Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Interpretation of pediatric lung function: impact of ethnicity.

RATIONALE: To evaluate the appropriateness of spirometric and plethysmographic reference equations in healthy young children according to ethnic origin. METHODS: Spirometry data were collated in 400 healthy children (214 Black and 186 White) aged 6-12 years. Of these children, 68 Black and 115 White children also undertook plethysmography. Results were expressed as percent predicted according to commonly used equations for spirometry and plethysmography. RESULTS: Black children had lower lung function for a given height compared to White children. The magnitude and direction of these differences varied according to specific outcome. In the studied age range (6-12 years) the ethnic-specific Wang equations were adequate for spirometry (mean results approximating 100% predicted in both ethnic groups). By contrast, significant differences were found between observed and % predicted plethysmographic lung volumes according to published equations derived from White children: Among the Black children, function residual capacity (FRC) and total lung capacity (TLC) were on average, 14 and 6% lower than predicted, whereas mean residual volume (RV) and RV/TLC were 4 and 10% higher. Among White children, the Rosenthal equations gave the best fit, with the exception of FRC which was, on average, 9% lower than predicted. CONCLUSION: Spirometry equations may suffice in Black children; however, interpretation of static lung volumes in Black children is limited due to inappropriate reference equations. More appropriate plethysmographic reference equations that are applicable to all ethnic groups across the entire age range are urgently needed.

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in mouse urine by (13)C NMR and mass spectrometry and comparison to rat.

Species differences in the metabolism of acetylenic compounds commonly used in the formulation of pharmaceuticals and pesticides have not been investigated. To better understand the in vivo reactivity of this bond, the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, was examined in rats and mice. An earlier study (Banijamali, A. R.; Xu, Y.; Strunk, R. J.; Gay, M. H.; Ellis, M. C.; Putterman, G. J. J. Agric. Food Chem. 1999, 47, 1717-1729) in rats revealed that PA undergoes extensive metabolism primarily via glutathione conjugation. The current research describes the metabolism of PA in CD-1 mice and compares results for the mice to those obtained for rats. [1,2,3-(13)C;2,3-(14)C]PA was administered orally to the mice. Approximately 60% of the dose was excreted in urine by 96 h. Metabolites were identified, directly, in whole urine by 1- and 2-D (13)C NMR and HPLC/MS and by comparison with the available reference compounds. The proposed metabolic pathway involves glucuronide conjugation of PA to form 2-propyn-1-ol-glucuronide as well as oxidation of PA to the proposed intermediate 2-propynal. The aldehyde undergoes conjugation with glutathione followed by further metabolism to yield as final products 3,3-bis[(2-acetylamino-2-carboxyethyl)thio]-1-propanol, 3-[(2-acetylamino-2-carboxyethyl)thio]-3-[(2-amino-2-carboxyethyl)thi o]-1-propanol, 3,3-bis[(2-amino-2-carboxyethyl)thio]-1-propanol, 3-[(2-amino-2-carboxyethyl)thio]-2-propenoic acid, and 3-[(2-formylamino-2-carboxyethyl)thio]-2-propenoic acid. A small portion of 2-propynal is also oxidized to result in the excretion of 2-propynoic acid. On the basis of urinary metabolite data, qualitative and quantitative differences are noted between rats and mice in the formation of the glucuronide conjugate of PA and in the formation of 2-propynoic acid and metabolites derived from glutathione. These metabolites represent further variation on glutathione metabolism following its addition to the carbon-carbon triple bond compared to those described for the rat.

Relationship between disease and psychological adaptation in children in the Childhood Asthma Management Program and their families. CAMP Research Group.

OBJECTIVE: To test the hypotheses that the burden of childhood asthma compromises psychological adaptation and that the degree of compromise increases with disease severity. DESIGN: The Childhood Asthma Management Program (CAMP) is a multicenter randomized clinical trial initiated and funded by the National Heart, Lung, and Blood Institute. SETTING: Study sites were located in Albuquerque, NM, Baltimore, Md, Boston, Mass, Denver, Colo, St Louis, Mo, San Diego, Calif, Seattle, Wash, and Toronto, Ontario. PARTICIPANTS: A total of 1,041 children aged 5 to 12 years were randomized to the trial after confirming their mild to moderate asthma. MAIN OUTCOME MEASURES: Psychological questionnaires administered at baseline to parents and participants assessed anxiety, depression, behavioral competence, social support, and family functioning. RESULTS: Psychological difficulty was not increased in this group of asthmatic children and their families. Psychological adaptation in the children was associated with the psychological adaptation of the family but not with disease-related variables. Scores from the Impact on Family Scale, a measure of family quality of life related to the child's illness, were associated more strongly with the overall psychological characteristics of the family and child and very little with disease characteristics or severity. CONCLUSIONS: Mild to moderate asthma has imposed modest effects on the daily life but not the psychological health of this group of children. Variation in the psychological characteristics of these children was, as is the case for most children, traceable to the overall psychological adaptation of their families.

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in rat urine by (13)C NMR and mass spectrometry.

Little is known about the metabolism of acetylenic (C&tbd1;C) compounds commonly used in the formulation of pesticides. To better understand the in vivo reactivity of this bond, we examined the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, used extensively in the chemical industry. [1,2,3-(13)C, 2,3-(14)C]PA was administered orally to male Sprague-Dawley rats. Approximately 56% of the dose was excreted in urine by 96 h. Major metabolites were characterized, directly, in the whole urine by one- and two-dimensional (13)C NMR. To determine the complete structures of metabolites of PA, rat urine was also subjected to TLC followed by purification of separated TLC bands on HPLC. The purified metabolites were identified by (13)C NMR and mass spectrometry and by comparison with available synthetic standards. The proposed metabolic pathway involves oxidation of propargyl alcohol to 2-propynoic acid and further detoxification via glutathione conjugation to yield as final products: 3, 3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, 3-(carboxymethylthio)-2-propenoic acid, 3-(methylsulfinyl)-2-(methylthio)-2-propenoic acid, 3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[(2-amino-2-carboxyethyl)t hio]-1-propanol and 3-[[2-(acetylamino)-2-carboxyethyl]sulfinyl]-3-[2-(acetylamino)-2-car boxyethyl]thio]-1-propanol. These unique metabolites have not been reported previously and represent the first example of multiple glutathione additions to the carbon-carbon triple bond.

A tool to organize instructions at discharge after treatment of asthmatic children in an emergency department.

Asthma exacerbations continue to be a major cause of visits to emergency departments (ED). Comprehensive care in the outpatient setting, with planning for early intervention for exacerbations, can reduce emergency visits. Thus, a major goal of ED intervention is to establish a link between the patient and the provider of ongoing asthma care, where complete education can be achieved and reinforced over time. When designing the Asthma 1-2-3 Plan discharge teaching tool for the ED, consideration was given to educational format, readability, patient population, and setting in which education was to be delivered. To evaluate use of the plan, ED records of patients enrolled in a separate asthma study, the Neighborhood Asthma Coalition (NAC), were audited for two 8-month intervals, May-December 1993 (before initiation of the plan) and May December 1994 (starting 1 month after completion of pilot testing on the plan in the ED). To evaluate effectiveness of the plan, records of physicians who cared for children in the NAC were evaluated. The database was reviewed for the date of the first visit for planned review of asthma that occurred after the acute asthma ED visit. After introduction of the plan, the proportion of children told to return to the physician for follow-up increased from 54% to 81%. The proportion of children given advice to return to their physician within the recommended 3 days or less increased from 11% to 54%. Chi2 Analyses showed that these changes were both statistically significant (p<0.0001). The plan was not effective in achieving increased follow-up visits for regular asthma care, in that 7% returned for follow-up within 7 days after an ED visit before the plan and only 6% returned for such a visit after the Plan. Successful initiation of a focused discharge teaching tool into the routine of the ED increased appropriate advice given at time of discharge from the ED. Although unsuccessful in increasing appropriate follow-up, the present intervention uses the ED not as a base for asthma education, but as a point for contacting patients in need of regular care and education, and for promoting access to that regular care.

Fatal and near-fatal asthma questionnaire: prelude to a national registry.

BACKGROUND: Asthma mortality rates continue to be unacceptably high in the United States. As a follow-up to the initiatives proposed by the Asthma Mortality Task Force in 1987, the Committee on Asthma Mortality of the American Academy of Allergy, Asthma, and Immunology developed a questionnaire on fatal and near-fatal asthma. OBJECTIVE: This study assessed completeness of answers from participating physicians and described characteristics of patients with fatal and near-fatal asthma. METHODS: There were 111 survey items intended to characterize patients with fatal or near-fatal exacerbations of asthma. The questionnaire was sent to the members of the American Academy of Allergy, Asthma, and Immunology (approximately 3900), and a total of 143 usable questionnaires were received. RESULTS: Responding physicians had information on most items in the questionnaire; the mean number of responses was 120 of 143 possible, with a median of 128 and a range of 40 to 143. Patient demographics, description of the event, identification of overall risk for the event, use of medications, and characteristics of asthma management had the most complete responses (median response rates were 126-143). Presence of factors contributing to the event had fewer responses (range, 44-125). The physicians frequently had information on some psychologic characteristics (eg, 108 responses for depression and/or hopelessness and 127 responses for social support) but less information on several others (eg, 62 responses for family dysfunction). Statistical analysis of the completed surveys indicated that only 2 characteristics distinguished fatal from near-fatal asthma: progression in minutes (adjusted odds ratio, 4. 89; 95% confidence interval, 2.05-12.90) and absence of a past history of intubation (adjusted odds ratio, 3.55; 95% confidence interval, 1.55-8.97). CONCLUSIONS: There is a need to gather further data on patients with fatal and near-fatal events to design appropriate prospective studies on asthma morbidity and mortality rates. Physicians can contribute important information about these patients. Gathering such data would be enhanced by establishing a national registry on fatal and near-fatal asthma.

Absence of diurnal variability of airway reactivity and hypoxic ventilatory drive in adolescents with stable asthma.

BACKGROUND: Symptoms from asthma are often prominent at night. In adults significant circadian variation has been shown with reduced peak expiratory flow rates and increased bronchial reactivity to methacholine in the early morning hours. Because adolescence is the age group with the greatest increase in asthma-related deaths in the 1980s, we hypothesized that adolescents might be susceptible to circadian variation of airway reactivity. OBJECTIVE: We sought to measure circadian variation of reactivity to methacholine (PC20) and hypoxic ventilatory drive (HVD), both of which would accentuate asthma that occurs at night and may predispose to death. METHODS: Sixteen children with asthma of various severity, aged 9 to 18 years, were studied at 4 PM and again at 4 AM to define circadian variation in FEV1, PC20, and HVD. Eleven children were studied on a second day 4 to 10 weeks after the first study. RESULTS: There was no systematic variation between 4 PM and 4 AM for FEV1 (P =.69), PC20 (P =.94), or HVD (P =.47). Six of the 16 children had PC20 values that were greater than 2-fold different between 4 PM and 4 AM; 3 of these were more reactive (requiring less methacholine) at 4 PM, and 3 were more reactive at 4 AM. At the second study, results were similar, with no systematic variation. Diurnal variability for PC20 was not consistent over the 2 study days, and at the second study all children with diurnal variability were more reactive at 4 PM. CONCLUSION: These data on airway reactivity, HVD, and other measures modulated by cholinergic neural mechanisms do not identify any systematic diurnal variation that would place an adolescent at risk for nighttime problems with asthma.

Acute asthma in the pediatric emergency department.

The management of children with acute asthma remains a difficult and challenging process. Although newer asthma medications are being developed, they are unlikely to have a large impact on the management of children with acute asthma. The leukotriene inhibitors are new anti-inflammatory agents for asthma and are beneficial for the treatment of patients with chronic asthma but have no therapeutic effect during the acute phase of an exacerbation. Older treatments, including the use of magnesium and heliox, have been revisited. Although some children with severe asthma may respond, these do not provide relief for most children with acute exacerbation. The new challenge for asthma care is finding ways to link children with their primary care providers so that regular asthma care can be established. The NHLBI recommends that children with asthma have regular visits with their primary care providers (e.g., four times a year). Regular care results in better adherence to medical and preventive management plans and improves the relationship between patients and physicians. Instituting an asthma action plan, which instructs families on when and how to begin therapy for an acute exacerbation, may prevent progression to a more severe condition.

Impaired production of both normal and mutant C1 inhibitor proteins in type I hereditary angioedema with a duplication in exon 8.

In the autosomal dominant disorder type I hereditary angioedema, reduced levels of C1 inhibitor may be due in part to increased turnover and decreased synthesis of normal C1 inhibitor protein. A type I hereditary angioedema patient was recently described in whom the C1 inhibitor mutation consisted of a 20-bp duplication of nucleotides 1414 to 1433 in exon 8 that introduced a frame shift predicting the loss of a normal stop codon and the translation of a protein 52 amino acids longer than normal. In this study, we analyzed the expression of C1 inhibitor in fibroblasts obtained from a skin biopsy of this patient. Two proteins of approximately 78 and 94 kDa were found intracellularly, corresponding to the products of normal and mutated alleles, respectively. Pulse-chase analysis showed a complete lack of secretion of the mutated form. In addition, there was decreased extracellular production of the normal C1 inhibitor, suggesting either decreased secretion or increased intracellular catabolism of the normal protein because of the presence of the mutant allele. The production of other complement proteins was normal. This study provides a model for further analysis of autosomal dominant genetic disorders in which production of the functional protein may be affected by the product of the mutated allele.

Acceptability and feasibility of a community approach to asthma management: the Neighborhood Asthma Coalition (NAC).

Understanding of asthma and co-management between patient and physician improves outcome. Feasibility of programs to achieve these goals in underserved settings is not documented. We used the Precede-Proceed model to document (a) community acceptance of a program to engage peer support of asthma management and care; (b) program revision to emphasize greater attention to availability of care and promotional events as channels for education; (c) engagement of intended audiences in planning and implementation; (d) participation of parents in program activities; and (e) peer-based education/support to reach parents, including socially isolated parents whose children experience heightened morbidity.

Synthesis of complement proteins in amnion.

The amnion is a metabolically active tissue that has been identified as a site of synthesis of numerous products. We report that amnion tissue explants and amnion-derived epithelial cells synthesize and secrete six proteins of the complement system, C1r, C1s, C1 inhibitor, factor B, C3, and factor H. Synthesis of C2 was minimal and variable, and C5 was not detected. The six synthesized proteins had size and subunit composition characteristic of proteins synthesized in HEp2, a long term cell line derived from malignant epithelial cells. Constitutive and regulated synthesis of five of the six proteins was similar in amnion tissue and cells. However, synthesis of factor B was different in tissue and cells; constitutive synthesis was 12-fold higher in tissue than in cells, and interleukin-1 did not alter synthesis in tissue, but increased synthesis by 11.7-fold in cells. These results indicate that amnion may be a source of complement proteins present in the amnion fluid and may contribute to local host defense along with endometrial glandular epithelial cells, which synthesize C3. Furthermore, our results suggest that amnion tissue is stimulated in vivo to synthesize factor B and cannot respond to interleukin-1 with a further increase in the synthesis rate.

Regulation of synthesis of complement protein C4 in human fibroblasts: cell- and gene-specific effects of cytokines and lipopolysaccharide.

Synthesis and secretion of the class III major histocompatibility complex (MHC) gene product, C4, were detected in human skin fibroblasts by metabolic labelling, immunoprecipitation and SDS-PAGE analysis. Pro-C4 (approximately 185,000 MW) was present in intracellular lysates, and the mature protein was present in extracellular media, with three bands of approximately 93,000, 75,000 and 33,000 MW, corresponding to the alpha, beta and gamma chains, respectively. C4 expression was increased in a dose-dependent manner by interferon-gamma (IFN-gamma), but was unaffected by interleukin-1 beta (IL-1 beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) alone, each of which augmented the expression of factor B, C3 and other complement proteins synthesized in fibroblasts. Simultaneous incubation of fibroblasts with IFN-gamma and TNF resulted in a synergistic increase in C4 synthesis. RNA blot analyses indicated that regulation of C4 synthesis by IFN-gamma and the combination of IFN-gamma and TNF was mediated primarily at a pretranslational level. Lipopolysaccharide (LPS) had no effect on C4 or HLA-DR synthesis in fibroblasts, either constitutive or IFN-gamma-regulated. These results are in contrast to the effects of LPS in monocytes, where LPS decreased constitutive synthesis and counter-regulated the IFN-gamma-enhanced expression of both C4 and HLA-DR. C2 expression in fibroblasts was also increased primarily by IFN-gamma. However, C2 synthesis was increased by LPS, 1L-1 and TNF, although to a lesser extent than the increase in synthesis of factor B stimulated by these mediators. These results show that up-regulation by IFN-gamma is a common feature of C2 and C4 expression in human cells that constitutively synthesize these proteins. In contrast, regulation of MHC class III and class II genes by LPS, TNF, IL-1, and IL-6 is cell- and gene-specific.

Developmentally regulated effects of lipopolysaccharide on biosynthesis of the third component of complement and factor B in human fibroblasts and monocytes.

Developmental regulation of the effects of lipopolysaccharide (LPS) on complement protein biosynthesis was studied in human fibroblasts from fetuses, newborn infants and adults, and in human monocytes from newborn infants and adults, using RNA blot analysis and immunoprecipitation of metabolically radiolabelled cell lysates. The responsiveness of the third component of complement (C3) and factor B protein synthesis to LPS is limited by translational mechanisms in the newborn infant and by pretranslational mechanisms in the fetus. Translation of RNA from LPS-induced cells in a rabbit reticulocyte lysate cell-free translating system indicated no differences in specific translational activity between LPS-induced adult and neonatal RNA, suggesting that LPS-induced neonatal C3 and factor B transcripts are translationally competent, but lack either access to relevant protein synthetic pathways or co-factor(s) necessary for translation. Interferon-gamma (IFN-gamma) enhanced translational activity of LPS-induced C3 and factor B transcripts in neonatal cells, suggesting that lack of translation in these cells may be due to the absence of a necessary co-factor. Experiments with LPS and cycloheximide or LPS and interleukin-1 alpha (IL-1 alpha) suggested that a newly synthesized protein did not participate in translational regulation and that LPS induction did not alter translational activity of IL-1 alpha-induced C3 and factor B transcripts. We conclude that the responsiveness of C3 and factor B protein synthesis to LPS is regulated at developmentally unique and specific steps in gene expression.

Transinhibition of C1 inhibitor synthesis in type I hereditary angioneurotic edema.

To ascertain the mechanism for decreased synthesis of C1 inhibitor (C1 INH) in certain patients with the autosomal dominant disorder hereditary angioneurotic edema, we studied expression of C1 INH in fibroblasts in which the mutant and wild type mRNA and protein could be distinguished because of deletion of exon 7 (delta Ex7). In the HANE delta Ex7 cells, the amount of wild type mRNA (2.1 kb) was expressed at 52 +/- 2% (n = 5) of normal, whereas the mutant mRNA was 17 +/- 1% (n = 5) of normal. Rates of synthesis of both wild type and mutant proteins (11 +/- 3 and 3 +/- 1% of normal, respectively) were lower than predicted from the mRNA levels. There was no evidence of increased C1 INH protein catabolism. These data indicate that there are multiple levels of control of C1 INH synthesis in type I hereditary angioneurotic edema. Pretranslational regulation results in < 50% of the mutant truncated 1.9-kb mRNA. In addition, translational regulation results in decreased synthesis of both wild type and mutatn C1 INH proteins. These data suggest a transinhibition of wild type C1 INH translation by mutant mRNA and/or protein.

Crisis in asthma care.

Reports of increases in both hospitalizations and deaths due to asthma have provided a sense of crisis in asthma care. This article examines issues concerning this sense of crisis. The authors review current trends in prevalence, morbidity, hospitalization, and mortality from asthma and examine possible reasons for changes that have occurred. A review of data suggesting that asthma can result in irreversible, chronic airway obstruction is presented. Finally, the authors discuss the role of the primary care physician in the management of asthma.

C1 inhibitor hinge region mutations produce dysfunction by different mechanisms.

Heterozygosity for a mutant dysfunctional C1 inhibitor protein, a member of the serine proteinase inhibitor (serpin) superfamily, results in type II hereditary angioneurotic oedema. We identified a "hinge" region mutation in C1 inhibitor with a Val to Glu replacement at P14 Val-432. Recombinant C1 inhibitors P10 Ala-->Thr and P14Val-->Glu did not form stable complexes with fluid phase C1s or kallikrein. The P14 Val-->Glu mutant, however, was cleaved to a 96K form by C1s, while the P10 Ala-->Thr mutant was not. The recombinant P10 mutant also did not complex with C1s, kallikrein or beta-factor Xlla-Sepharose. The two mutations, therefore, result in dysfunction by different mechanisms: in one (P14 Val-->Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala-->Thr), interaction with target protease is blocked.