Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.

Previously, nonsense mutations in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R) have been described in three patients with severe congenital neutropenia (SCN) (Proc Natl Acad Sci USA 1994; 91: 4480; New Engl J Med 1995; 333: 487). The mutations resulted in the truncation of the carboxy-terminal region of G-CSF-R essential for transduction of maturation signals. Two of these patients developed acute myeloblastic leukemia (AML). We present the results of a search among 20 additional cases of congenital neutropenia (CN) and SCN for the presence of mutations in the cytoplasmic domain of G-CSF-R. This series includes patients with familial and nonfamilial forms of CN and SCN. Mutations in the G-CSF-R gene were found in two new SCN cases. These mutations were nonsense mutations, located in the same cytoplasmic region of G-CSF-R as those found earlier, resulting in the truncation of the C-terminus. Both of these patients developed AML. None of the other patients showed clinical symptoms or cytogenetic features indicative of AML or progression to leukemia. The analysis in this extended series of patients thus has revealed five SCN cases with G-CSF-R mutations, four of whom developed AML. These results add support to the notion that mutations in the G-CSF-R gene, affecting the maturation signaling function of the receptor, define a distinct subgroup of SCN with increased susceptibilty to AML.

Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age.

OBJECTIVE: The objectives of this study were (1) to determine the effects of gestational age on ceftazidime pharmacokinetics in the preterm infant, (2) to relate these effects to changes in glomerular filtration rate (GFR), and (3) to establish appropriate dosage recommendations for preterm infants on day 3 of life. METHODS: Multiple-dose pharmacokinetics of ceftazidime (administered twice daily in a 25 or 50 mg/kg body weight intravenous dose) were evaluated in 136 preterm infants on day 3 of life. Blood samples were collected from an arterial catheter 0, 1/2, 1, 2, 4, 8, and 12 hours after the intravenous dose. An HPLC method was used to determine ceftazidime concentrations in serum. The GFR was studied simultaneously by means of the 24-hour continuous inulin infusion technique. RESULTS: The total body clearance, volume of distribution, and elimination serum half-life of ceftazidime (mean +/- SD) were 55.7 +/- 34.4 ml/hr (37.3 +/- 11.9 ml/hr/kg), 496 +/- 228 ml (350 +/- 96 ml/kg), and 6.95 +/- 2.32 hours, respectively. The mean +/- SD peak and trough levels were 114.9 +/- 39.4 and 33.9 +/- 17.8 mg/L. All infants had a serum trough level above 5 mg/L. Clearance and volume of distribution of ceftazidime and GFR increased significantly with increasing gestational age, whereas serum trough levels and serum half-life of ceftazidime decreased significantly with increasing gestational age. Ceftazidime clearance increased significantly with increasing GFR. Prenatal exposure to indomethacin resulted in significantly lower GFR values and ceftazidime clearances. CONCLUSIONS: Dosage recommendations for ceftazidime administration in preterm infants during the first week of life should be based on gestational age and GFR. Additional adjustments in dosage are indicated in preterm infants who are exposed prenatally to indomethacin.

Relation between cytokines and routine laboratory data in children with septic shock and purpura.

OBJECTIVE: To establish the relation between routine laboratory data (lactate, fibrinogen, CRP) and cytokines (TNF,IL-1 and -6) and to estimate their prognostic value in pediatric patients with severe infectious purpura on admission. DESIGN: Prospective study. SETTING: Pediatric intensive care unit (PICU). PATIENTS: 17 children aged 5-172 months (median 46) were hospitalized in our PICU in 1989-90 with severe infectious purpura. Neisseria meningitidis was isolated in 15 children and Haemophilus influenzae in two. The patients were divided into 3 groups: non-shock, shock and severe shock leading to death. Shock was defined by standard criteria. MEASUREMENTS: Arterial blood was sampled for lactate, CRP, fibrinogen, TNF, and IL-1 and -6 on admission. The PRISM (pediatric risk of morality)-score was recorded. METHODS: Statistical analysis was performed with the Student's t-test using the logarithmic values of the cytokine concentration, and Spearman correlation analysis. RESULTS: According to the shock criteria, 9 patients were in shock of whom 4 did not survive. Significant differences existed between the 3 groups concerning lactate, TNF, and IL-6. Fibrinogen, CRP, IL-1, and PRISM-score discriminated only between survivors and non-survivors. A highly significant correlation existed between cytokines, the PRISM-score and lactate (TNF: r = 0.69, IL-1: r = 0.56, IL-6: r = 0.65, PRISM: r = 0.65). A significant inverse correlation existed between cytokines and CRP (TNF: r = -0.55, IL-1: r = -0.64, and IL-6: r = -0.56), and IL-6 and fibrinogen (r = -0.65). CONCLUSION: These results show a significant correlation between cytokines and lactate, and lactate, TNF and IL-6 are closely associated with the severity of septic shock with purpura in children.

Lung function and bronchial responsiveness in children who had infantile bronchiolitis.

A number of studies have shown that children who had infantile bronchiolitis are at increased risk of recurrent episodes of wheezing. A genetic predisposition to atopy is mentioned in some studies and is contested by others. Lung function abnormalities and increased bronchial responsiveness (BR) have been described after infantile bronchiolitis. We investigated children who had had the clinical syndrome of bronchiolitis during infancy and compared them with asthmatic and healthy children of the same age regarding bronchial caliber, smooth muscle tone, and responsiveness to histamine. Lung function was measured by forced oscillometry. We found that most children with current symptoms had either decreased baseline bronchial caliber, increased bronchial smooth muscle tone, or increased BR. These patients are comparable to mild asthmatics. The children without current symptoms are comparable to healthy children in these respects. Recurrent respiratory symptoms after bronchiolitis should be regarded as mild asthma and treated as such.

Prolonged recovery from exercise-induced asthma with increasing age in childhood.

It has been suggested that children with asthma recover more quickly from exercise-induced bronchoconstriction than adults. On the basis of clinical observation we hypothesized that recovery rate from exercise-induced asthma (EIA) in childhood also decreases with age. In 14 children (aged 7-12 years) with a history of EIA, we measured spontaneous recovery from bronchoconstriction induced by two different stimuli: exercise and histamine. The children visited the laboratory three times. After a screening exercise test on the first visit, standardized bronchoprovocation tests with either exercise or histamine were performed on the following two visits in random order. The degree of bronchoconstriction induced by histamine was matched for that observed after exercise. During recovery, forced expiratory volume in 1 second (FEV1) was measured repeatedly up to 2 hours postchallenge. The recovery rate (% increase in FEV1/min) was calculated from the linear slope of the time-response curve. Differences in recovery rate between the two stimuli were analyzed by paired t-test, and age-related differences were analyzed using multiple regression analysis. For the group as a whole, recovery rate was not different between the two stimuli (mean +/- SD: 1.22 +/- 0.91 for exercise, and 1.46 +/- 0.65, for histamine, P = 0.31). However, the recovery rate for exercise-induced bronchoconstriction decreased significantly with age (r = -0.74, P = 0.003), in contrast to the recovery rate for histamine (r = -0.15, P = 0.60). Consequently, in the oldest age group (11-12 years, n = 5) recovery rate from exercise challenge was significantly slower than in the younger age group (7-10 years, n = 9), i.e., 0.54 +/- 0.17 and 1.60 +/- 0.93, respectively, P = 0.009, and slower than the recovery rate from histamine challenge: 0.54 +/- 0.17 and 1.33 +/- 0.54, respectively, P = 0.03. In the younger age group the recovery rates from exercise and histamine were not different (1.60 +/- 0.93 and 1.54 +/- 0.73, respectively, P = 0.83). We conclude that recovery from EIA in childhood decreases with increasing age. These data suggest that the mechanism of exercise-induced asthma in childhood changes with age. This might be due to changes in mediator production or response to mediator release.

Staphylococcal pneumonia in childhood: will early surgical intervention lower mortality?

Staphylococcus aureus pneumonia (SAP) continues to be a serious bacterial infection which is associated with a high incidence of complications. We retrospectively reviewed the case records of 36 infants and children admitted with SAP to the Sophia Children's Hospital between 1970 and 1992 to analyse changes over time in the clinical presentation, diagnostic work-up, management and complications. Fifteen of these 36 children (42%) were less than 1 year old. Fever (97%) and respiratory distress (83%) were the most common symptoms at the initial presentation. Chest X-ray findings on admission or during hospitalisation included pleural effusion (75%), pneumothorax (47%), and abscess and/or pneumatocele (39%). Diagnostic and/or therapeutic thoracentesis of pleural fluid was performed in 17 of the 36 patients (47%). Twenty-one patients (58%) needed chest tube drainage. Twelve had a thoracotomy (33%). Artificial ventilation was needed in 13 of the patients (36%). Extrapulmonary complications included convulsions in 6 patients (17%) and osteomyelitis in 2 children (6%). The mean duration of hospitalization was 36 days. Two of the 36 children died (6%). The low mortality rate in this study may be the result of the relatively high rate of thoracotomy and of improvements in supportive treatment.

Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma.

When treating bronchial hyperresponsiveness to so-called direct and indirect stimuli, distinct pathophysiological mechanisms might require differences in dose and duration of inhaled corticosteroid therapy. To test this hypothesis in children with asthma, we investigated the time- and dose-dependent effects of 2 doses of fluticasone propionate (FP, 100 or 250 microg bid.) in improving exercise- (EIB) and methacholine-induced bronchoconstriction during 6 months of treatment, using a placebo-controlled parallel group study design. Thirty-seven children with asthma (aged 6 to 14 years; forced expired volume in 1 sec (FEV(1)) >/=70% predicted; EIB >/=20% fall in FEV(1) from baseline; no inhaled steroids during the past 4 months) participated in a double-blind, placebo-controlled, 3-arm parallel study. Children receiving placebo were re-randomized to active treatment after 6 weeks. Standardized dry air treadmill exercise testing (EIB expressed as %fall in FEV(1) from baseline) and methacholine challenge using a dosimetric technique (expressed as PD(20)) were performed repeatedly during the study. During FP-treatment, the severity of EIB decreased significantly as compared to placebo within 3 weeks, the geometric mean % fall in FEV(1) being reduced from 34.1% to 9.9% for 100 microg FP bid, and from 35.9% to 7.6% for 250 microg FP bid (P < 0.05). These reductions in EIB did not differ between the 2 doses and were sustained throughout the treatment period. PD(20) methacholine improved significantly during the first 6 weeks as compared to placebo (P < 0.04) and steadily increased with time in both treatment limbs (P = 0.04), the difference in improvement between doses (100 microg FP bid, 1.6 dose steps; 250 microg FP bid, 3.3 dose steps) approaching significance after 24 weeks (P = 0.06). We conclude that in childhood asthma, the protection afforded by inhaled fluticasone propionate against methacholine-induced bronchoconstriction is time- and dose-dependent, whereas protection against EIB is not. This suggests different modes of action of inhaled steroids in protecting against these pharmacological and physiological stimuli. This has to be taken into account when monitoring asthma treatment.

Bronchial carcinoid tumor in a 12-year-old child.

Symptoms (hemoptysis, recurrent pulmonary infections), diagnostic work-up (roentgenology, bronchoscopy with biopsy), and treatment (surgical resection of a bronchial carcinoid tumor in a 12 year old girl) are discussed. Special attention was paid to the tumor histochemistry, showing serotonin containing granules. Levels of circulating hormones and vasoactive agents, including serotonin, were within normal limits.

The treatment of chronic sinusitis: a controversial issue.

The persistence of sinusitis after upper respiratory tract infection is influenced by a range of aetiological factors such as anatomical variation which may be surgically corrected, mucociliary abnormalities and immune deficiency. The latter is more common than previously realised, encompassing IgG subclass deficiency, reduced opsonization and Fc gamma receptor polymorphism. This has therapeutic implications, with the possibility of IgG replacement therapy and vaccination. CT scanning suggests that the age of the patient and anatomical abnormalities are important aetiological factors in chronic rhinosinusitis. Only when medical therapy fails, is surgery considered. Although a range of surgical procedures are available, an endoscopic approach may be directed at the ostiomeatal complex and is generally very conservative. Scanning is a prerequisite to this surgery, demonstrating both the extent of disease and the anatomy but requires careful interpretation. Furthermore, an endoscopic technique can be employed for a number of other sinus conditions though this should only be undertaken by an experienced surgeon. A long-term prospective study of children undergoing radical sinus surgery for neoplasia strongly suggests that concerns that surgery in the middle meatus might disturb subsequent facial development are unfounded.

[Indications for influenza vaccination in children with lung disorders. Dutch Association for Pediatric Medicine]. / Indicaties voor influenzavaccinatie bij kinderen met longaandoeningen. Nederlandse Vereniging voor Kindergeneeskunde.

The Dutch Association for Paediatric Medicine has formulated guidelines regarding influenza vaccination of children with pulmonary disease. Influenza virus is the most frequent cause of airway infections in humans over two years of age. It may lead to serious morbidity in children with pulmonary disease: exacerbations, (transient) disturbances in pulmonary function, and symptoms lasting weeks, but mortality is probably very low. The effects of influenza vaccination of children with pulmonary disease are similar to those in normal healthy children. A positive long-term effect on the asthma has never been demonstrated. It is advised that children with moderate to severe asthma who require treatment to be vaccinated against influenza every year. If the first vaccination ever occurs before the age of six years, it should be followed by a booster vaccination after four weeks. In both instances, a full vaccination dose should be administered.

[Respiratory syncytial virus infections and preventive options]. / Infectie met respiratoir syncytieel virus en mogelijkheden voor preventie.

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.

[An infant with AIDS]. / Een zuigeling met AIDS.

A four-month-old girl was hospitalized with pneumococcal sepsis from which she recovered. Subsequently she developed various other infectious diseases, including chronic diarrhoea caused by Cryptosporidium. After a period with neurological symptoms, later sagittal sinus thrombosis and cerebral atrophy, she died at age 13 months. It was found that the child suffered from AIDS. The mother was seropositive and the virus had probably been transmitted via the placenta. Rapid recognition of infants and young children with AIDS is necessary, for in the near future more cases of this disease will occur. Antiviral treatment may bring about improvement in children as well.

[Lung infections with atypical features]. / Longinfecties met atypische aspecten.

The clinical difference between a lobar pneumonia caused by pneumococci or other bacterial agents and lower respiratory tract infections presenting with atypical symptoms is important. Mycoplasma pneumoniae, chlamydia species, Coxiella burnetii and several viruses amongst others are micro-organisms which cause atypical symptoms. All the time new types of micro-organisms like Ureaplasma urealyticum are found as a cause of pneumonia with atypical symptoms. Special diagnostic tools like cultures, serological or antigen detection are often needed to determine the exact causative agent. Clinical data are important to suspect a specific micro-organism.