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Infants are screened for cystic fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the US FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002 to 2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and zero or one mutation were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG) to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially available panels, and could be considered for NBS, clinical, or research laboratories conducting CF screening.

Infants are screened for cystic fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the US FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002 to 2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and zero or one mutation were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG) to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially available panels, and could be considered for NBS, clinical, or research laboratories conducting CF screening.

Asthma is characterized by reversible lower airway obstruction. Pulmonary function tests (PFTs) are a useful way to objectively measure the degree, location, and reversibility of lung compromise in children who have or may have asthma. PFTs can be used to help confirm the diagnosis in children with straightforward or atypical presentations, estimate the severity of airway inflammation, and follow the response to management changes. In the initial evaluation of a child with straightforward asthma, PFTs can confirm the clinician's diagnosis as well as rule out problems that may present with similar clinical findings, such as muscle weakness, vocal cord dysfunction, and habit cough. The evaluation of children presenting with more atypical symptoms, such as chest pain, cough, or atypical exercise intolerance may be focused considerably by the use of PFTs. Reversibility of the obstruction as measured by increases or decrements in air flow or gas trapping provides an estimate of the degree of airway hyper-reactivity. The percentage improvement in air flow after bronchodilation increases in children with a large amount of airway inflammation, and decreases when the asthma is under control. Measurement of airway hyperreactivity can be helpful at the time of diagnosis, during times of seasonal exacerbations, and after aggressive anti-inflammatory therapy. This article reviews specific pulmonary function tests and examples of the use of PFTs in clinical situations that may be encountered in the management of children with asthma.

Purpose. To determine the long term effects of ribavirin therapy in children hospitalized for respiratory syncytial virus (RSV) lower respiratory tract infection. Methods. Fifty-four of 60 children in randomized trials of ribavirin therapy were enrolled in a prospective follow-up study. Subjects were examined annually and had age-appropriate pulmonary function tests; interim histories were obtained from families and personal physicians. Results. Recurrent lower respiratory tract illness was reported at least once for 79% of the ribavirin and 73% of placebo group. In the first 5 years after RSV, 54% of the ribavirin group and 50% of the placebo group reported wheezing. There were no significant differences between the groups in annual rates, timing, or severity of recurrent lower respiratory tract illness. No significant differences in pulmonary function were detected by tests of oxygen saturation, peak expiratory flow and spirometry. Conclusions. Children in the ribavirin treatment group did not have exacerbated respiratory symptoms compared with those in the control group, and their pulmonary function measurements were equal to those of the placebo-treated group, suggesting no long term adverse effect or benefit of ribavirin therapy.

Home oxygen and ventilation therapies are used to treat children who have varying degrees of chronic respiratory insufficiency from many causes. Potential sequelae to even mild or intermittent respiratory insufficiency have been identified. Infants with bronchopulmonary dysplasia who still require oxygen can be discharged earlier from hospitals with appropriate discharge planning and family support. Children with progressive diseases may eventually require oxygen or ventilation therapies to improve the duration or quality of their lives. Obstructive sleep apnea has been treated with supplemental oxygen and nasal continuous positive airway pressure. Guidelines exist for initiation and home management of oxygen and invasive or noninvasive mechanical ventilation.

Objective measurements of a wide variety of aspects of respiratory function can be useful in the evaluation and management of children and adolescents who have respiratory symptoms or disorders. Many of the tests described in this article can be performed reasonably in the pediatrician's office. Pediatricians can be comfortable in measuring and interpreting pulse oximetry, blood gas analysis, spirometry, and peak flow. They also should be familiar with the indications for the less common tests of pulmonary function that now are widely available.

Objective measurements of a wide variety of aspects of respiratory function can be useful in the evaluation and management of children and adolescents who have respiratory symptoms or disorders. Many of the tests described in this article can be performed reasonably in the pediatrician's office. Pediatricians can be comfortable in measuring and interpreting pulse oximetry, blood gas analysis, spirometry, and peak flow. They also should be familiar with the indications for the less common tests of pulmonary function that now are widely available.

Little is known of the developmental aspects of mucociliary transport. Previous studies have documented that newborn ferret trachea has very few ciliated cells but numerous immature secretory cells in the epithelium and only rudimentary submucosal glands. Rapid and complete maturation occurs in the first postnatal month. This study examines mucociliary transport during this period of rapid maturation. We made direct observations of particle movement across the epithelium of ferret tracheas. No mucus transport could be demonstrated on the first day of life. Transport was discernible, although sporadic and slow, by 7 days and reached adult levels (10.7 +/- 3.7 mm/min) by 28 postnatal days. The emergence of transport capability correlated well with previously described developmental changes in ciliation, mucus secretion, and ion permeability and transport. Threshold mucus transport occurred at 1 wk of age when 20–25% of the surface cells are ciliated. The neonatal ferret appears to be a useful model for assessing integrated epithelial structure-function relationships that are important not only during early development but also during repair after airway injury involving deciliation.

Epidemiologic and experimental evidence suggests that exposure to acidic aerosols may affect human health. Brief exposures to acidic aerosols alter mucociliary clearance and increase airway responsiveness, but effects on host defense mechanisms at the alveolar level have not been studied in humans. Twelve healthy, nonsmoking volunteers between 20 and 39 yr of age were exposed for 2 h to aerosols of approximately 1,000 micrograms/m3 sulfuric acid (H2SO4) or sodium chloride (NaCl [control]), with intermittent exercise, in a randomized, double-blind fashion. Each subject received both exposures, separated by at least 2 wk. Bronchoalveolar lavage (BAL) was performed 18 h after exposure in order to detect evidence of an inflammatory response, changes in alveolar cell subpopulations, or changes in alveolar macrophage (AM) function, which is important in host defense. When compared with NaCl, exposure to H2SO4 did not increase polymorphonuclear leukocytes in BAL fluid. The percentage of T lymphocytes decreased in association with H2SO4 exposure, but the difference was not statistically significant (14.9% after NaCl, 11.5% after H2SO4; p = 0.14). Antibody-mediated cytotoxicity of AM increased in association with H2SO4 exposure (percent lysis 19.1 after NaCl, 23.6 after H2SO4; p = 0.16). No significant change was seen in release of superoxide anion or inactivation of influenza virus in vitro. Brief exposures to H2SO4 aerosol at 1,000 micrograms/m3 do not cause an influx of inflammatory cells into the alveolar space, and no evidence was found for alteration in antimicrobial defense 18 h after exposure.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency and chronic endobronchial infection. Although it was initially defined and diagnosed based on clinical features and sweat chloride measurement, an in vivo method of assessing CFTR function, the discovery of the CFTR gene in 1989 revealed a broad spectrum of CF phenotypes associated with specific CFTR gene mutations. In this article, we will review the indications for sweat testing, alternative techniques to diagnose CF, and the approach to patients with an ambiguous or indeterminate diagnosis of CF.

Exposure to ozone injures respiratory epithelium, and the mechanisms may involve the generation of reactive oxygen species (ROS). This study tested the hypothesis that ozone exposure increases the airway burden of ROS to a greater degree in smokers than nonsmokers, and that this effect is independent of ozone-induced changes in spirometry. Healthy subjects were selected as either responders (decrement in FEV1 > 15%) or nonresponders (decrement in FEV1 < 5%) to ozone; each underwent 2 exposures to ozone and 1 to air, with bronchoalveolar lavage (BAL) performed 30 min (early) and 18 h (late) after exposure. Release of superoxide anion (O2(-)) was used as a measure of ROS release by all BAL cells, and flow cytometry was used to detect ROS production in alveolar macrophages (AM) only. Recovery of AM was approximately threefold greater in smokers than nonsmokers. Unstimulated, but not stimulated, cells obtained by BAL from smokers released approximately twofold greater amounts of O2(-) than cells from nonsmokers, both early and late after ozone exposure (p =.012 and p =.046, respectively). Stimulated, but not unstimulated, ROS generation by AM from smokers increased following ozone exposure, but the ozone effect was not significant. ROS production by AM decreased in nonsmokers (air vs. ozone late, p =.014). Total protein, albumin, and immunoglobulin M (IgM) increased in BAL fluid, consistent with an increase in epithelial permeability. In addition, the concentration of alpha2-macroglobulin increased approximately threefold 18 h after exposure in nonsmokers (p

In a study of 159 school-age children whose histories of outpatient visits for lower respiratory illness (LRI) had been documented from early infancy, we observed lower mean levels of small airway function in boys who had experienced two or more episodes of wheezing-associated LRI before 6 yr of age. To determine whether allergy was an important factor influencing this result, we examined relationships among the results of RAST tests for seven common inhalant allergens and concurrent lung function in 126 subjects who consented to venipuncture. Increasing values for the sum of scores for the seven RAST tests were associated with progressively lower mean levels of small airways function in boys with histories of recurrent wheezing LRI during the preschool years. The association of allergy with lower levels of lung function was largely accounted for by dust mite allergy. RAST results were not correlated with lung function in boys who had experienced zero or 1 wheezing LRI before 6 yr of age or in girls. A history of recurrent wheezing LRI during the preschool years was also associated with significantly lower mean levels of small airways function in boys who had negative RAST tests. A subset of 49 boys was reevaluated after an average interval of 4 yr with RAST tests, spirometry, and methacholine challenge. Dust mite allergy was associated with an increased prevalence of bronchial hyperreactivity independent of early childhood wheezing LRI history.(ABSTRACT TRUNCATED AT 250 WORDS)

Munchausen by proxy has been reported involving children who have been given various drugs or toxins. In addition, there is a body of adult literature regarding covert anticoagulant ingestion. This is a case of an 11-month-old female who appears to combine features of both of these syndromes. This child presented with an acute left hemorrhagic otitis media. The physical examination was unremarkable except for the following: weight, fifth percentile; left external auditory canal filled with blood with the right external canal and tympanic membrane being normal; and several scattered 1 X 2 cm firm, movable, nontender, purple nodules on extremities, chest and forehead. The coagulation studies were consistent with Vitamin K deficiency secondary to anticoagulant ingestion. A serum warfarin study confirmed our suspicions. The mother was noted to have a dependent relationship with her child and characteristics of those involved in Munchausen by proxy: falsifying information and thwarting medical assessment. In addition, she displayed some of the characteristics found commonly in anticoagulant malingerers. She was depressed, with limited medical knowledge, and had access to warfarin. The mother was admitted for inpatient psychiatric care and the patient placed with an extended family member. This case report describes the use of an anticoagulant to induce illness in a child by a psychologically ill mother. This form of child abuse must be considered in the differential diagnoses of hemorrhagic disorders.

We examined the relationship between lower respiratory illness (LRI) experience in early childhood and lung function and bronchial reactivity in 57 boys, 11 to 22 yr of age, whose histories of outpatient physician visits for wheezing and nonwheezing LRI had been documented prospectively during their first 6 yr of life. These boys were a subpopulation of 159 children whose early childhood LRI experience and spirometric performance had been studied an average of 4 yr previously. The majority of boys had been free of chronic respiratory symptoms in the 2 yr before evaluation. Boys with histories of 2 or more preschool wheezing illnesses had lower mean levels of performance for FEV1, FEF25-75, FEF50, FEF75, and FEV1/FVC than did boys who had zero or 1 preschool wheezing illness, replicating observations that had been made when the boys had been studied 4 yr previously. Boys with lower spirometric performance relative to the study population on initial testing continued to have lower relative levels of spirometric performance 4 yr later. Neither preschool wheezing nor nonwheezing illness experience was associated with the degree of methacholine sensitivity measured in adolescence. Increasing degrees of methacholine sensitivity were associated with lower levels of spirometric performance; however, preschool wheezing illness experience remained a significant correlate of spirometric performance after adjustment for level of methacholine sensitivity. We conclude that recurrent preschool wheezing illness in these adolescent boys was associated with persistently lower lung function, but not enhanced methacholine sensitivity, during the middle to late school years.