Endotypes of difficult-to-control asthma in inner-city African American children.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

Are peak flow and symptom measures good predictors of asthma hospitalizations and unscheduled visits?

Epidemiologic studies of pediatric respiratory health often include objective measures such as peak expiratory flow (PEF), and subjective measures such as symptom reports. These measures, however, are poorly correlated with each other, and there is little evidence that PEF is useful in predicting important health outcomes. Within a cohort of 791 inner-city children with asthma, we examined correlations between a series of five peak flow measures and five symptom scores obtained from 2-week diaries. The strongest correlations were found between "total peak flow lability" defined as: [(diary maximum - diary minimum)/diary mean] and "% of days with chest tightness" (r = 0.31). Logistic models evaluated peak flow and symptoms as predictors of an important health outcome: hospitalization or emergency department or unscheduled clinic visit for asthma within 30 days of starting the diary. Each of the peak flow and symptom measures was significantly related to utilization. However, the predictive power of each measure was low (range of area under ROC curve, 0.54-0.67). Models including only peak flow or symptoms had greater prediction than models with risk factors such as atopy, asthma persistence, and age. The prediction from a model with the risk factors and symptoms was not improved by adding a peak flow measure to the model (increase in area under ROC, 0.67-0.68). Stratified analyses suggest that prediction was similar in the fall vs. winter, spring, and summer months. Greater prediction of health outcomes was found among more persistent asthmatics and children who were nonatopic. These findings suggest that in a research setting, peak flow monitoring in children did not add prediction beyond that obtained from symptom reports. Pediatr Pulmonol. 2001; 31:190-197. Published 2001 Wiley-Liss, Inc.

Ipratropium bromide plus nebulized albuterol for the treatment of hospitalized children with acute asthma.

OBJECTIVE: To determine whether the addition of repeated doses of nebulized ipratropium bromide (IB) to a standardized inpatient asthma care algorithm (ACA) for children with status asthmaticus improves clinical outcome. STUDY DESIGN: Children with acute asthma (N = 210) age 1 to 18 years admitted to the ACA were assigned to the intervention or placebo group in randomized double-blind fashion. Both groups received nebulized albuterol, systemic corticosteroids, and oxygen according to the ACA. The intervention group received 250 microg IB combined with 2.5 mg albuterol by jet nebulization in a dosing schedule determined by the ACA phase. The placebo group received isotonic saline solution substituted for IB. Progression through each ACA phase occurred based on assessments of oxygenation, air exchange, wheezing, accessory muscle use, and respiratory rate performed at prescribed intervals. RESULTS: No significant differences were observed between treatment groups in hospital length of stay (P =.46), asthma carepath progression (P =.37), requirement for additional therapy, or adverse effects. Children >6 years (N = 70) treated with IB had shorter mean hospital length of stay (P =.03) and more rapid mean asthma carepath progression (P =.02) than children in the placebo group. However, after adjustment was done for baseline group differences, the observed benefit of IB therapy in older children no longer reached statistical significance. CONCLUSION: The routine addition of repeated doses of nebulized IB to a standardized regimen of systemic corticosteroids and frequently administered beta-2 agonists confers no significant enhancement of clinical outcome for the treatment of hospitalized children with status asthmaticus.

Acute inpatient care of status asthmaticus.

The hospital management of status asthmaticus includes aggressive use of a limited armamentarium of medications. Understanding the appropriate use of available medications is key. Proper assessment of the severity of an acute episode and response to applied therapies is essential for optimum outcomes without undue delays in treatment and excessive costs. Ensuring that all patients discharged from the hospital receive an individualized treatment plan for the management of chronic stable, worsening, and acute asthma can help prevent future hospitalizations.

Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis.

In this report, we present an asymptomatic infant, seen for a second opinion, who was given the diagnosis of cystic fibrosis (CF) as a neonate based on the presence of two mutant alleles, DeltaF508 and R117H. The diagnosis of CF adversely affected the family's emotional, employment, and financial statuses. Our evaluation included sweat chloride, nasal transepithelial potential difference, and bronchoscopy with bronchoalveolar lavage measurements, all which were consistent with findings expected from an individual without CF. Genotype analysis for the sequence polymorphism in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene revealed the 7 thymidines and 9 thymidines alleles. We conclude that this patient probably expresses enough epithelial cell surface CFTR function such that she has a normal phenotype. Based on our evaluation, she does not meet the current diagnostic criteria for CF. Although genotype analysis can be an useful adjunct, it should not be the sole diagnostic criterion for CF.

Pediatric asthma care in the emergency department: measuring the quality of history-taking and discharge planning.

The National Asthma Education and Prevention Program NAEPP Guidelines include recommendations for history-taking and discharge planning during an asthma visit, but there are no tools to measure performance. The objectives of this study were to define and operationalize key elements of history-taking and discharge planning, to develop a tool for measuring these elements, and to evaluate the quality of history-taking and discharge planning in the emergency department (ED) during visits for asthma using the new tool. Expert opinion and extensive literature review were used to develop a 13-item checklist containing items that should be documented during history-taking and provided during discharge planning for an ED visit for an acute asthma exacerbation by children. A convenience sample of 90 pediatric emergency medicine physicians and allergists rated each item in the checklist. The checklist was used to score audiotapes of asthma visits in the ED. Subjects were 154 parents of asthmatic children aged 4-9 years seeking care in nine inner-city EDs affiliated with asthma centers participating in the National Cooperative Inner-City Asthma Study and the physician/providers who delivered care. Seven of the 13 items on the checklist were rated as required to be performed by more than 90% of the allergist/pediatric emergency medicine physicians. Only 10% of the 154 visits included all seven of the highly rated items, whereas 19% of the visits included three or fewer. Only 7 of the 13 items (54%) were performed in more than 50% of the visits, and 4 items were performed in fewer than 25% of visits. Based on expert ratings, the checklist for measuring elements of history-taking and discharge planning during asthma visits appears to have considerable face validity. In the visits studied, the overall performance of these elements was low. Interventions to improve performance on the checklist might lead to improved care for children with asthma who frequent the ED.

A cost-saving algorithm for children hospitalized for status asthmaticus.

OBJECTIVE: To test the ability of an assessment-driven algorithm for treatment of pediatric status asthmaticus to reduce length and cost of hospitalization. DESIGN: Nonrandomized, prospective, controlled trial. SETTING: Tertiary care children's hospital. PATIENTS: Children aged 1 to 18 years hospitalized for status asthmaticus; 104 were treated using the asthma care algorithm (intervention) and 97 using unstructured standard treatment (control). INTERVENTION: Patients were treated using either an assessment-based algorithm or standard care practices. The algorithm group was treated with standard medications (aerosolized albuterol, systemic corticosteroids, epinephrine, ipratropium) administered at a frequency driven by the patient's clinical condition. Specific criteria were outlined for decreasing or augmenting therapy, transferring to intensive care, and discharging to home. A unique patient record containing assessments, algorithm cues, and a treatment record was used. Intervention group patients were interviewed by telephone 1 week after discharge. MAIN OUTCOME MEASURES: Hospital length of stay, cost per hospitalization, relapse rate, protocol adherence. RESULTS: Average hospital stay for intervention patients was significantly shorter than for control patients (2.0 vs 2.9 days, P<.001). Although intervention patients received fewer aerosolized albuterol doses than controls, there was no difference in short-term relapse rate between groups. The intervention saved more than $700 per patient in hospital charges. Adherence to the protocol was excellent, with only 8 variances per patient stay out of more than 150 opportunities. CONCLUSION: An intensive, assessment-driven algorithm for pediatric status asthmaticus significantly reduces hospital length of stay and costs without increasing morbidity.

Pre- and perinatal risk factors for asthma in inner city African-American children.

The relations between pre- and perinatal risk factors and asthma were investigated using a case-control study of 262 African-American children aged 4-9 years, both asthmatic and nonasthmatic, all of whom resided in a poor urban area and received health care at a local hospital-based clinic. Risk factors were ascertained through review of obstetric, perinatal, and pediatric records. Asthmatic children had significantly lower birth weights and gestational ages than nonasthmatic children and were more likely to have required oxygen supplementation and positive pressure ventilation after birth than nonasthmatics (p < 0.05). The mothers of asthmatic children were more likely to have smoked during pregnancy (50% vs. 27%), to have gained less weight during pregnancy (26.3 pounds (11.9 kg) vs. 34.5 pounds (15.7 kg)), and to have had no prenatal care (12% vs. 2% ) than mothers of nonasthmatic children. Multiple logistic regression demonstrated that the strongest independent predictors of asthma were maternal history of asthma (adjusted odds ratio (OR) = 9,7), lack of prenatal care (OR = 4.7), history of bronchiolitis (OR = 4.7), positive pressure ventilation at birth (OR = 3.3), low maternal weight gain (<20 pounds (<9 kg)) (OR = 3.4), and maternal smoking during pregnancy (OR = 2.8). These data suggest that pre- and perinatal exposures may increase susceptibility to asthma in inner city children.

Hospital treatment of asthma: lack of benefit from theophylline given in addition to nebulized albuterol and intravenously administered corticosteroid.

STUDY OBJECTIVE: To determine the efficacy of theophylline when given in addition to nebulized albuterol and intravenously administered corticosteroid to children hospitalized with mild to moderate asthma. DESIGN: Randomized, prospective, placebo-controlled, double-blind trial. SETTING: Tertiary-care children's hospital. PATIENTS: Twenty-nine patients with asthma between the ages of 2 and 16 years completed the study. The treatment and placebo groups were similar in age, gender, race, illness severity, and emergency department treatment. INTERVENTIONS: All patients received intravenously administered methylprednisolone and nebulized albuterol. The treatment group received intravenous theophylline therapy and the placebo group dextrose in water. When intravenously administered medications were discontinued, therapy continued with oral administration of theophylline (or placebo) and of prednisone. MEASUREMENTS AND MAIN RESULTS: Twice-daily assessments of clinical asthma symptoms were made by using a scoring system consisting of respiratory rate, inspiratory/expiratory ratio, wheeze, and accessory muscle use. Time required to reach study discharge criteria (asthma score < or = 2) (30.4 +/- 16.8 vs 27.0 +/- 10.3 hours; p = 0.51) and the rate of improvement of the clinical asthma score (-0.10 +/- 0.05 unit/hr vs -0.11 +/- 0.09 unit/hr; p = 0.88) were not significantly different between the theophylline and placebo groups. The number of albuterol aerosol treatments required and the adverse effects experienced were not significantly different between groups. CONCLUSION: When the combination of systemically administered corticosteroid and inhaled albuterol is used in the treatment of children hospitalized with mild to moderate asthma, addition of theophylline may not be justified.

Resistance of human tracheal epithelial cells to killing by neutrophils, neutrophil elastase, and Pseudomonas elastase.

The airway disease of cystic fibrosis (CF) is characterized by massive polymorphonuclear leukocyte (PMN) infiltration and the presence of variable but substantial quantities of uninhibited elastases derived from both PMNs and the common infecting organism Pseudomonas aeruginosa. In order to determine whether these agents inflict fatal injury on the airway epithelium, we exposed primary cultures of human tracheal epithelial (HTE) cells to activated PMNs, PMN elastase (PMNE), and elastase from P. aeruginosa (PSE) and monitored cytotoxicity by 51Cr release assay. Activated PMNs did not kill HTE cells, and fewer than 2% of the added PMNs adhered to the HTE cell layer. Pretreatment of HTE cells with lipopolysaccharide, incubation of PMNs with cytochalasin B, or increasing the incubation period to 8 h did not increase PMN adherence or target cell killing. However, poor PMN adherence was not by itself responsible for lack of cytotoxicity, since PMNs were not cytotoxic for 9HTEo- cells, a HTE cell line to which PMNs adhere in large numbers. Purified PMNE, but not exogenous H2O2, caused a small but significant increase in cytotoxicity after 6 h of incubation, but only at the highest concentrations tested (10 and 50 micrograms/ml). The PMNE remained fully active throughout the incubation period. Some detachment of the cell layer occurred after 4 h of incubation with 10 micrograms/ml PMNE. PSE at concentrations > 1 micrograms/ml also caused slight cytotoxicity and removal of the cell layer from the culture substratum. Ultrastructural studies showed only minor cytoplasmic vacuole formation. We conclude that cultured HTE cells are resistant to cytolysis by PMNs and elastases.

Ferret tracheal epithelial cells grown in vitro are resistant to lethal injury by activated neutrophils.

Airway inflammation is often accompanied by accumulation of polymorphonuclear leukocytes (PMN) as well as epithelial sloughing. To determine whether PMN contribute to epithelial damage in inflammatory states, we examined the interaction of PMN and tracheal epithelial cells in culture. Ferret tracheal epithelial (FTE) cells were grown in primary culture on collagen-coated multiwell dishes. Confluent monolayers were loaded with [51Cr]O4 and exposed to resting and activated neutrophils. There was no significant increase in cell death as assessed by [51Cr]O4 release over 8 h of exposure, at effector (PMN)-to-target cell (epithelial cell) ratios up to 90:1, whether PMN were activated by maximal activating concentrations of phorbol myristate acetate or formylmethionylleucylphenylalanine with or without cytochalasin B. This result was confirmed by using a [3H]leucine release assay as well as by uptake of a supravital dye. However, exposure of FTE cells to activated PMN for 4 h resulted in separation of adjacent cells and formation of gaps in the monolayer, without significant detachment of epithelial cells from the dish. Gap formation was prevented by alpha 1-antitrypsin, N-methoxysuccinyl-Ala-Ala-Pro-Val-chloromethylketone, or 10% serum, was mimicked by PMN elastase (24 micrograms/ml), but not by hydrogen peroxide in concentrations up to 10 mM, or superoxide generated by xanthine/xanthine oxidase, and was reversible within 24 h of removal of elastase and exposure to fresh medium. We conclude that activated PMN do not kill FTE cells in culture. However, disruption of the epithelial cell monolayer probably by a proteolytic mechanism can result from exposure to activated PMN and may allow alteration of the epithelial barrier during airway inflammation.

Receptor-mediated cAMP production in adult and infant ferret tracheal epithelium.

Tracheal epithelial cells obtained from adult and infant ferrets were grown in primary culture in vitro. Cells from adult animals grew readily, and many ciliated cells were observed in the cultures. Successful cultures were derived from infant animals, but cell number in infant and adult cultures began to decrease after 6 d. Receptor-mediated activation of adenylate cyclase was determined by incubating monolayers of adult or neonatal cells with beta-adrenergic agonists, prostaglandin E2 (PGE2) and vasoactive intestinal peptide and measuring cAMP production. beta-adrenergic agonists and PGE2, but not vasoactive intestinal peptide, stimulated production of cAMP in both cell types. The 50% effective concentration for isoproterenol and PGE2 in neonatal ferret tracheal epithelial (NFTE) cells was nearly 10-fold more than for adult ferret tracheal epithelial (FTE) cells, but maximal agonist-stimulated cAMP production was significantly different between the cell types only for PGE2. Radioligand binding studies were performed using the beta-adrenergic antagonist [125I]iodocyanopindolol on membrane particulates from confluent monolayers and freshly isolated FTE cells. Binding of iodocyanopindolol was saturable, stereoselective, and of high affinity (binding affinity = 26.1 +/- 6.6 pmol/L, adult; 16.5 +/- 5.7 pmol/L, NFTE). Competition studies with the specific beta 2-adrenergic receptor antagonist, ICI 118 551 revealed a predominance of beta 2-adrenergic receptors on both adult FTE and NFTE cells. Receptor density was significantly higher in adult FTE compared with NFTE cells (48.2 +/- 9.1, 18.1 +/- 1.5 fmol/mg, respectively). Basal adenylate cyclase activity was significantly lower in neonatal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine 3:5' cyclic monophosphate synthesis by human tracheal epithelial cells.

Intracellular cyclic AMP (cAMP) regulates many critical differentiated functions of tracheal epithelial cells. An in vitro model system for reliable study of cAMP metabolism in these cells has been developed. Viable tracheal epithelial cells could be recovered from greater than 50% of necropsy specimens. Culture success rate was not significantly affected by age of subject, endotracheal intubation, or time between death and autopsy, although most specimens were obtained within 24 h of death. Human tracheal epithelial cells grown in primary culture displayed a typical histologic epithelial appearance, and the ultrastructure showed microvilli, junctional complexes, and tonofilaments. The cells uniformly stained with fluorescent antibody to cytokeratin, and expressed receptors for isoproterenol and vasoactive intestinal peptide. Human tracheal epithelial cells grown serum-free in an equal volume mix of Ham's F12 medium and Dulbecco's minimal essential medium containing growth supplements (Medium A) and cholera toxin (CT) had higher basal cAMP levels and greater increase in intracellular cAMP in response to phosphodiesterase inhibition than cells grown in Medium A without CT. Cells grown in Medium A without CT had similar morphology and grew at a comparable rate but attached to the culture substratum less readily than cells grown in Medium A with CT. Cells grown in Medium A without CT had less cAMP response to phosphodiesterase inhibition, less rapid accumulation of cAMP, and greater proportional response to receptor-mediated stimulation of cAMP production compared to cells grown with CT, though the final cAMP levels achieved were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenergic receptors on human tracheal epithelial cells in primary culture.

Human tracheal epithelial cells in suspension, whether obtained by brushing at bronchoscopy or from necropsy specimens by proteolytic digestion and EDTA treatment, increase adenosine 3',5'-cyclic monophosphate (cAMP) production in response to isoproterenol. These cells in primary culture also respond to beta-adrenergic agonists in order of potency isoproterenol greater than epinephrine greater than norepinephrine. The response is inhibited by propranolol or ICI 118551 (a beta 2-adrenergic selective blocker) but not by atenolol (a beta 1-adrenergic blocker). Binding of [125I]iodocyanopindolol (ICYP) to membranes was rapid, stereoselective, and saturable and displayed receptor density 8.0 +/- 4.6 fmol/mg protein (mean 228 receptors/cell) and a dissociation constant (KD) for ICYP of 35 +/- 14 pM for freshly isolated cells and a KD of 25 +/- 13 pM and receptor density of 17 +/- 17 fmol/mg protein for cells in culture. The 50% inhibitory concentration (IC50) for atenolol was 470 microM and for ICI 118551 was 0.012 microM. Analysis of the ICI 118551 displacement curve indicates that greater than 90% of the receptors are of the beta 2-adrenergic class. Prostaglandins E1 or E2, vasoactive intestinal peptide, carbachol, phenylephrine, or platelet-activating factor did not affect either the maximal cAMP response or the isoproterenol dose-response relationship. Neither clonidine nor epinephrine plus propranolol altered cellular cAMP content, and cyclooxygenase inhibition did not change the cAMP response to epinephrine. We conclude that in human tracheal epithelial cells in primary culture, adrenergic stimulation affects cAMP levels only through beta 2-adrenergic receptors and that modulation of this system by platelet-activating factor or muscarinic, alpha 1-, or alpha 2-adrenergic agents does not occur.

Bronchoscopic findings in infants treated with high-frequency jet ventilation versus conventional ventilation.

To identify tracheobronchial abnormalities associated with assisted ventilation, 40 infants with respiratory distress syndrome randomized to receive either short-term (48 hours) conventional or high-frequency jet ventilation were studied. Flexible fiberoptic bronchoscopy (n = 13) was performed and/or clinical and radiographic assessments were used to evaluate for laryngeal, tracheal, and bronchial lesions. There was no bronchoscopic evidence of necrotizing tracheobronchitis after either high-frequency jet ventilation (n = 8) or conventional ventilation (n = 5). Laryngotracheomalacia and nodular vocal cords were the most common abnormalities noted, and they occurred with equal frequency in both groups. Study infants who were not bronchoscoped had no clinical or radiographic evidence of tracheal or mainstem bronchial obstruction. One patient did have microscopic evidence of necrotizing tracheobronchitis at autopsy, however. It is concluded that short-term treatment of respiratory distress syndrome with high-frequency jet ventilation may be performed without undue risk of tracheobronchial injury.

Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response.

The pharmacokinetics of ceftazidime were assessed following a single-dose in 20 patients (8 to 30 years) with cystic fibrosis. All patients received 50 mg/kg (0.9 to 3.5 g) bolus over 30 to 60 sec. Multiple timed samples were obtained over 8 h and analysed by a sensitive HPLC technique. Two-compartment pharmacokinetic analysis revealed means (+/- S.D.) T 1/2 alpha, 0.45 (0.20) h; T 1/2 beta, 1.74 (0.63) h; Vd, 270.0 (50.0) ml/kg; Vc, 190.0 (50.0) ml/kg and Cl beta, 133.7 (22.8) ml/min/1.73 m2. Probenecid pretreatment in six patients was without effect on T 1/2 beta and Cl beta. Urinary excretion was (% of dose) 0 to 2 h, 65.4 (11.1); 2 to 4 h, 14.9 (3.4) and 4 to 8 h, 9.8 (5.8). Ceftazidime was used to treat pulmonary exacerbations in 12 adult cystic fibrosis patients with multiply-resistant Pseudomonas species. Each patient received 2 g iv 8-hourly for 14 to 35 days. Ten of 12 patients showed dramatic improvement as determined by increased appetite and weight gain and arterial pCO2. No hepatic, renal or bone-marrow toxicity was noted. Ceftazidime is an effective antipseudomonal agent possessing favourable pharmacokinetic characteristics with potential use in the treatment of pulmonary exacerbations in cystic fibrosis.