that repeated pneumococcal conjugate vaccination is necessary to induce an increase in salivary IgG antibodies and effectuate clearance of S. pneumoniae from the nasopharyngeal mucosa of children with recurrent acute otitis media. We hypothesize that the increase in salivary IgA is caused by the local boosting of the mucosal immune response by carriage and recurrent infections, which occurs less often in the PCV group compared to the control children.

[Agranulocytosis induced by an antithyroid drug in a 14-year-old girl]. / Thyreostaticumgeïnduceerde agranulocytose bij een 14-jarig meisje.

A 14-year-old girl with Graves' disease developed a fever, sore throat and a severe systemic infection after being treated with antithyroid drugs for 1 year. Agranulocytosis was diagnosed. After long-term antibiotic treatment and supportive therapy she recovered. Agranulocytosis is a known side-effect of antithyroid drugs and is seen in 0.2 to 0.5% of the patients. It usually occurs within the first 3 months of treatment. Patients above the age of 40 seem to be more susceptible. Since the onset of agranulocytosis is relatively acute, routine blood monitoring is not very useful. It is more important to instruct patients who use a thyreostatic to contact their physician in case of unexplained fever or a sore throat.

Molecular epidemiology of pneumococcal colonization in response to pneumococcal conjugate vaccination in children with recurrent acute otitis media.

A randomized double-blind trial with a 7-valent pneumococcal conjugate vaccine was conducted in The Netherlands among 383 children, aged 1 to 7 years, with a history of recurrent acute otitis media. No effect of vaccination on the pneumococcal colonization rate was found. However, a shift in serotype distribution was clearly observed (R. Veenhoven et al., Lancet 361:2189-2195, 2003). We investigated the molecular epidemiology of 921 pneumococcal isolates retrieved from both the pneumococcal vaccine (PV) and control vaccine (CV) groups during the vaccination study. Within individuals a high turnover rate of pneumococcal restriction fragment end labeling genotypes, which was unaffected by vaccination, was observed. Comparison of the genetic structures before and after completion of the vaccination scheme revealed that, despite a shift in serotypes, there was clustering of 70% of the pneumococcal populations. The remaining isolates (30%) were equally observed in the PV and CV groups. In addition, the degree of genetic clustering was unaffected by vaccination. However, within the population genetic structure, nonvaccine serotype clusters with the serotypes 11, 15, and 23B became predominant over vaccine-type clusters after vaccination. Finally, overall pneumococcal resistance was low (14%), and, albeit not significant, a reduction in pneumococcal resistance as a result of pneumococcal vaccination was observed. Molecular surveillance of colonization in Dutch children shows no effect of pneumococcal conjugate vaccination on the degree of genetic clustering and the genetic structure of the pneumococcal population. However, within the genetic pneumococcal population structure, a clear shift toward nonvaccine serotype clusters was observed.

Colony blot assay: a useful method to detect multiple pneumococcal serotypes within clinical specimens.

The efficacy of pneumococal conjugate vaccines in young children may be complicated by serotype replacement. We developed a colony blot assay which enables the identification of re-colonization with novel serotypes (replacement), overgrowth by minor co-colonizing serotypes or suppression of previously predominant vaccine serotype strains as a result of vaccination. This method allows the identification of multiple serotypes in a single specimen in a ratio of 1:1000. In order to demonstrate the potential of our method, we investigated the consecutive nasopharyngeal samples of 26 children who had shown a shift in pneumococcal colonization after conjugate vaccination. Mixed colonization was found once in 15 pre-vaccination samples and four times in 26 post-vaccination samples. In the remaining children 'true replacement' had presumably occurred. Hence, we conclude that the colony blot assay is an easy to apply method, which allows the identification of different pneumococcal serotypes within single clinical specimens.

Pneumococcal vaccines for preventing otitis media.

BACKGROUND: Acute otitis media (AOM) is one of the most common diseases in early infancy and childhood. Long term effects of recurrent episodes of otitis media, rapid emergence of drug resistant bacteria associated with AOM worldwide and huge estimated direct and indirect annual costs associated with otitis media have emphasized the need for an effective vaccination program to prevent episodes of AOM. OBJECTIVES: The object of this review was to assess the effect of pneumococcal vaccination in preventing AOM in children up to 12 years of age. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 2, 2003) which contains the Cochrane Acute Respiratory Infection Group's specialised register (30th June 2003), MEDLINE (January 1966 to June 2003), EMBASE (January 1990 to June 2003) and reference lists of all studies and review articles retrieved. We also contacted two vaccine manufacturers and first or corresponding authors of some of the included studies. SELECTION CRITERIA: Randomised controlled clinical trials of pneumococcal vaccination with prevention of AOM as outcome in children aged 12 years or younger and a follow-up of at least six months after vaccination. DATA COLLECTION AND ANALYSIS: Five reviewers independently assessed trial quality and two reviewers extracted data. Two study authors were contacted. MAIN RESULTS: Eight trials on 8-to 14-valent pneumococcal polysaccharide vaccine (PPV) and four trials on 7-to 9-valent pneumococcal conjugate vaccine (PCV) were included. The highest efficacy of PPV was found in children aged 24 months and older: the rate ratio was 0.779 [95% CI: 0.625-0.970]. PPV has little effect on the prevention of AOM in children without documented prior episodes of AOM and only a moderate effect in the group of children with documented AOM episodes prior to vaccination. Pooled results of the four PCV trials in infants vaccinated as early as two months of age and toddlers attending daycare and toddlers with recurrent AOM showed only a small effect on prevention of AOM (rate ratio 0.921; 95% CI: 0.894-0.950). REVIEWER'S CONCLUSIONS: Based on the currently available results of the effectiveness of pneumococcal vaccination for the prevention of AOM, a large scale use of pneumococcal polysaccharide and conjugate vaccination for this specific indication is not yet recommended. So far, pneumococcal conjugate vaccinations are not indicated in the management of recurrent AOM in toddlers and older children. The results of currently ongoing trials of 9- and 11-valent conjugate vaccines should provide more information as to whether pneumococcal vaccines are more effective in specific high-risk populations like infants and older children with recurrent AOM or immunodeficiency.

Pneumococcal vaccines for preventing otitis media.

BACKGROUND: Acute otitis media (AOM) is one of the most common diseases in early infancy and childhood. Long term effects of recurrent episodes of otitis media, rapid emergence of drug resistant bacteria associated with AOM worldwide and huge estimated direct and indirect annual costs associated with otitis media have emphasized the need for an effective vaccination program to prevent episodes of AOM. OBJECTIVES: The object of this review was to assess the effect of pneumococcal vaccination in preventing AOM in children up to 12 years of age. SEARCH STRATEGY: We searched the Cochrane Acute Respiratory Infection Group specialised register (last update, 26th April 2001), the Cochrane Library (Issue 4, 2000), MEDLINE (January 1966-August 2000) and reference list of all studies and review articles retrieved. We also contacted two vaccine manufacturers and first or corresponding authors of some included studies. SELECTION CRITERIA: Randomised controlled clinical trials of pneumococcal vaccination with prevention of AOM as outcome in children aged 12 years or younger and a follow-up of at least six months. DATA COLLECTION AND ANALYSIS: Five reviewers independently assessed trial quality and two reviewers extracted data. Two study authors were contacted. MAIN RESULTS: Eight trials on pneumococcal polysaccharide vaccine (PPV) and two trials on pneumococcal conjugate vaccine (PCV) were included. The highest efficacy of PPV was found in children aged 24 months and older: the rate ratio after adjustment for study was 0.833 [95%CI: 0.625-0.970]. The PPV has little effect on the prevention of AOM in children without documented prior episodes of AOM and only a moderate effect in the group of children with documented AOM episodes prior to vaccination. The results of the two PCV trials in healthy infants, which followed children from the age of two months until two years of age, could not be pooled because of lack of data. Both studies showed that the risk of recurrent disease decreased with 9% in the group of children receiving the PCV together with other childhood vaccinations at 2,4,6 and 14 months of age: Study Black et al 2000 : risk ratio=0.91[95%CI:0.86-0.96]; Study Eskola et al 2001: risk ratio=0.90 [95%CI:0.73-1.12]. REVIEWER'S CONCLUSIONS: Based on the currently available results of the effectiveness of pneumococcal vaccination for the prevention of AOM, a large scale use of pneumococcal vaccination for this indication is not recommended. The results of currently ongoing trials could provide more information whether pneumococcal vaccines are effective in specific high-risk (otitis-prone) populations.

Hypertrichosis cubiti: two new cases and a review of the literature.

Two cases of hypertrichosis cubiti in combination with short stature, facial dysmorphias and retarded development are reported with a review of the literature. Hypertrichosis cubiti, the hairy elbows syndrome, consists of a localized form of long vellus hair on the extensor surfaces of the distal third of the upper arm and the proximal third of the forearm bilaterally. It can be associated with short stature and other physical abnormalities. The mode of inheritance has not been established yet; an autosomal recessive as well as an autosomal dominant inheritance trait are postulated.

[Cytomegalovirus infection: congenital or postnatally acquired? Importance of the Guthrie card]. / Cytomegalovirusinfectie: congenitaal of postnataal verworven? Rol voor het hielprikkaartje.

A girl aged 4 weeks had persistent pulmonary hypertension of the newborn, haematological abnormalities and hepatosplenomegalia due to a cytomegalovirus (CMV) infection; thereafter she had a psychomotoric retardation. A girl aged 6 months had psychomotoric retardation and microcephaly due to a CMV infection, with epilepsy and perception deafness. A polymerase chain reaction (PCR) for CMV-DNA in the blood on the Guthrie card demonstrated retrospectively in both cases that the infection was congenital. A 4-month-old boy had parents who had both experienced a CMV infection around the birth of the child. The child was infected with CMV but the absence of CMV-DNA in the blood on the Guthrie card revealed that the infection was not congenital. Only 10% of infants with congenital CMV infection are symptomatic at birth; the prognosis is then poor. Up to 10-15% of the asymptomatic patients will develop neurological manifestations. For the diagnosis of congenital CMV infection virus isolation is required within 3 weeks after birth. However, when CMV infection is not considered during this period it is later still possible to diagnose congenital CMV infection with a PCR for CMV-DNA in blood spots of Guthrie cards taken during the first week of life.

[Vaccination against acute otitis media]. / Vaccinatie tegen otitis media acuta.

Acute otitis media (AOM) is the most frequent bacterial infection in childhood. Because of the high morbidity, the costs of AOM and growing concern about increasing resistance of pneumococci, the most common bacterial cause of AOM, prevention of AOM is important. Vaccination with the recently developed pneumococcal conjugate vaccines leads to a reduction in the number of AOM cases caused by the serotypes present in the vaccine, but the reduction in overall AOM incidence is below 10%. In particular the children with recurrent episodes of AOM may benefit more from these pneumococcal conjugate vaccines.

[Asthmatic child without asthma]. / Een astmatisch kind dat geen astma heeft.

Two boys aged 13 and 7 years, displayed chronic coughing, dyspnoea on exertion, anorexia, weight loss, and fatigue. At first a diagnosis of asthma was made. However, a correct interpretation of anamnestic and clinical features, laboratory findings and radiographic results led to the diagnosis of 'pigeon breeder's disease' in both cases. Both patients recovered after drug treatment and avoidance of re-exposure to pigeon antigen.

[Neutropenia due to antibodies against Type III Fc receptors on neutrophil granulocytes: 3 children with different clinical courses]. / Neutropenie door antistoffen tegen Fc-receptoren type III op neutrofiele granulocyten: 3 kinderen met verschillend ziektebeloop.

Three children (girls) suffered from neutropenia mediated by anti-neutrophil IgG-Fc receptor type III (Fc gamma RIII) antibodies. The first patient (newborn) had asymptomatic and transient neutropenia caused by maternal Fc gamma RIII iso-antibodies. The second patient (6 months), whose neutropenia was diagnosed as a 'benign neutropenia of childhood' caused by transient anti-NAI autoantibodies, suffered from mild bacterial infections. The third patient (12 years) suffered from serious infections. The anti-Fc gamma RIII autoantibodies showed neither anti-NA1 nor anti-NA2 specificity. She also developed autoimmune thyroiditis (Graves' disease). Both the duration of the neutropenia and the seriousness of the bacterial infection were variable in our patient group. The first two patients both made spontaneous recoveries, while the third patient depended ultimately on granulocyte-colony stimulating factor (G-CSF).

An immunocompetent infant with cow's milk allergy and cytomegalovirus colitis.

UNLABELLED: A 5-week-old, severely ill, infant is described with diarrhoea and rectal bleeding, followed by vomiting and dehydration after introduction of a cow's milk formula. A diagnosis of cow's milk allergy was made because of the clinical presentation of an allergic enterocolitis, the rapid improvement after introduction of a hypo-allergenic formula and development of colic directly after rechallenge with cow's milk. Furthermore a highly specific IgE for alpha-lactalbumin strongly supported the diagnosis. Because of recurrent rectal bleeding a limited colonoscopy was performed at the age of 10 weeks. Surprisingly a second diagnosis of histopathologically proven cytomegalovirus (CMV) colitis was made. Extensive immunological screening revealed no signs of immunodeficiency. The child thrived without any treatment for CMV and developed normally. This is the first description of an immunocompetent infant with CMV colitis. CONCLUSION: It cannot be excluded that the allergic colitis facilitated the CMV colitis, or vice versa CMV colitis triggered cow's milk protein induced entero-colitis. Further attention should be given to children with bloody diarrhoea to establish a possible relationship between CMV infection and cow's milk protein allergy.

[2 patients with atypical manifestations of cat-scratch disease]. / Twee patiënten met atypische manifestaties van kattenkrabziekte.

In 2 boys aged 8 years and 10 months, respectively, uncommon manifestations of cat scratch disease were seen. The first patient had acute encephalopathy: coma and generalized tonic-clinic convulsions. The second patient was presented with fever and peripheral lymphadenopathy in combination with hypodense lesions in the liver on ultrasound. Diagnosis was established on the clinical picture and the positive results of serological testing of antibody titres for Bartonella henselae. Both patients recovered completely within 2 months.

Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy.

The purpose of this study was to test the hypothesis that a high lactate signal and a low N-acetyl-aspartate/choline ratio in neonates with postasphyxial encephalopathy indicated a high chance of an adverse outcome in vivo when proton magnetic resonance spectroscopy was used. Twenty-one full-term asphyxiated neonates were examined at a mean postnatal age of 7.1 d. Five patients died, and five survivors had handicaps. Eleven of the 16 survivors (seven without handicaps and four with handicaps) had a second examination at 3 mo of age. After magnetic resonance imaging, spectra were obtained at 1.5 tesla. A 20-mm-thick slice was selected through the basal ganglia. After optimizing the B-0 field, we used a double spin-echo pulse sequence (90-180-180 degrees) with a time to repeat of 2000 ms and a time to echo of 272 ms. Two-dimensional spectroscopic imaging was performed by 32 x 32 phase encoding steps in two directions in a 225-mm field of view, resulting in 1-mL volumes, followed by computerized processing. Neuromotor development was examined at 6 wk, 3 mo, and every 3 mo thereafter. Lactate resonances were seen only in the five patients with grade 3 postasphyxial encephalopathy. Lactate was distributed diffusely (n = 4), or localized in areas of infarction (n = 1). N-acetyl-aspartate/choline ratios were significantly lower in the patients with an adverse outcome than in the survivors without handicaps, both neonatally (p < 0.005, Wilcoxon's rank sum test) and at 3 mo (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)