Acute management of severe childhood asthma

Severe childhood asthma is a serious, life-threatening disease that presents a challenge for patients, families, and caregivers. Despite evolving medical and pharmacologic therapies, the incidence and severity of asthma are increasing. Vasoactive substances are released in response to environmental and intrinsic triggers and result in bronchospasm, bronchial mucosal edema, and mucus plugging of the airways. Early recognition of symptoms and prompt, aggressive treatment, including oxygen, beta agonists, corticosteroids, and anticholinergic agents, are essential in halting the progression of asthma symptoms. In the most severe cases, intubation, mechanical ventilation, and treatment with anesthetic agents may be needed to avoid significant morbidity and mortality. This article reviews epidemiology, pathophysiology, and acute care of the child experiencing an acute asthma exacerbation.     

Fatal varicella zoster infection in a severe steroid dependent asthmatic patient receiving methotrexate

A case is described of fatal haemorrhagic varicella zoster in a steroid dependent asthmatic patient concurrently receiving methotrexate. The future management of patients on immunosuppressive steroid sparing drugs is discussed.     

Methotrexate in juvenile rheumatoid arthritis. Evidence of age dependent pharmacokinetics

Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5-16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg.kg-1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.     

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma

The anti-asthmatic effects of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 microg x day(-1). The trial was designed as a randomized, double-blind, parallel-group study in several European countries. Sixty nine patients were treated for 6 weeks with theophylline plus BDP 400 microg x day(-1), compared to 64 patients treated with BDP 800 micro x day(-1). The mean+/-SD serum theophylline concentration was 10.1+/-4.2 mg x L(-1). Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p<0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p<0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 microg x day(-1) and beclomethasone dipropionate 800 microg x day(-1) in patients whose asthma is not controlled on beclomethasone dipropionate 400 microg x day(-1). The results support the use of theophylline as a steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.     

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma

The anti-asthmatic effect of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 micrograms/day. The trial was designed as a randomized, double-blind, parallel-group study in several European countries. 69 patients were treated for 6 weeks with theophylline plus BDP 400 micrograms/day, compared to 64 patients treated with BDP 800 micrograms/day. The mean +/- SD serum theophylline concentration was 10.1 +/- 4.2 mg/l. Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow rate (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p < 0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p < 0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 micrograms/day and beclomethasone dipropionate 800 micrograms/day in patients whose asthma is not controlled on beclomethasone dipropionate 400 micrograms/d. The results support the use of theophylline as steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.     

Serum matrix metalloproteinase-9:Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma

Asthma presents a variable clinical response to corticosteroids (CS). Because CS more likely act on inflammation than on tissue remodeling, the presence of bronchial structural changes in certain asthmatics may explain their limited clinical response to CS. Matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), are, respectively, involved in tissue inflammatory processes and fibrogenic processes. Previous reports have suggested that MMP-9:TIMP-1 ratio may reflect the balance between these two processes in various diseases. This study evaluated the relation of this ratio and the response to CS in severe asthma. Twenty asthmatics with low baseline FEV1 (59 +/- 4% predicted) and >/= 30 % increase with beta2-agonist were recruited. Serum MMP-9 and TIMP-1 levels were measured and correlated with response to an oral CS trial (methylprenisolone 40 mg/d for 14 d). With oral CS, FEV1 changes (DeltaFEV1) ranged from -15 to +43%. The DeltaFEV1 closely correlated with the MMP-9:TIMP-1 ratios (rho = 0. 79, p = 0.0006). In conclusion, serum MMP-9: TIMP-1 ratio could predict the response of oral CS therapy in asthma. The low MMP-9:TIMP-1 ratio observed in subjects with little or no FEV1 improvement with CS supports the hypothesis that, in these asthmatic subjects, bronchial fibrogenesis predominates over inflammation.     

Advances in the management of bronchial asthma

The ultrastructure of rat precorneal tear film was visualized by the quick freezing-freeze substitution (QF-FS) method and the conventional fixative method under the scanning electron microscope (SEM). In the QF-FS method, the eyeballs of rats were quickly frozen with an isopentane-propane mixture cooled by liquid nitrogen applied directly to the eyes. After enucleating the eyes and fracturing the frozen corneas, the corneas were prepared for SEM observation. In contrast to the conventional fixative method, by which the microvilli of the surface epithelial cells could be visualized clearly, a very thin membrane-like structure was observed to cover the corneal surface in the eyes prepared by the QF-Fs method. Between the membrane-like structure and corneal surface, a homogeneous and fine network-like structure was observed. The results suggest that the structure of the tear film might be different from the one we have believed to consist of three layers until now. The QF-FS method is considered to be useful for the morphological study of the precorneal tear film.     

Cyclosporin in severe steroid-requiring bronchial asthma

BASIC PROBLEM: Treatment of chronic severe bronchial asthma with corticosteroids is inadequate in a minority of patients and is often accompanied by considerable side effects. Additional specific immunosuppression appears to be therapeutically promising. PATIENTS AND TREATMENT: Three patients (2 women, aged 44 and 29, a man aged 57 years), all with chronic severe asthma requiring corticosteroids, were given cyclosporin (mean dose 1.8 mg/kg; serum level 72 +/- 35 ng/ml) additional to conventional bronchospasmolytic drugs for 9 to 20 months. COURSE: The frequency and intensity of asthmatic attacks markedly decreased in all three patients. The mean peak-flow measurements in the mornings before broncholysis had increased by 23% over the precyclosporin level of the calculated normal value. Peak flow variability improved by 13%. The mean one-second forced expiratory volume (FEV1) rose from 37 to 66% of the normal value (P < or = 0.05) and correlated with the serum cyclosporin level (correlation coefficient 0.58-0.97). The frequency of acute severe asthmatic attacks (FEV1 < or = 40%) requiring additional hospitalization with intravenous administration of glucocorticoids fell by 30%. The systemic corticosteroid maintenance dosage could be significantly reduced or the drug discontinued in two patients. CONCLUSION: These observations indicate that cyclosporin can be useful in the treatment of selected cases of chronic severe steroid-refractory asthma. Prospective studies are needed to judge its long-term efficacy.     

Investigations on the renin-angiotensin system in acute severe asthma

The renin-angiotensin system is activated in acute severe asthma. The precise mechanism of activation is at present unknown, but may involve, beta2-agonists, catecholamines or proteases released in airway inflammation. This study aims to identify potential factors involved in the activation of the renin-angiotensin system in acute asthma. Forty asthmatics with severe exacerbations of asthma, assessed by measurement of peak expiratory flow rate (mean (SD) 35 (18)% predicted), oxygen saturation (94 (4)%) and pulse rate (108 (16) beats x min(-1)) were recruited. Nineteen (48%) asthmatics had elevated plasma angiotensin II levels (median (interquartile range) 10.9 (4.3-23.5) pg x mL(-1) (normal range 3-12 pg x mL(-1))) and 10 (25%) had elevated plasma renin concentration (22.0 (10.0-50.0) microU x mL(-1) (normal range 9-50 microU x mL(-1))). Plasma renin and angiotensin II correlated strongly, implying renin-dependent angiotensin II formation. No correlation was found between plasma salbutamol, adrenaline, nor-adrenaline, endothelin-1, histamine, eosinophilic cationic protein, serum angio-tensin-converting enzyme (ACE) activity, total immunoglobulin E (IgE), urea and electrolytes, indicators of the severity of the attack, atopic status, blood pressure and renin or angiotensin II levels. We conclude that although a subpopulation of asthmatics appear to have raised renin and angiotensin II during attacks of acute, severe asthma, the mechanism of activation of the renin-angiotensin system remains unclear.     

Hyperlactatemia during acute severe asthma

The prevalence of the four human malaria parasites was investigated among malaria patients at northern, central and southern towns in Thailand along the border with Myanmar between September 1995 and May 1996. Thin smears obtained from 548 Thai and Burmese patients were reviewed by an acridine orange staining method, and many mixed infections with two to four species, including P. malariae and P. ovale, were detected. These diagnostic results were compared with those by two PCR-based diagnoses, microtitre plate hybridization (MPH) and a nested PCR method, both of which targets the same, species-specific regions in the 18S rRNA genes. In both PCR diagnoses, many P. malariae and P. ovale infections were also detected. Detection sensitivity of P. malariae infection was higher in nested PCR than MPH, and a total prevalence of P. malariae infection estimated by nested PCR reached 24.3% (133/548). In 16 of them, the size of PCR products amplified by the P. malariae-specific primer was about 20-bp shorter than the expected size of 115-bp. Four of 16 possessed two different bands with normal and shorter sizes, suggesting that P. malariae isolates may be separated into two types, and that those with shorter products may be new variant form (s) with a nucleotide deletion in the target region. On the other hand, 21 P. ovale infections (3.8%) were detected by nested PCR, but four of them were MPH-negative because of the sequence variation at the probe region. These results indicated that the prevalence of P. malariae and P. ovale along the Thai-Myanmar border may be substantially higher than previously reported.     

New strategies in the medical management of asthma

Asthma, a common chronic inflammatory disease of the airways, may be classified as mild intermittent or mild, moderate, or severe persistent. Patients with persistent asthma require medications that provide long-term control of their disease and medications that provide quick relief of symptoms. Medications for long-term control of asthma include inhaled corticosteroids, cromolyn, nedocromil, leukotriene modifiers and long-acting bronchodilators. Inhaled corticosteroids remain the most effective anti-inflammatory medications in the treatment of asthma. Quick-relief medications include short-acting beta2 agonists, anticholinergics and systemic corticosteroids. The frequent use of quick-relief medications indicates poor asthma control and the need for larger doses of medications that provide long-term control of asthma. New guidelines from the National Asthma Education and Prevention Program Expert Panel II recommend an aggressive "step-care" approach. In this approach, therapy is instituted at a step higher than the patient's current level of asthma severity, with a gradual "step down" in therapy once control is achieved.     

Pharmacological management of asthma

Asthma management is changing, and there are many potential new drugs undergoing early and late phase trials. Nonetheless, it is unlikely that any dramatic alterations in therapy will occur within the next 3 years. The asthma treatment paradigm has altered over the past 10 or so years, with the emphasis on symptom relief from short acting beta agonists giving way to preventive treatment of underlying airway inflammation with inhaled corticosteroids. More recently, long acting beta agonists have been demonstrated to reduce the need for increasing doses of inhaled steroids in patients with poorly controlled asthma. This article reviews these trends.     

Intramuscular high-dose triamcinolone acetonide in the treatment of severe chronic asthma

We describe our experience with administering intramuscular triamcinolone acetonide to 22 steroid-dependent patients with asthma. These patients represent the minority of those with asthma whose disease is characterized by frequent emergency department visits, hospital admissions, and long-term dependency on oral corticosteroid therapy. The participants were randomly assigned to 2 treatment groups, one group receiving 120 mg of intramuscular triamcinolone acetonide, the second receiving 360 mg as a series of three 120-mg daily doses. We determined relative efficacy by comparing peak expiratory flow rates and incidents of emergency department visits, hospital admissions, and ventilatory failure of the study and during the 12 months before enrollment. Peak expiratory flow rates improved significantly in both groups. The mean (+/- standard deviation [SD]) monthly percentage of predicted peak expiratory flow on the study was 88.6 +/- 3.7% and 91.2 +/- 3.9% compared with 63 +/- 15.1% and 64 +/- 14.5% at entry in patients receiving 120 and 360 mg, respectively (P < 0.02). Patients receiving 120 mg required 8 hospital stays and 8 emergency department visits compared with 27 hospital stays and 72 emergency department visits in the previous year (P < 0.05). Patients receiving 360 mg required 5 hospital stays and 5 emergency department visits compared with 33 hospital stays and 34 emergency department visits in the previous year (P < 0.05). The average monthly interval (+/- SD) between exacerbations was 2.7 +/- 2.3 and 7.8 +/- 3.5 for patients receiving 120 mg and 360 mg, respectively. A total of 25 intubations was required in the previous year and only 1 during the study. The incidence of cushingoid facies, weight gain, and hypertension was reduced in both groups (P < 0.05). Total steroid use was reduced in both groups (P < 0.02). A dose of 360 mg produced a longer exacerbation-free period than 120 mg (P < 0.02).     

Endotracheal intubation and mechanical ventilation in severe asthma

Retrospective analysis of all patients with acute bronchial asthma who required intubation and mechanical ventilation was performed in 1987-1993. Our study group comprised 29 patients with a total of 31 episodes of mechanical ventilation. Indications for intubation and ventilation were cardio-respiratory arrest in 9 episodes, and deterioration of clinical status despite aggressive therapy in 22 episodes. Mechanical ventilation strategy was to avoid high air-way pressures of more than 50 cm H2O even if respiratory acidosis persisted. The risk of barotrauma was thus eliminated; other complications were few and reversible, and all patients survived. We conclude that intubation and mechanical ventilation in severe asthma is beneficial and safe, and the prognosis very good.     

Psychiatric family history in adolescents with severe asthma

OBJECTIVE: To examine the hypothesis that an association exists between severe asthma and familial affective and anxiety disorders. METHOD: A parent, usually the mother, of 62 adolescents admitted to a tertiary care asthma center was administered the Family History-Research Diagnostic Criteria Interview. Lifetime prevalence rates of psychiatric disorders in first-degree relatives were compared with previously reported rates. RESULTS: In relatives of asthmatic adolescents, rates for depression, mania (females only), substance abuse (males only), and antisocial personality disorder were significantly higher than the rates in the non-ill comparison sample. Rates for substance abuse (males only) and antisocial personality disorder were higher than the rates for relatives of the depressed comparison sample. Rates for anxiety disorders were not higher than rates in epidemiological samples. Rates of attention-deficit hyperactivity disorder (females only) and posttraumatic stress disorder in relatives were higher than in community samples. CONCLUSIONS: These results support the presence of a link between severe asthma and familial affective disorders, posttraumatic stress disorder, antisocial personality disorder, and substance abuse. Whether these disorders are genetically associated with asthma or represent an association with severe asthma because of environmental effects on the growing child is discussed.     

Salivary theophylline estimation in the management of asthma in children

Simultaneous sampling was performed to determine whether saliva could replace plasma in the monitoring of theophylline dosages. Forty-eight children with moderate to severe asthma received oral theophylline preparation (usually sustained release) on a daily basis. They provided simultaneous saliva and plasma samples at routine out-patient visits. Saliva and plasma theophylline concentrations showed a wide variation between individuals, and their ratios also differed. Saliva theophylline concentrations below 7 micrograms/ml reflect plasma concentrations below 10 micrograms/ml, i.e. sub-therapeutic, while saliva concentrations above 7 micrograms/ml are consistent with therapeutic dosage. Estimation of saliva theophylline concentration on routine visits avoids the discomfort of blood sampling. It reflects whether daily oral theophylline dosage in childhood asthma is below or within the therapeutic range. The need for changes in dosage and the degree of patient-compliance with therapy can be usefully indicated.