Beta agonists, inhaled steroids, and the risk of intensive care unit admission for asthma.

Although inhaled corticosteroid (ICS) use is associated with a decreased risk of hospitalization for asthma, the impact of ICS on the risk of life-threatening asthma exacerbation is less clear. The effect of ICS and inhaled beta agonist (IBA) dispensing on the risk of intensive care unit admission for asthma, a surrogate for life-threatening exacerbation, is evaluated. Using computerized International classification of diseases (ICD)-9 discharge diagnoses, a cohort of all 2,344 adult Northern California members of a health maintenance organization hospitalized for asthma over a 2-yr period were identified. Computerized pharmacy data was used to ascertain asthma medications dispensed during the 3-,6-, and 12-month intervals preceding index hospitalization for asthma. During the 3-months preceding hospitalization, a minority of subjects had no IBA units dispensed (34%), with 14% receiving low level (1 unit), 20% medium level (2-3 units), and 32% high level (> or = 4 units) therapy. A substantial proportion received no ICS units (55%), whereas 13% had low, 16% medium, and 15% high level therapy. In multiple logistic regression analysis, high level IBA use was associated with a greater risk of intensive care unit (ICU) admission for asthma after controlling for asthma severity. There was no relationship, however, between low or medium level IBA use and ICU admission. Conversely, medium level and high level ICS use were associated with a reduced risk of ICU admission. Analysing 6- and 12-month medication dispensing data, similar risk patterns were observed. Inhaled corticosteroid dispensing was associated with reduced risk of intensive care unit admission among adults hospitalized for asthma, whereas the opposite applied for high dose beta agonist usage. This suggests that ICS prescription to adults with moderate-to-severe asthma could reduce the risk of life-threatening exacerbation.

Computer-based models to identify high-risk adults with asthma: is the glass half empty of half full?

This study developed and evaluated the performance of prediction models for asthma-related adverse outcomes based on the computerized hospital, clinic, and pharmacy utilization databases of a large health maintenance organization. Prediction models identified patients at three- to four-fold increased risk of hospitalization and emergency department visits, and were valid for test samples from the same population. A model that identified 19% of patients as high risk had a sensitivity of 49%, a specificity of 84%, and a positive predictive value of 19%. We conclude that prediction models that are based on computerized utilization data can identify adults with asthma at elevated risk, but may have limited sensitivity and specificity in actual populations.

Computer-based models to identify high-risk children with asthma.

Effective management of populations with asthma requires methods for identifying patients at high risk for adverse outcomes. The aim of this study was to develop and validate prediction models that used computerized utilization data from a large health-maintenance organization (HMO) to predict asthma-related hospitalization and emergency department (ED) visits. In this retrospective cohort design with split-sample validation, variables from the baseline year were used to predict asthma-related adverse outcomes during the follow-up year for 16,520 children with asthma-related utilization. In proportional-hazard models, having filled an oral steroid prescription (relative risk [RR]: 1.9; 95% confidence interval [CI]: 1.3 to 2.8) or having been hospitalized (RR: 1.7; 95% CI: 1.1 to 2.7) during the prior 6 mo, and not having a personal physician listed on the computer (RR: 1.6; 95% CI: 1.1 to 2.3) were associated with increased risk of future hospitalization. Classification trees identified previous hospitalization and ED visits, six or more beta-agonist inhalers (units) during the prior 6 mo, and three or more physicians prescribing asthma medications during the prior 6 mo as predictors. The classification trees performed similarly to proportional-hazards models, and identified patients who had a threefold greater risk of hospitalization and a twofold greater risk of ED visits than the average patient. We conclude that computer-based prediction models can identify children at high risk for adverse asthma outcomes, and may be useful in population-based efforts to improve asthma management.

Outpatient management practices associated with reduced risk of pediatric asthma hospitalization and emergency department visits.

OBJECTIVES: Effective outpatient care is believed to prevent hospitalization and emergency department (ED) visits resulting from childhood asthma. The aim of this study was to suggest priority areas for intervention by identifying outpatient management practices associated with the risk of these adverse outcomes in a large population. METHODS: This case-control study included children aged 0 to 14 years with asthma who were members of a regional health maintenance organization. Cases were children undergoing either a hospitalization or an ED visit for asthma during the study period. Control subjects were children with asthma without a hospitalization or an ED visit during the study period who were matched to patients on age, gender, and number of asthma-related hospitalizations in the past 24 months. Data on provider and parent asthma management practices were collected using chart review, closed-ended telephone interviews with parents, and computerized use databases. Multivariate analyses were conducted using conditional logistic regression models. RESULTS: Data were collected on 508 cases and 990 control subjects. A total of 43% of cases were reported by their parents to have moderately severe or severe asthma, compared with 20% of control subjects. Parents of cases with hospitalization were less likely than control subjects to have a written asthma management plan (44% vs 51%) and to report washing bedsheets in hot water at least twice a month (77% vs 86%). Cases with hospitalization were more likely to have a nebulizer (74% vs 56%). In the final multivariate model, race/ethnicity was not associated with having had either a hospitalization or an ED visit, as was lower socioeconomic status. Having a written asthma management plan [odds ratio (OR): 0.54; 95% confidence interval (CI): 0.30, 0.99] and washing bedsheets in hot water at least twice a month (OR: 0.45; 95% CI: 0.21, 0.94) were associated with reduced odds of hospitalization. Having a written asthma management plan (OR: 0.45; 95% CI: 0.27, 0.76) and starting or increasing medications at the onset of a cold or flu were associated with reduced odds of making an ED visit. CONCLUSIONS: Practices that support early intervention for asthma flare-ups by parents at home, particularly written management plans, are strongly associated with reduced risk of adverse outcomes among children with asthma.

Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children.

Oral methylprednisolone combined with troleandomycin has been reported to be successful in treating poorly controlled, severe asthma in adults. We found this drug combination to be effective in treating 11 steroid-dependent children with poorly controlled asthma who were aged 7 to 13 years, for 12 to 28 months. Improvement of clinical and pulmonary functions was achieved within seven days, with the forced expiratory volume in 1 s increasing by 38% and the maximal midexpiratory flow rate increasing by 55% over the baseline value. By one year, the former improved to 98% of predicted value and the latter, to 79% of predicted value. Compared with the prior 12 months, patients at this time required fewer emergency visits, missed fewer days of school, and had fewer hospitalizations. Side effects included transient-increased cushingoid features, abdominal pain, and liver enzyme level elevation. Patients showed less evidence of adrenal suppression.

Neutrophil and T lymphocyte characteristics of two patients with hyper-IgE syndrome.

Immunologic parameters including quantitative and qualitative immunoglobulin studies, various T cell functions and neutrophil chemotaxis were evaluated in two patients with the Hyper-IgE syndrome. Both exhibited pruritic dermatitis in locations atypical for atopic dermatitis, marked elevations in serum IgE levels (to 40,000 IU/ml), recurrent staphylococcal abscesses, coarse facial features and variable chemotactic defects characteristic of this syndrome. Both patients responded favorably to courses of trimethoprim-sulfamethoxazole, particularly in helping control the cutaneous infections. We believe that this is a useful therapeutic alternative to anti-staphylococcal antibiotics and prophylactic treatment has permitted therapeutic response. Serum IgG, IgG subclasses, IgM, and IgA were normal for age. Serum IgD was markedly deficient in one patient. Functional IgM was normal with positive isohemagglutinin titers. IgG poliovirus titers were present in both patients; however, tetanus titers were not detectable in either patient, despite repeated immunizations. Despite normal E rosette numbers, subtle T cell abnormalities were noted with variable responses to both in vivo SK-SD, candida, and mumps skin tests and in vitro PHA-, Con A-tetanus-induced lymphocyte proliferation. Lymphocyte production of macrophage inhibitory factor and interferon and responsiveness in a mixed lymphocyte culture were normal in both patients. Considerable Con-A-induced suppressor cell activity was present in one patient, but diminished in the other. In vivo chemotaxis determined by a Rebuck skin window, revealed a markedly delayed PMN migration in both patients during a time when both patients were clinically free of furunculosis or dermatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylate cyclase, cyclic AMP and IgE-mediated desensitization in rat mast cells.

Rat peritoneal mast cells were desensitized up to 100% with 1-4 additions of suboptimal concentrations of anti-rat IgE over 60-90 min. Desensitized cells rechallenged with anti-IgE showed a 2- to 10-fold increase in cAMP during the initial 1-5 min. Membrane preparations from desensitized cells showed up to a 100-fold rise in cyclase activity following incubation with anti-IgE, compared to a 5- to 10-fold rise in control cells. Control and desensitized cell membranes rechallenged with anti-IgE showed nearly identical levels of phosphodiesterase activation. We conclude that following desensitization, repetitive low levels of anti-IgE binding induce atypically high and sustained activation of adenylate cyclase which may reflect primary or secondary regulatory events in the development of desensitization.

Basophil releasability in the newborn: factors limiting immunoglobulin E-mediated histamine release.

Cord basophil preparations from 53 term neonates were studied for various factors affecting immediate hypersensitivity reactions including: basophil IgE receptor density and histamine releasability following incubation with calcium ionophore A23187, zymosan-activated serum (C5a), and anti-IgE. Basophil histamine content (geometric mean, 0.4 pg/basophil, with content in 14/28 cord blood samples below 0.2 pg/cell) is considerably below that of atopic and nonatopic individuals (geometric mean, 2.3 pg/basophil). Histamine release is normal with both A23187 (range 33% to 88%) and C5a (range 11% to 58%). Normal release with anti-IgE was shown in five of nine cord blood samples (range 13% of 52%), but four of five cell preparations required IgE preincubation. Indirect evidence indicates that basophils from newborns contain less than 30,000 total IgE receptors/cell. IgE-mediated histamine release in basophils from newborns is minimized by suboptimal IgE binding. Optimal IgE binding is not favored in basophils from neonates because of low serum IgE and low IgE receptor density. Serum IgE and IgE receptors increase to a variable degree as the child grows older and may determine the clinical onset of allergic disease.

Subthreshold and suboptimal desensitization of human basophils. II. Nonspecificity and irreversibility of desensitization.

Desensitization in human basophils was induced by suboptimal levels of antihuman IgE or antigen under normal calcium buffer conditions. Low doses of anti-IgE triggered only 0-12% histamine release during a 3-hour preincubation, yet initiated up to 100% desensitization upon rechallenge. After 24-27 h preincubation with allergen a, the cells did not regain releasability when rechallenged with either allergen a, allergen b or anti-IgE. Low dose, IgE-mediated desensitization in human basophils may lead to an irreversible and nonspecific inhibition of degranulation.

Subthreshold and suboptimal desensitization human basophils. I. Kinetics of decay of releasability.

The kinetics of desensitization in normal calcium buffer was studied in leukocytes resuspended at a maximum concentration of 50,000 basophils/ml (total available histamine, greater than 5 x 10(-7) M). The time constant of desensitization, k, ranged between 0.01 and 0.02 under subthreshold preincubation conditions (50% inactivation; t 1/2 = 60-120 min). Fractional addition of antigen reduced preincubation histamine release. The degree of IgE bridging required for virtually complete desensitization was complete within the first seconds of incubation of cells with anti-IgE. Hence the slow development of subthreshold and suboptimal desensitization in the presence of calcium must be related to events which occur after IgE cross-linking.

Reversibility of IgE-mediated rat mast cell desensitization.

Desensitization in normal rat peritoneal mast cells was induced by subthreshold and suboptimal levels of antirat IgE under normal calcium buffer conditions. Low doses of anti-IgE which triggered 0-10% net histamine release, initiated up to 100% desensitization. The rate of desensitization was highly variable in different rats, resulting in an irregular decay of releasability over the first 30 min. After 120-150 min of desensitization, rat mast cells in 3 of 5 experiments spontaneously regained releasability. We hypothesize that IgE-mediated desensitization in rat mast cells may represent a potentially reversible physiologic blockade in the degranulation process.

Candida esophagitis and laryngitis in chronic mucocutaneous candidiasis.

Five children (aged 11 to 19 years) with lifelong chronic mucocutaneous candidiasis had 12 episodes of esophageal and/or laryngeal candidiasis documented by endoscopy. Symptoms included hoarseness (8/12), dysphagia (6/12), and hemoptysis (1/12). There was poor correlation between oral lesions and esophageal or laryngeal involvement. On fiberoptic endoscopy, the esophagus was involved alone in four episodes (33%), the larynx in two episodes (17%), and both structures in six episodes (50%). In six of eight instances, the esophagram was nondiagnostic or markedly underestimated the extent of inflammation. Intravenous amphotericin B or miconazole resulted in the resolution of these infections for variable periods of time. Repeat endoscopy was used to follow the course of the disease. Aerosolized amphotericin B was effective on one occasion in clearing candidal lesions of the larynx and one small area of the left mainstem bronchus. Oral topical therapy was not beneficial. Since the signs and symptoms of laryngitis or esophagitis are often minimal or absent and complications, including strictures, may arise from chronic inflammation, periodic endoscopy and systemic therapy may be necessary.

Noncytotoxic IgE-mediated release of histamine and serotonin from murine mastocytoma cells.

Cultured murine mastocytoma (AB-CBF1-MCT-1) cells were stimulated to release endogenous or incorporated histamine or serotonin by an IgE-mediated mechanisms without loss of viability. Stimulation was achieved by incubation of the cells with rat IgE-anti-IgE, rat IgE-anti-light chain, fluoresceinated rat IgE-anti-fluorescein, IgE-enriched mouse anti-ovalbumin-ovalbumin, or covalently linked dimers of rat IgE, at doses similar to those optimal for normal peritoneal mast cells. Active cell metabolism and Ca++ were required to obtain release. Despite the latter, no dose of the calcium ionophore, A23187, could be found which caused release without concomitant cytotoxicity. Phosphatidylserine did not enhance release.

Disparity of IgE binding between normal and tumor mouse mast cells.

The binding constants of rat and mouse IgE to normal and neoplastic rat and mouse mast cells have been measured. None of the cells distinguishes between rat and mouse IgE. Rat normal and neoplastic mast cells and mouse mastocytoma cells show very similar binding properties: k1 approximately 10(5), k-1 approximately 10(-5) and, therefore, KA approximately 10(10). Normal mouse mast cells also show a forward rate constant, k1, of 10(5) but the dissociation rate constant, k-1, is 50 times higher (5 X 10(-4)). The detergent-solubilized receptors reflect the properties of the cell-bound receptors. The discrepancy in binding by normal and neoplastic mouse mast cells remains unexplained but appears to be a reproducible finding for the cells from three strains of normal mice and three different mastocytomas studied.