Death due to asthma in children: what the pediatrician can do.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
R C Strunk
Publications and source records attributed to R C Strunk.
Cardiovascular fitness in children with asthma correlates with psychologic functioning of the child.
Abnormalities in fitness in asthmatic children are assumed to derive from illness severity. We studied 90 children with moderately severe to severe but stable asthma for (1) fitness levels using bicycle ergometry, (2) measures of asthma severity, (3) clinician's impression of child (Child Global Assessment Scale), and (4) mother's rating of child's behavior (Child Behavior Checklist). Fitness values ranged from 15% to 120% of normal values for age, sex, and body surface area: 48% were abnormal (less than 2 SD below mean) and 5% were borderline (1 to 2 SD below mean). Associations between levels of fitness and medical and psychologic criteria were tested using regression analyses. Of the 11 medical variables used to define the severity of asthma, recent exacerbation of disease, forced expiratory volume in 1 second, and specific airway conductance together accounted for 8.1% of the variability in the workload ratios (ie, R2 = 0.081). The importance of the psychologic factors in determining the variability in the workload ratios was tested after the importance of the medical variables had been considered: Child Global Assessment Scale accounted for a significant amount of variability, improving the R2 to 0.180 (an increase to 0.100, P = .003). These data suggest that, within the spectrum of disease presented by the patients in this study, adjustment to the disease is at least as important as severity of disease in determining fitness.
Adolescent↗
Synthesis and regulation of complement protein factor H in human skin fibroblasts.
The alternative pathway of C activation is Ag-independent and forms a first line of defense against infection before immune response. The C3 convertase, C3bBb, formed during activation of the alternative pathway is tightly regulated, with destabilization produced by factor H. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrated that human skin fibroblasts synthesized and secreted factor H protein. Two forms of the protein were identified, the approximately 160-kDa form seen more prominently in serum and a 45-kDa form that has also been identified in serum. The cells contained two forms of factor H mRNA, 4.4 and 1.8 kb. IFN-gamma increased factor H protein synthesis and mRNA content. No effect was observed with LPS. Neither HepG2 cells or human peripheral blood monocytes synthesized factor H protein or contained factor H mRNA.
Cell Line↗
Differential regulation of gene expression during macrophage activation with a polyribonucleotide. The role of endogenously derived IFN.
The activation of macrophages by exposure to the polyribonucleotide, poly [I:C], is accompanied by a large stimulation of the synthesis of the C components factor B and C3, and a concomitant inhibition of the synthesis of the lysosomal enzyme beta-glucuronidase. Northern blot analysis of poly [A+] RNA extracted from poly [I:C]-stimulated cells revealed that the changes in the synthesis of factor B and C3 were related to changes in the levels of their respective mRNA and hence the expression of these proteins appeared to be regulated at a pre-translational level. The down-regulation of the synthesis of beta-glucuronidase appeared to be regulated at both translational and pre-translational levels. In view of the proposed role of macrophage-derived IFN in the regulation of macrophage activation, we investigated the possible role of IFN-alpha/beta in the regulation of the synthesis of factor B, C3, and beta-glucuronidase. Exposure of macrophages to mouse IFN-alpha and IFN-beta induced limited changes in the synthesis of factor B, C3, and beta-glucuronidase. However, pretreatment of macrophages with only 500 U/ml of IFN-beta primed the cells thereby increasing their sensitivity to poly [I:C]. IFN-alpha was less effective as a priming agent. When macrophages were exposed to poly [I:C] in the presence of an anti-mouse IFN-alpha/beta antiserum, the changes in the synthesis of factor B, C3, and beta-glucuronidase were partially inhibited. Collectively, these data indicate first, that exposure of mouse bone marrow-derived macrophages to poly [I:C] differentially regulates the expression of the products of the genes for factor B, C3, and beta-glucuronidase. Second, IFN-alpha and IFN-beta prime macrophages to increase the sensitivity of macrophages to poly [I:C]. Third, in the absence of exogenous IFN, macrophage-derived IFN appears to participate in priming the cells in an autocrine or paracrine fashion.
Animals↗
Synergism between gamma interferon and lipopolysaccharide for synthesis of factor B, but not C2, in human fibroblasts.
Four different human fibroblast cell lines synthesized C2 and factor B. Factor B synthesis was increased 12.1-fold by 50 ng/ml LPS and 7.1-fold by 100 U/ml IFN-gamma. C2 synthesis was increased only 2.1-fold by LPS, but 6.4-fold by IFN-gamma. Both LPS and IFN-gamma increased levels of factor B mRNA. LPS induced a 4.7-fold greater increase in factor B protein than in factor B mRNA, whereas IFN-gamma stimulated comparable increases in protein and mRNA. These data suggest that LPS acts to increase factor B synthesis at both pretranslational and translational sites, while IFN-gamma acts primarily at a pretranslational level. In contrast to factor B, increases in C2 protein and C2 mRNA were comparable for both stimuli. A synergistic effect between the two stimuli was observed for factor B only: protein synthesis was increased 54.5-fold or 2.8-fold greater than the additive effects of the stimuli separately. The rate of synthesis in the presence of LPS and IFN-gamma together could not be achieved by increasing concentrations of, or the times of incubation with, either stimulus separately. The synergism was not the result of an increased sensitivity of the cells to either stimulus and was not reproduced by preincubation with one stimulus before incubation with the other stimulus. Several lines of evidence suggest that the synergism, like the stimulation of factor B synthesis by LPS, was dependent on both translational and pretranslational regulation of factor B mRNA. C2 and factor B synthesized in human fibroblasts may play a role in host defense in inflammatory reactions before increases in vascular permeability and recruitment of other complement producing cells.
Cells, Cultured↗
Determination of fitness in children with asthma. Use of standardized tests for functional endurance, body fat composition, flexibility, and abdominal strength.
Children with asthma frequently have exercise-induced disease that can limit their participation in both organized sports and vigorous free play. We measured fitness in a group of children with moderately severe to severe asthma with an instrument that is used widely and is available to clinicians for assessment of the physical capability of their patients. Abnormalities in physical fitness were present primarily in the area of endurance, with performance in the nine-minute run frequently found to be low. Increased skin-fold thickness was also present more frequently than in the normal population. Abdominal strength and flexibility were normal. Abnormalities in fitness were not well explained by measures indicating the presence of poorly controlled disease. All children with significant asthma probably should be tested to document the level of fitness so that appropriate intervention can be initiated.
Adolescent↗
Synovial fibroblast-like cells synthesize seven proteins of the complement system.
Fibroblast-like cells from synovial tissue obtained during arthroscopy in 4 young adults with recent knee trauma were biosynthetically labeled with 35S-methionine, and protein production was quantitated by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Synovial fibroblast-like cells synthesized C1r, C1s, C1 inhibitor, C2, C3, factor B, and factor H, all with the same sizes and subunit structures as the proteins synthesized in skin fibroblasts. The capacity to synthesize these proteins was not lost with passages or freeze-thawing. Gamma-interferon stimulation increased synthesis of all 7 proteins. Lipopolysaccharide increased synthesis of only C3 and factor B. Unlike in whole rheumatoid tissue, C4 and C5 were not detected. Synovial lining cells may be an important source of local complement for participation in local defense or development of pathologic states.
Cell Adhesion↗
Need for theophylline in severe steroid-requiring asthmatics.
Concern about side-effects of theophylline prompted us to investigate whether this drug could be eliminated from the multi-medication regimen of severe asthmatics. We studied patients with a demonstrated requirement for systemic steroids who were taking most other available anti-asthma medications in an attempt to reduce systemic steroids while maintaining clinical stability. Five in-patients, 12-15 years old, completed a double-blind, cross-over trial of theophylline vs placebo. All were stable for 4 weeks prior to the study with normal spirometry and mildly elevated lung volumes. Regular medications consisted of long-acting theophylline with levels between 12 mcg/ml and 16 mcg/ml, and prednisone 10-30 mg on alternate days. In addition, they were all taking inhaled metaproterenol, cromolyn sodium, atropine sulphate, and beclomethasone dipropionate four times daily (qid). Patients received either theophylline or placebo during two drug periods. All other medications were unchanged. Parameters measured were symptom score, number of extra respiratory treatments (prn RTs), increase in steroid dosage, and daily spirometry. During the placebo period, all five patients required increased steroids, daily spirometry decreased and three patients developed severe exacerbations unrelated to viral infection. A marked increase in symptom score occurred within 48 hr of discontinuing theophylline in all. These findings emphasize that theophylline is beneficial in a subset of severe asthmatics who cannot be controlled with all other available bronchodilators, cromolyn, and inhaled and systemic steroids.
Adolescent↗
Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways.
The serum complement system is a major mediator of inflammation reactions. Two of the complement proteins, the third (C3) and fifth (C5) components, are precursors of potent phlogistic molecules, C3a and C5a. C5a has potent chemotactic activity and plays an active role in pulmonary inflammation. We present evidence suggesting that several complement proteins, including C5, are synthesized locally in the lung in alveolar type II epithelial cells. Lung tissue from normal mice synthesized and secreted C5 protein similar to the C5 protein in mouse serum, whereas lung tissue from C5-deficient mice did not. Lung tissues from both normal and C5-deficient mice synthesized C3. Rat lung tissue synthesized and secreted C5, as well as C2, C4, C3, and factor B. Cultures of type II cells (95% type II cells, 5% macrophages) regularly synthesized all these proteins. In contrast, cultures of macrophages alone synthesized large amounts of C2 and factor B, and in some experiments C3 and C4, but never C5. The C5 synthesized by the rat cells was slightly larger than serum C5 (200 kD compared with 180 kD) and was not processed to the two-chain molecule seen in serum. Rat lung tissue and purified type II cells contained C5 mRNA with the same molecular mass as the C5 mRNA in rat liver and in mouse lung and liver. Human type II cells also synthesized C5, as well as C2, C4, C3, and factor B. Human pulmonary macrophages synthesized only C2, factor B, and, in some experiments, C3. Synthesis of complement proteins in cells that line the alveolar wall may provide a local source of these proteins for inflammatory responses in the lung. Local synthesis of complement proteins could be regulated independently of the synthesis in the liver.
Animals↗
Methacholine inhalation challenge in young children: results of testing and follow-up.
The diagnosis of asthma is often difficult in young children because their symptoms may not be typical and pulmonary function testing cannot be performed by the patient. We therefore performed methacholine inhalation challenges (MIC) in 24 patients 1 to 5.8 years of age in whom the diagnosis of asthma was uncertain. These patients had histories of recurrent respiratory symptoms for a mean duration of 2.4 years (range = 0.5 to 5.1) in the absence of other systemic diseases. Testing was done by either the 5-breath technique or 1-min inhalation via face mask until wheezing or coughing and retractions developed or a maximum methacholine concentration of 5 to 25 mg/mL was reached. Eighteen MIC were positive and six negative. The mean provocative dose was 3.0 mg/mL (range = 0.6 to 10). No patients suffered serious or delayed reactions and all symptoms reversed with inhaled bronchodilators (BD). During the MIC, the progression of symptoms often mimicked progression of those observed in the past and was useful in teaching the parents. Patients were followed for 0.5 to 3.8 years (mean = 2.3). All patients with a positive MIC have continued to have recurrent respiratory symptoms and require regular or intermittent BD. Only one patient with a negative MIC at 5 mg/mL has recurrent respiratory symptoms and requires daily BD 3 years after the initial evaluation. We conclude that MIC can safely be performed in young children in whom the diagnosis of asthma is uncertain. A positive MIC in this context demonstrates increased bronchial reactivity and is supportive of a clinical diagnosis of asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Asthma↗
The fifth component of complement (C5) in the mouse. Analysis of the molecular basis for deficiency.
C5-deficient mice differed from C5-sufficient mice both quantitatively and qualitatively in C5 protein, C5 mRNA, and the C5 gene. C5-deficient protein was present as decreased amounts of an unprocessed, single-chain precursor. C5-deficient mRNA was decreased in amount and present in two forms, the smaller of which was the same as the single form in normal cells. Nuclei from both normal and deficient cells contained the larger form of C5 mRNA, and C5-deficient DNA demonstrated differences from the normal pattern on Southern analysis for two restriction enzymes. These data suggest that the primary transcript of the C5-deficient gene is abnormal, retarding the processing of the C5 mRNA, and that the C5-deficient mRNA codes for an abnormal protein.
Animals↗
Asthma deaths in childhood: identification of patients at risk and intervention.
Explore the source record for details and available documents.
Adolescent↗
Myocardial contraction band lesions in patients with fatal asthma: possible neurocardiologic mechanisms.
Myocardial contraction band necrosis (MCBN) occurs in catecholamine infusion, central nervous system stimulation, stress, and transient myocardial ischemia with reperfusion. In 4 of 13 children who died with asthma, MCBN was present, suggesting that this cardiac lesion may contribute to the deaths of some asthmatic patients. Two of the 4 patients who had MCBN had not received sympathomimetics intravenously or by an intracardiac route. Therefore, mechanisms other than infusions of large doses of catecholamines are probably involved in production of this cardiac lesion in asthmatics.
Adolescent↗
Psychomotor adaptation in children with severe chronic asthma.
Acute effects of steroid medications or hypoxic-induced brain damage have been hypothesized to cause neuropsychologic impairment in children with severe asthma. The present investigation included neuromotor, cognitive, psychosocial, and medical evaluations of 67 hospitalized asthmatic children from 9 to 14 years of age, at risk for motor dysfunction. Mean scores from the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) were similar to test norm means and were not indicative of neuromotor impairment. Scores of the BOTMP correlated significantly (P less than .01) with measures of child and family psychosocial adaptation but not with measures of cognitive ability, steroid dose at admission, or severity of asthma. Thirteen children had battery composite scores more than 1 SD below age means but did not demonstrate decreased IQ or increased steroid use, respiratory failure, seizures, or abnormal neurologic signs compared with the other 55 children. These results indicate that most severely asthmatic children, including many with histories of hypoxia and high-dose steroid use, do not demonstrate psychomotor impairments indicative of brain damage. It is concluded that neuromotor development in asthmatic children is associated with psychologic characteristics that influence adaptation to illness and activity level.
Adaptation, Psychological↗
Regulation of the synthesis of the third component of complement and factor B in cord blood monocytes by lipopolysaccharide.
We compared the regulation of C3 and factor B synthesis in cord blood and adult monocytes by using techniques for identification and quantification of newly synthesized proteins, lipopolysaccharide (LPS) from several Gram-negative organisms, and precursors of LPS. Synthesis of C3 and factor B in cord blood monocytes was unaffected by lipid A (the active moiety of LPS extracted by the Westphal procedure). In contrast, adult monocytes increased C3 synthesis by 11.5-fold and factor B synthesis by 3.1-fold in response to LPS. This difference in cord blood monocyte response to LPS was specific in that other LPS-induced monocyte functions (superoxide production and phagocytosis) were stimulated comparably in both cord blood and adult monocytes by LPS. To characterize further this regulatory difference, the roles of LPS precursors, arachidonic acid metabolites, and of factor(s) released by adult monocytes were examined. Precursors of the lipid portion of LPS (lipid X and lipid Y), LPS isolated by trichloroacetic acid extraction, and endotoxin-associated protein (EAP) increased C3 and factor B synthesis in cord blood monocytes. Inhibitors of the lipoxygenase pathway (dexamethasone, ETYA) but not of the cyclooxygenase pathway (indomethacin) abrogated the response of adult monocytes to lipid A and EAP and of cord blood monocytes to EAP. Finally, co-incubation of adult monocytes and cord blood monocytes in LPS-containing medium resulted in enhancement of C3 and factor B synthesis in cord blood monocytes. These data suggest that the difference in LPS response between cord blood and adult monocytes may result from differences in lipid processing or protein recognition of LPS, differences in the production of lipoxygenase pathway products, and/or one or more regulatory factors. The availability of human mononuclear phagocytes which exhibit distinct differences in biosynthetic responsiveness to LPS should permit investigation of the molecular mechanism(s) by which LPS affects C3 and factor B gene expression.
5,8,11,14-Eicosatetraynoic Acid↗
Regulation of complement protein biosynthesis in mononuclear phagocytes.
Proteins of the complement system (with the exception of the terminal components C6-9) are synthesized in mononuclear phagocytes. The extrahepatic macrophage is therefore an important local source of the complement proteins which may serve as a first-line host defence mechanism. Net synthesis and secretion of complement by these cells is a function of maturation of the mononuclear phagocytic series, the tissue from which the cells are isolated, and the state of macrophage activation. To define some of the mechanisms for regulation of complement gene expression in mononuclear phagocytes, the major histocompatibility complex class III genes and C3 have been investigated. These genes are expressed constitutively in hepatocytes and monocytes/macrophages. In the mononuclear phagocyte, interferon-gamma, at physiological concentrations, effects a dose- and time-dependent increase in factor B and C2 mRNA and a corresponding increase in factor B and C2 biosynthesis. This effect is specific inasmuch as the expression of other genes (e.g. C3) is decreased by interferon-gamma, and interferon-alpha and beta at concentrations one to two logs greater have only a minimal effect on C2 and factor B gene expression. Endotoxin acting directly on monocytes has qualitatively different effects on expression of the complement genes. These complex regulatory mechanisms are being investigated with the use of murine fibroblasts transfected with human DNA bearing the relevent complement genes.
Animals↗
Regulation of complement proteins C2 and factor B by interleukin-1 and interferon-gamma acting on transfected L cells.
Explore the source record for details and available documents.
Acute-Phase Reaction↗
Normalization of cardiopulmonary endurance in severely asthmatic children after bicycle ergometry therapy.
Sixty-five children with severe asthma were tested on a bicycle ergometer to determine their cardiopulmonary endurance and to determine whether they could achieve normal levels of endurance after a physical rehabilitation program. Workloads on entry into the study ranged from 12% to 222% (median 70%) of predicted. Abnormalities in cardiopulmonary endurance did not correlate with historical features commonly used to define severe asthma or degree of airways obstruction. Forty (58%) patients required further bicycle ergometry training two to five times per week: 32 had scores less than 2 SD below the mean, and eight had scores between 1 and 2 SD below the mean. No adverse side effects were encountered during either testing or training. Of the children with scores less than 2 SD below the mean, 84% achieved normal workloads within 2 to 17 weeks of hospitalization. Rates of improvement were similar in the 27 children who subsequently passed and the five children who did not pass, suggesting that duration of program participation was the most important variable in determining success. Thus severely asthmatic children with abnormal fitness levels can achieve normal cardiopulmonary fitness after training on the bicycle ergometer.
Adolescent↗