Paediatric apnoeas are not related to a specific respiratory virus, and parental reports predict hospitalisation.

AIM: The aim of this study was to determine the frequency of apnoeas in previously healthy young infants with acute respiratory tract infection (ARI) and correlate their occurrence with isolated micro-organisms, clinical findings, disease severity and outcome. METHODS: We performed reverse transcriptase real-time polymerase chain reaction (RT-PCR) on the nasal wash specimens of a prospective cohort study of 582 children with ARI. Clinical data on a subgroup of 241 infants under three months of age, with and without apnoeas, were compared. RESULTS: Our study found that 19 (7.9%) of the 241 infants under three months old had a history of apnoeas: eight had a respiratory syncytial virus (RSV), five had a different virus than RSV and seven RT-PCR results were negative. Infants with apnoeas were more likely to have cyanosis, had longer hospital stays and required extra oxygen for a longer period. Most patients with parental reported apnoeas also experienced apnoeas during hospitalisation. CONCLUSION: This study observed apnoeas irrespective of the isolated micro-organism, and we hypothesise that they were related to the pathophysiology of the respiratory infection and not to the micro-organism itself. Parental reported apnoeas were a major warning sign and predicted that apnoeas would occur in hospital.

Decline of IgG pertussis toxin measured in umbilical cord blood, and neonatal and early infant serum.

Maternal pertussis-specific antibodies are passively acquired by infants during pregnancy. An IgG pertussis toxin (IgG-PT) concentration of >20 U/ml is considered to protect neonates against pertussis. To evaluate the IgG concentration at birth and during the first two months of life, we examined the IgG-PT concentration in the umbilical cord blood and three times during the neonatal and early infant period. IgG-PT was measured by validated IgG-specific enzyme-linked immunosorbent assays (ELISA) in umbilical cord blood and in Guthrie card blood samples of umbilical cord blood in 2,790 children, born between 1 August 2006 and 1 December 2008. These measurements were comparable. All children with concentrations of IgG-PT >30 U/ml were included. IgG-PT was also measured in Guthrie card blood samples, when the neonates or early infants were 5 days, 1 month and 2 months old. The mean concentrations of IgG-PT were calculated. The mean concentration of IgG-PT in umbilical cord blood was 60.1 U/ml (LN 4.1; 0.6 SD; n = 103). At the age of 5 days, 1 month and 2 months, the mean concentration of IgG-PT was 40.6 U/ml (LN 3.7; 0.5 SD; n = 103), 20.7 U/ml (LN 3.0; 0.7 SD; n = 62) and 16.7 U/ml (LN 2.8; 0.9 SD; n = 61), respectively. Four percent of the neonates had a concentration of IgG-PT >30 U/ml in umbilical cord blood, which declined to levels around the concentration needed for protection against pertussis (>20 U/ml) in the first two months of life. Hence, it is of great importance to further investigate the safety of maternal immunisation during pregnancy to prevent life-threatening pertussis in newborns.

A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens.

We studied the time course of serum IgG antibodies against 3 different pertussis vaccine antigens: PT (pertussis toxin), FHA (filamentous hemagglutinin), Prn (pertactin) in sera from individuals vaccinated with four different pertussis vaccines at 4 years of age: (N=44, 44, 23 and 23, respectively,) and compared the responses to/after natural infection with Bordetella pertussis (N=44, age 1-8 years). These longitudinal data were analyzed with a novel method, using a mathematical model to describe the observed responses, and their variation among subjects. This allowed us to estimate biologically meaningful characteristics of the serum antibody response, like peak level and decay rate, and to compare these among natural infections and vaccine responses. Compared to natural infection, responses to PT after vaccination with the tested vaccines are smaller in magnitude and tend to decay slightly faster. When present in vaccines, FHA and Prn tend to produce high peak levels, higher than those in naturally infected patients, but these decay faster. As expected, the Dutch whole cell vaccine produced lower antibody responses than the acellular vaccines. This model allows a better comparison of the kinetics of vaccine induced antibody responses and after natural infection over a long follow up period.

Antibody levels against B. pertussis in neonates measured in dried blood spots.

AIM: We designed this study to investigate if immunoglobuline G-Pertussis toxin (IgG-PT) against Bordetella pertussis in umbilical cord blood can reliably be determined in dried blood spots on filter paper (Guthrie) cards. PATIENTS AND METHODS: We prospectively included 129 mothers and their newborns born in a general hospital in the Netherlands. The relation between IgG-PT against B. pertussis from the umbilical cord measured in dried blood spots (Guthrie card) and in serum samples was studied by means of a Bland-Altman graph, using regression analysis to evaluate the level of agreement of both measurement methods. RESULTS: IgG-PT in Guthrie cards show a high coefficient of correlation with IgG-PT in serum samples from the umbilical cord when calibrated against blood spot calibrators (p<0.05). CONCLUSION: Maternal IgG-PT against B. pertussis measured in cord blood applied to Guthrie cards and calibrated against blood spot calibrators show good agreement with measurement of IgG-PT in cord serum. This offers new perspectives for future studies concerning B. pertussis antibodies.

Bordetella species in children with cystic fibrosis: what do we know? The role in acute exacerbations and chronic course.

Despite vaccination, pertussis is still endemic in the Netherlands. A literature search was performed to verify what is known about the role of Bordetella species in children with cystic fibrosis, with regard to the incidence of Bordetella infections, the involvement in pulmonary exacerbations and the influence on chronic course. Little is known about the frequency of Bordetella infections and the involvement of Bordetella species both in relation to the chronic course of cystic fibrosis and to pulmonary exacerbations. Since it is difficult to detect Bordetella species in cultures and few sputum cultures investigated have been obtained during an exacerbation, it is likely that the frequency of Bordetella species in CF patients is underestimated. Identification of Bordetella species in these patients may have serious consequences for the treatment of exacerbations in CF. Future research investigating the role of Bordetella species in cystic fibrosis should use specific techniques to detect Bordetella in cultures.

Motor Development of Premature Infants Born between 32 and 34 Weeks.

Little is known about motor development in late preterm born infants. Our objective was to determine long-term outcome of motor skills of infants born between 32 and 34 weeks. All infants were assessed at corrected ages of 3 and 9 months, using the Alberta Infant Motor Scale. At corrected ages of 4 years, the Movement Assessment Battery for Children was done. Seventy infants were seen at 4 years of age (median of 3 assessments per infant). Abnormal assessment at 3 or 9 months of age resulted in normal outcome in almost 80% at 4 years. On the other hand, a normal outcome in the first year of life resulted in an abnormal outcome at 4 years in 10% of the infants. Our results suggest that long-term followup of these late preterm born infants is necessary, as the assessments in the first year do not predict the long-term outcome.

An enterovirus epidemic in infants in the summer and fall of 2006.

The aim of this study was to evaluate the diagnostic procedures in infants presenting with febrile illness in the summer and fall of 2006. Infants younger than 90 days presenting with febrile illness were included. A sepsis evaluation was performed. Stool and/or cerebrospinal fluid were tested for enterovirus (polymerase chain reaction [PCR]). Twenty-four infants were included, with a median age of 36 days (range 5-87). Nineteen infants (79%) were diagnosed with enterovirus infection. In nine infants, both stool and cerebrospinal fluid were tested for enterovirus; both specimens were positive in three infants. In seven infants, only the stool and in three infants, only the cerebrospinal fluid was tested. The five infants without enterovirus infection were only partly tested; in four infants, only the stool and in one infant, only the cerebrospinal fluid was tested. Three infants (13%) were diagnosed with a urinary tract infection, one of which tested positive for enterovirus as well. Twenty-three infants received antibiotic treatment. The median duration of antibiotic treatment of infants without bacterial infection was 3.2 days. Thorough diagnostic evaluation for enterovirus in different specimens is important, as, often, only one specimen is positive for enterovirus. When enterovirus is diagnosed, patient management may be influenced.

Renal Fanconi syndrome with ultrastructural defects in lysinuric protein intolerance.

Renal Fanconi syndrome developed rapidly in a 3-year-old Moroccan girl with established lysinuric protein intolerance. She was hospitalized because of lowered consciousness, uncoordinated movements and hepatosplenomegaly after a febrile period. Laboratory investigations revealed plasma ammonia 270 micromol/L (normal <70 micromol/L), ferritin 159 micromol/L (normal 2-59 micromol/L), LDH 1180 U/L (normal 26-534 U/L). LPI was diagnosed based on the findings of reduced plasma ornithine, arginine and lysine, and an increased level of glutamine. Urinary orotic acid (645 micromol/mmol creatinine; normal <3.6) was strongly increased. A defect in the SLC7A7 amino acid transporter was established (homozygous c.726G > A mutation). Detailed renal function tests including an acid challenge test, bicarbonate loading, and tubular maximal reabsorption of glucose showed complex tubular dysfunction. No evidence of respiratory chain defects was found in muscle or kidney tissue. No morphological abnormalities were demonstrated in the mitochondria. Ultrastructural analysis of proximal tubular cells showed vacuolization and sloughing of the apical brush border (Fig. 1). Renal involvement in LPI has only been described in a few reports; however, no detailed studies of the renal acidification mechanism were performed. Our patient had evidence of a full-blown Fanconi syndrome. Surprisingly, a metabolic acidosis was found with a moderately increased serum anion gap combined with repeatedly normal plasma organic acid values. This finding is in contrast with the diagnosis of renal tubular acidosis. Patients with hyperlysinaemia have a similar heavy load on the renal tubules; they never develop a renal Fanconi syndrome. Therefore, we consider the intratubular accumulation of lysine an unlikely candidate for the development of the renal Fanconi syndrome.

Somatic and psychiatric co-morbidity in children with attention deficit hyperactivity disorder.

AIM: To describe the prevalence of somatic and psychiatric co-morbidity in children diagnosed with ADHD and other behavioural problems compared to this prevalence in children seen at the outpatient department without either of these conditions. METHODS: A retrospective controlled case study was conducted in 369 children. All children with ADHD were diagnosed by a clinical psychologist in a hospital setting according to the DSM IV classification. Co-morbidity was determined by pediatricians. RESULTS: Somatic co-morbidity was seen in 94 % of the children. However, there was no significant difference in the prevalence of somatic co-morbidity in patients with ADHD nor in patients with behavioural problems other than ADHD when compared with the control group. Only two differences slight were observed. In the ADHD group and the group with behavioural problems motor impairment was seen more often and in the control group constipation was diagnosed more frequently. CONCLUSION: Except for motor impairment, somatic co-morbidity of any kind does not seem to occur more frequently in children with ADHD.

A new deletion defect leading to alpha-thalassaemia in a large Dutch Caucasian family.

alpha-thalassaemia is a common inherited haemoglobin disorder that can cause only mild symptoms in carriers and is often either not diagnosed or mistaken for iron deficiency anaemia in the Netherlands. Although considered rare in North-Europeans, we also regularly observe common and rare defects in this population. It is important to be alert for the mild symptoms of these carriers because compound heterozygous and homozygous combinations can result in intermediate, severe or fatal disease in the progeny of healthy carriers. Using a new technical application, a novel alpha degrees -thalassaemia deletion was recently detected in our laboratories in a propositus of a large Dutch Caucasian family. We report the phenotypic and molecular study of this new form of alpha(o)-thalassaemia (called--(OH)alpha-thalassaemia deletion), which was observed in 10 of the 19 individuals studied in the index family. Our results indicate that the frequency of these unsuspected alpha(o)-thalassaemia defects is probably underestimated in the Netherlands.

Mycobacterium avium intracellulare otomastoiditis: case report and literature review.

Otomastoiditis caused by Mycobacterium avium intracellulare (MAI) is rare. Sub-optimal management of this condition can lead to significant morbidity and serious damage to the middle ear. Diagnosis is difficult, especially since most physicians are not familiar with the mode of presentation and symptoms. Presented here is a new case, followed by a review of the literature on MAI mastoiditis.

Bordetella pertussis and mixed infections.

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.

Carrier diagnostics and prevention of hemoglobinopathies in early pregnancy in The Netherlands: a pilot study.

BACKGROUND: We have offered, for the first time in The Netherlands, carrier diagnostics for hemoglobinopathies (HbP) to early pregnant women. The aim of this study was to establish whether carrier analysis would be welcome by the public and feasible at the outpatient level. METHOD: One hundred and thirty-nine randomly selected women were informed and offered basic carrier diagnostics at the first pregnancy control. RESULTS: Carrier diagnostics was accepted by 136 women (97.8%). The population consisted of 31% of recent immigrants and 69% of native Dutch. One carrier of HbS and one of beta-thalassemia were found, both among the group of the recent immigrants. In both cases, partners were tested excluding a couple at risk. In addition, five carriers of alpha(+)-thalassemia were diagnosed at the molecular level, one of them in the native Dutch population. Basic carrier analysis was done both at the Hospital Laboratory and at the Reference Laboratory. No discrepancies were found. CONCLUSIONS: This pilot study shows that (1) as predicted the prevalence of risk-related HbP and of alpha(+)-thalassemia is high in the immigrant population. (2) The compliance with carrier analysis in both native Dutch and immigrants is virtually total and (3) carrier diagnosis in early pregnancy and partner analysis in Hospital Laboratories is possible and is an effective tool for primary prevention of HbP in The Netherlands.

Community-acquired pathogens associated with prolonged coughing in children: a prospective cohort study.

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.

Age-specific long-term course of IgG antibodies to pertussis toxin after symptomatic infection with Bordetella pertussis.

To investigate the possible dependence on age of the rate of decline of IgG antibodies to pertussis toxin (IgG-PT) after natural infection with Bordetella pertussis we measured IgG-PT in follow-up sera of 121 patients (age 0-94 years) obtained after 123 episodes of B. pertussis infection. For analysis we applied a dynamic model for the inactivation of B. pertussis by the immune system. There were no significant differences in rise, peak and decline of IgG-PT between different age groups, although there was a tendency for a more rapid increase, a higher peak and a faster decline with increasing age. The IgG-PT cut-off of 100 U/ml for serodiagnosis of pertussis appeared valid in all age groups. A decline of IgG-PT to < 10 U/ml was associated with increased risk of re-infection with B. pertussis.

Neonatal ovarian cysts.

UNLABELLED: Foetal and neonatal ovarian cysts have previously been considered uncommon. With the development of sonography, however, the detection of cysts has increased. As ovarian cyst formation in the perinatal period is a self-limiting process, treatment options depend on the risk of complications and on the ability to differentiate these benign cysts from other pathology. The history of two neonates with an ovarian cyst detected antenatally with ultrasound techniques is described. CONCLUSION: It is important that paediatricians have knowledge about the incidence, treatment and prognosis of foetal neonatal ovarian cysts.

Laboratory-confirmed reinfections with Bordetella pertussis.

UNLABELLED: Susceptibility to infection with Bordetella pertussis re-emerges several years after pertussis vaccination. However, the duration of immunity after natural infection with B. pertussis, postulated to be lifelong, is not known. In an ongoing study, the longitudinal course of pertussis antibodies in patients who have had laboratory-confirmed pertussis is being followed using sera obtained at irregular intervals. In 4 patients a reinfection with Bordetella pertussis is described respectively 7 (patient A), 12 (patients B and C) and 3.5 (patient D) y after the first infection. It seems that the longer the interval between the infections the more severe the complaints. CONCLUSION: To the authors' knowledge. these are the first patients in whom symptomatic reinfection with B. pertussis has definitely been proven by laboratory confirmation of both episodes. Bordetella pertussis infection should be considered in patients with symptoms of typical or atypical whooping cough, irrespective of their vaccination status or previous whooping cough.