The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children.

BACKGROUND: Although respiratory syncytial virus (RSV) lower respiratory tract infections (LRTIs) in early life are followed by later airway hyperreactivity, it is unclear whether there is a causal relationship between this and an atopic diathesis. OBJECTIVES: To separate the effects of RSV LRTI and an atopic diathesis on subsequent recurrent wheezing, we examined the protective effect of previous palivizumab administration against subsequent recurrent wheeze in infants with and without a family history of atopy. METHODS: A prospective multicenter, matched, double cohort study was conducted in 27 centers in Europe and Canada. The rates of physician-diagnosed recurrent wheezing in premature infants <36 weeks gestation who had received palivizumab in the first year of life were compared to those of gestational age-matched controls. RESULTS: The relative protective effect of palivizumab on physician-diagnosed recurrent wheezing through the ages of 2 to 5 years was 68% in those with no family history of asthma (odds ratio, 0.32; (95% CI, 0.14-0.75; N = 146 palivizumab-treated, 171 untreated) and 80% in those with no family history of atopy or food allergies (odds ratio, 0.20; 95% CI, 0.07-0.59; N = 101 palivizumab-treated, 100 untreated). In contrast, there was no effect of palivizumab on subsequent recurrent wheezing in the 90 children with a family history of atopy or food allergies compared to 130 untreated infants with atopic families. CONCLUSION: Respiratory syncytial virus prophylaxis in nonatopic children decreases by 80% the relative risk of recurrent wheezing but does not have any effect in infants with an atopic family history. This suggests that RSV predisposes to recurrent wheezing in an atopy-independent mechanism.

Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing.

OBJECTIVE: Children who experience respiratory syncytial virus (RSV) lower respiratory tract infections (LRTIs) early in life have high rates of subsequent recurrent wheezing. Palivizumab, an anti-RSV monoclonal antibody, has 78% to 80% efficacy in preventing RSV hospitalization in premature infants without chronic lung disease. We hypothesized that palivizumab, by ameliorating or preventing early RSV LRTI in preterm infants, might decrease later recurrent wheezing. STUDY DESIGN: A cohort of preterm infants who had received palivizumab and were not hospitalized for RSV (n = 191) or who never received palivizumab (n = 230; 76 who were hospitalized for RSV and 154 who were not), were prospectively followed for 24 months beginning at a mean age of 19 months. The subjects were assessed for recurrent wheezing by caretaker or physician report. RESULTS: The incidences of recurrent wheezing and physician-diagnosed recurrent wheezing were significantly lower in the 191 palivizumab-treated subjects (13% and 8%, respectively) compared with all 230 untreated subjects (26%, P = .001 and 16%, P = .011, respectively) and with the 154 patients in the subgroup not hospitalized for RSV LRTI (23%, P = .022 and 16%, P = .027, respectively). The effect of palivizumab treatment remained significant after adjustment for potential confounding variables. CONCLUSIONS: Our study suggests that preventing RSV LRTI with palivizumab may reduce subsequent recurrent wheezing in premature infants.

Tracheobronchial anomalies and stenoses: detection with low-dose multidetector CT with virtual tracheobronchoscopy--comparison with flexible tracheobronchoscopy.

PURPOSE: To prospectively assess the sensitivity and specificity of low-dose multidetector computed tomography (CT) with virtual tracheobronchoscopy (VT) for evaluation of suspected airway stenoses and/or abnormalities by using flexible tracheobronchoscopy (FT) as the reference standard. MATERIALS AND METHODS: The study was approved by the local ethics committee; parental consent was obtained. Forty-five patients with clinically and/or radiographically suspected tracheobronchial stenosis and/or anomaly underwent FT and contrast material-enhanced single-phase multidetector CT with VT. CT was performed with an age- and weight-adjusted low-dose protocol: 120 or 80 kV; 120 or 60 mA; collimation, 1.5 or 0.75 mm; gantry rotation, 0.5 second. Mean effective dose was calculated for all examinations. Postprocessing was performed with surface rendering of VT images and multiplanar reformations. CT images were analyzed in consensus by two radiologists who were blinded to FT results. Statistical analysis was performed with 2 x 2 contingency tables; 95% confidence intervals (CIs) were calculated with the Blyth-Still-Casella procedure. RESULTS: Mean patient age was 4.4 years (range, 2 months to 16 years; 53% male patients). Tracheobronchial narrowing and/or abnormality were depicted at FT in 38 of 45 patients. In 33 of 38 patients, multidetector CT with VT depicted a tracheobronchial narrowing and/or anomaly. In 10 of 38 patients, tracheobronchial stenosis was induced by vascular anomalies. Five patients with normal findings at multidetector CT with VT had tracheobronchomalacia with inspiratory airway stenosis at FT. Sensitivity and specificity of CT with VT were 86.8% (95% CI: 73.3%, 94.7%) and 85.7% (95% CI: 44.6%, 99.3%), respectively. Positive and negative predictive values were 97.1% (95% CI: 84.9%, 99.9%) and 54.5% (95% CI: 25.0%, 80.0%), respectively. Overall accuracy was 86.7% (95% CI: 74.3%, 94.0%). Mean effective dose was 1.1 mSv (range, 0.5-1.8 mSv). CONCLUSION: Multidetector CT with VT with a low-dose protocol had high sensitivity and specificity for depiction of tracheobronchial narrowings and/or anomalies. However, tracheal narrowing due to tracheobronchomalacia was difficult to diagnose at single-phase multidetector CT with VT.

Evaluation of clinical, radiologic, and laboratory prebronchoscopy findings in children with suspected foreign body aspiration.

BACKGROUND: Foreign body aspiration (FBA) in infants and young children is a common and potentially life-threatening event. Although studies have extensively described the signs and symptoms of suspected FBA (sFBA), only few systematically compared their value for predicting bronchoscopy results. OBJECTIVES: The objectives of this study were to describe the clinical and radiologic signs and symptoms of sFBA and to identify predictors of bronchoscopically proven FBA (pFBA). SETTING: This study was conducted at a referral tertiary university hospital with an outpatient clinic and a 90-bed pediatric unit. METHODS: Signs and symptoms were retrospectively analyzed for all children who had received bronchoscopy between July 1992 and April 2000 because of sFBA. Radiologic signs of FBA were reviewed and scored by 2 independent radiologists. RESULTS: One hundred sixty children (mean age, 2.8 years; range, 11 months to 16.8 years) were enrolled in the study. Foreign body aspiration, mostly affecting the right main bronchus, was proven bronchoscopically in 122 (76%) of these children. Independent predictors of pFBA in multivariable analyses were focal hyperinflation on chest radiograph (beta = 45.4; 95% confidence interval [CI] = 5.3-390.5; P = .001), witnessed choking crisis (beta = 18.6; 95% CI = 4.7-73.0; P < .001), and white blood cell count greater than 10,000/muL (beta = 4.2; 95% CI = 1.2-14.7; P = .026). The cumulative proportion of pFBA cases increased with the number of risk factors (0, 16%; 1, 47%; 2, 96%; 3, 100%). CONCLUSIONS: Clinical judgment to perform bronchoscopy for sFBA was correct in 76% of the children investigated. Focal hyperinflation, witnessed choking crisis, and elevated white blood cell count were strongly associated with pFBA; bronchoscopy can be strongly recommended in the presence of at least 2 risk factors when FBA is suspected.

Pulmonary haemosiderosis in infants and children.

Pulmonary haemosiderosis (PH) results from recurrent bleeding into alveolar spaces and interstitial lung tissue. If untreated, fibrosis and restrictive lung disease will develop and may lead to death. A distinction can be made between primary and secondary pulmonary haemosiderosis as a manifestation of auto-immune small vessel vasculitides, coagulation disorders or diseases with increased venous pressure. Interestingly, in some cases of 'idiopathic' PH, exposure to moulds and van Willebrand's disease may contribute to the pathogenesis. Haemosiderosis usually begins with haematemesis. Anaemia, alveolar infiltrates on chest x ray and siderophages in broncho-alveolar lavage fluid are diagnostic factors. Immunosuppressive treatment has improved the prognosis in recent years.

Evaluation of chronic infectious interstitial pulmonary disease in children by low-dose CT-guided transthoracic lung biopsy.

BACKGROUND: Children with chronic infectious interstitial lung disease often have to undergo open lung biopsy to establish a final diagnosis. Open lung biopsy is an invasive procedure with major potential complications. Transthoracic lung biopsy (TLB) guided by computed tomography (CT) is a less-invasive well-established procedure in adults. OBJECTIVE: Detailing the role of low-dose CT-guided TLB in the enhanced diagnosis of chronic lung diseases related to infection in children. MATERIALS AND METHODS: A group of 11 children (age 8 months to 16 years) underwent CT-guided TLB with a 20-gauge biopsy device. All investigations were done under general anaesthesia on a multidetector CT scanner (SOMATOM Volume Zoom, Siemens, Erlangen, Germany) using a low-dose protocol (single slices, 120 kV, 20 mAs). Specimens were processed by histopathological, bacteriological, and virological techniques. RESULTS: All biopsies were performed without major complications; one child developed a small pneumothorax that resolved spontaneously. A diagnosis could be obtained in 10 of the 11 patients. Biopsy specimens revealed chronic interstitial alveolitis in ten patients. In five patients Chlamydia pneumoniae PCR was positive, in three Mycoplasma pneumoniae PCR was positive, and in two Cytomegalovirus PCR was positive. The average effective dose was 0.83 mSv. CONCLUSION: Low-dose CT-guided TLB can be a helpful tool in investigating chronic infectious inflammatory processes in children with minimal radiation exposure. It should be considered prior to any open surgical procedure performed for biopsy alone. In our patient group no significant complication occurred. A disadvantage of the method is that it does not allow smaller airways and vessels to be assessed.

Prospective population-based study of viral lower respiratory tract infections in children under 3 years of age (the PRI.DE study).

UNLABELLED: Population-based incidence data from Europe on the disease burden of lower respiratory tract infections (LRTI) due to respiratory syncytial viruses (RSV), parainfluenza viruses (PIV) and influenzaviruses (IV) are lacking, especially with respect to the disease burden. In a 2-year prospective multicentre study of children aged <3 years in Germany, we registered population-based cases as outpatients (n=2386), inpatients (n=2924), and nosocomially-acquired (n=141). Nasopharyngeal secretions were tested for viral RNA. The annual incidence for physician visits per 100 children for all LRTI was 28.7, RSV 7.7, PIV 3.8 and IV 1.1. Annual hospitalisation rates per 10(5) children were for all LRTI 2941, RSV 1117, PIV 261 and IV 123. Annual nosocomial cases per 10(5) hospital days were for all LRTI 79, RSV 29, PIV 9 and IV 1.5. All five children (0.27%) who died had an underlying disease and four were nosocomially acquired. CONCLUSION: Hospitalisation rates due to lower respiratory tract infections in healthy children were similar to those reported elsewhere; the rates for outpatient visits were approximately ten times higher.

Evaluation of tracheobronchial anomalies in children using low-dose multidetector CT: report of a 13-year-old boy with a tracheal bronchus and recurrent pulmonary infections.

Tracheobronchial anomalies in children may be associated with recurrent episodes of pulmonary infections and symptoms of recurrent or persistent airway obstruction. Diagnosis by conventional imaging may be difficult. Multidetector computed tomography (MDCT) offers the possibility to generate a virtual three-dimensional bronchoscopy, thus enabling detailed overview of the tracheobronchial system. We report on a 13-year old boy, admitted to hospital after recurrent episodes of bronchial infections. Functional studies showed airway obstruction with no response to bronchodilators. A chest radiograph was normal. Flexible bronchoscopy revealed tracheobroncho malacia of the distal trachea and the right main bronchus. The ostium of an accessory right-sided tracheal bronchus, which could not be entered by the endoscope, was also detected. MDCT using a low-dose protocol was performed on a four-section scanner (Somatom Volume Zoom, Siemens, Erlangen, Germany). A three-dimensional virtual bronchoscopy based on surface rendering was generated, which confirmed moderate narrowing of the trachea and right main bronchus. Furthermore, an accessory and stenotic tracheal bronchus including poststenotic segments, ventilating parts of the right upper lobe, could be clearly visualized. MDCT can be a valuable instrument in the diagnostic pathway of assessing tracheobronchial anomalies in children, including visualization of poststenotic bronchial structures. The use of low-dose protocols provides adequate image quality to perform virtual bronchoscopy, thus reducing administered radiation to a tolerable amount.

IgG subclass concentrations in certified reference material 470 and reference values for children and adults determined with the binding site reagents.

BACKGROUND: There is currently no international reference preparation for IgG subclass (IgGSc) quantification. This situation has led to calibration differences among assays and a variety of reference interval values with consequential difficulties in comparing results. We therefore evaluated IgGSc concentrations in Certified Reference Material 470 (CRM 470). METHODS: Pure, polyclonal IgG1, -2, -3, and -4 were prepared from a large serum pool for use as primary standards. The IgG mass in each preparation was calculated from amino-acid analysis data. IgGSc concentrations were assessed in CRM 470 by nephelometry with modern analytical techniques, using these reference preparations. Subsequently, IgGSc concentrations were measured in 380 healthy individuals (250 males and 130 females), and age-dependent reference intervals were established. RESULTS: IgGSc concentrations in CRM 470 were as follows: IgG1, 5028 mg/L; IgG2, 3418 mg/L; IgG3, 579 mg/L, and IgG4, 381 mg/L, with a total IgG concentration of 9406 mg/L, 2.83% below the certified total IgG value of 9680 mg/L. Age-dependent percentile curves for the four IgGSc were constructed using a Box-Cox transformation. Maximum median values were as follows: IgG1, 6.02 g/L at 11 years; IgG2, 3.45 g/L at 31 years; IgG3, 0.63 g/L at 17 years; and IgG4, 0.48 g/L at 14 years. No significant sex-related differences were observed. CONCLUSIONS: The correlation between the summation of individual IgGSc and separate measurements of total IgG concentrations was good and supports the accuracy of the results. The results are based on The Binding Site assays and should not be considered appropriate for other assays unless so demonstrated.

Levels of antibodies specific to tetanus toxoid, Haemophilus influenzae type b, and pneumococcal capsular polysaccharide in healthy children and adults.

Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) and for tetanus toxoid were measured in serum samples of 386 age-stratified subjects. The study group consists of healthy adult blood donors and hospitalized children undergoing elective surgery, excluding individuals with a history of infection. In children, anti-tetanus toxoid antibody levels displayed two peaks of 1.20 IU/ml (20.4 mg/liter) and 1.65 IU/ml (28.1 mg/liter) related to the schedule of routine childhood immunization in the first year and at 8 years of age. Eighty percent of the antibodies are of the immunoglobulin G1 (IgG1) isotype. For pneumococcal capsular polysaccharide (PCP), the specific antibody levels represent the acquisition of natural immunity. The initial concentration of 9.2 mg/liter was low in infancy (0.5 to 1 years of age) and remained low until 3 to 4 years of age (14.6 mg/liter). During this period PCP antibodies were almost 100% of the IgG2 subclass. Thereafter, IgG anti-PCP antibody titers increased steadily to adult levels (59.5 mg/liter). The data are intended to provide reference ranges to aid in the interpretation of specific antibody determinations in the clinical setting.

Establishment of age-dependent reference values for IgA subclasses.

BACKGROUND: Recently, subclass-specific antisera have been introduced for application in a nephelometric assay. The aim of this study was to establish age-dependent reference values for serum concentrations of the two IgA subclasses in children and adults. METHODS: Serum levels of IgA1 and IgA2 were measured by automated immunonephelometry in samples from 235 clinically healthy children between 6 months and 18 years of age and 36 healthy adults. RESULTS: Both IgA1 and IgA2 were detectable in all samples, and both IgA1 and IgA2 increased with increasing age. In adults, the mean value for IgA1 is 1.46 g/l for IgA2 0.21 g/l and for total IgA 1.94 g/l. Individual IgA2 values correlate significantly (p < 0.0001) with IgA1 values (r(2) = 0.5433). In addition, there was a highly significant (p < 0.0001) correlation (r(2) = 0.9530) between the measured total IgA and the sum of the two IgA subclasses indicating that immunonephelometry using highly specific polyclonal antisera might be superior to other methods. CONCLUSIONS: These results and the availability of age-dependent reference values make it worthwhile to reassess the role of IgA subclasses in immunodeficiency and autoimmune diseases where conventional methods have led to conflicting results.

Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment.

We have identified 14 patients with diverse primary immunodeficiencies who have developed progressive neurodegeneration of unknown etiology. All patients had received immunoglobulin replacement therapy for a mean duration of 6.5 years (range of 0.5-13.5 years) at the time of first neurological symptoms. Diagnostic tests of blood and cerebrospinal fluid analyses included chemistry, cultures, PCR for viral genomes, and cytology. In addition, neuroimaging and electrophysiologic studies were performed. Brain tissue histology (n = 5) revealed nonspecific encephalitis with microglial infiltration and neuronal loss. Twelve patients died 6 months to 15 years (median 4.3 years) after onset of neurologic findings. No evidence of any infectious disease that could have explained our patients' progressive encephalopathy was found either during their lifetimes or postmortem. These patients may have had an unusual manifestation of primary immunodeficiency diseases, an autoimmune reaction against neuronal tissue, a yet undefined infectious agent, or a complication of IVIG therapy. To help determine the etiology of this rare complication, an international surveillance system for primary immunodeficiency patients who develop progressive neurodegeneration of unknown cause is recommended.