Rapid Effects of Inhaled Corticosteroids in Acute Asthma: An Evidence-Based Evaluation

doi:10.1378/chest.130.5.1301

Chest

Volume 130, Issue 5, November 2006, Pages 1301-1311

https://doi.org/10.1378/chest.130.5.1301 Get rights and content

Background

Current reviews on the use of inhaled corticosteroids (ICS) for acute asthma underestimated their early (minutes) clinical impact and produced conclusions of questionable validity.

Objective

The analysis of the best evidence available on the early (1 to 4 h) clinical impact of ICS for patients with acute asthma in the emergency department (ED) setting.

Methods

Published (from 1966 to 2006) randomized controlled trials were retrieved using different databases (MEDLINE, EMBASE, Cochrane Controlled Trials Register), bibliographic reviews of primary research, review articles, and citations from texts. Primary outcome measures were admission and ED discharge rates.

Results

Seventeen studies met criteria for inclusion in the review (470 adults and 663 children and adolescents). After 2 to 4 h of protocol, a greater reduction in admission rate was observed with trials that used multiple doses of ICS (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.16 to 0.55), especially when they were compared with placebo. Patients treated with ICS also displayed a faster clinical improvement compared with placebo or systemic corticosteroids (SCS), increasing the probability of an early ED discharge (OR, 4.70; 95% CI, 2.97 to 7.42; p = 0.0001). The advantage of the use of ICS was also demonstrated in spirometric and clinical measures as early as 60 min. These benefits were obtained only when patients received multiple doses of ICS along with β-agonists compared with placebo or SCS.

Conclusions

Data suggests that ICS present early beneficial effects (1 to 2 h) when they were used in multiple doses administered in time intervals ≤ 30 min over 90 to 120 min. The nongenomic effect is a possible candidate by covering the link between molecular pathways and the clinical effects of corticosteroids.

Section snippets

Genomic Effects of CS

The mechanisms of action of CS on the inflammatory process are complex. The classic antiinflammatory effects implicate the activation or repression of multiple genes involved in the inflammatory process. Thus, CS produce their effects on cells by activating glucocorticoid receptors that alter transcription through direct DNA binding or transcription factor inactivation.11, 12 As a consequence, CS increase the synthesis of antiinflammatory proteins, or inhibit the synthesis of many inflammatory

Rapid Nongenomic Effects of CS

Although the major part of the investigation has been performed in the last decade, already in 1942 Hans Selye¹³ observed that some CS-induced effects (anesthesia) only minutes after their application, constituting the first notification of a nongenomic effect of CS. Two decades later, acute cardiovascular effects of aldosterone (after 5 min of its administration) were reported in humans.¹⁴ Lately, CS have also been shown to acutely decrease nasal itching in allergic rhinitis patients.¹⁵ These

Materials and Methods

The main component of an evidence-based review that distinguishes it from the traditional narrative or state-of-the-art reviews is an extensive, structured, and explicit search strategy targeted at identification of all relevant studies.²⁴ Initially, we need to develop a well-defined, clinically relevant, and concise question. In view of previous considerations, we formulated the question as follows: In children and adults with acute asthma, does the addition of ICS to a standard treatment of β₂

Results

A total of 50 articles were identified in the initial search. Of these, there were 24 articles potentially eligible. Reasons for subsequent exclusion were studies on chronic asthma (n = 1) and long-term studies (n = 6). Finally, 17 studies29, 3031, 3233, 3435, 3637, 3839, 4041, 4243, 44, 45 (6 studies29, 3132, 3540, 44 including adults and 11 studies30, 3334, 3637, 3839, 4142, 43, 45 including children) were selected. All eligible reports were described as randomized, double-blind,

Discussion

The purpose of this systematic review was the analysis of the best evidence available on the early clinical impact of ICS for patients with acute asthma. In agreement with previous studies,19, 20 asthmatic patients present a significant increase in airway mucosal blood flow, and ICS would decrease it by modulating sympathetic control of vascular tone. This nongenomic action might reduce the airway obstruction, improving clinical and spirometric parameters in a short period of time.

References (50)

RoweBH et al.
Steroid use in the emergency department treatment of asthma exacerbations: a meta-analysis
Am J Emerg Med
(1992)
HendelesL et al.
Are inhaled corticosteroids effective for acute exacerbations of asthma in children?
J Pediatr
(2003)
HayashiR et al.
Effects of glucocorticoids on gene transcription
Eur J Pharmacol
(2004)
KarinM
New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?
Cell
(1998)
JadadAR et al.
Assessing the quality of reports of randomized controlled trials: is blinding necessary?
Control Clin Trials
(1996)
Der SimonianR et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986)
ScarfoneRJ et al.
Nebulized dexamethasone versus oral prednisone in the emergency department of asthmatic children
Ann Emerg Med
(1995)
VolovitzB et al.
Effectiveness and safety of inhaled corticosteroids in controlling acute asthma attacks in children who were treated in the emergency department: a controlled comparative study with oral prednisolone
J Allergy Clin Immunol
(1998)
AfilaloM et al.
Efficacy of inhaled steroids (beclomethasone dipropionate) for treatment of mild to moderately severe asthma in the emergency department: a randomized clinical trial
Ann Emerg Med
(1999)
TsaiYG et al.
A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma
J Pediatr
(2001)

RodrigoGJ et al.

Triple inhaled drug protocol for the treatment of acute severe asthma

Chest

(2003)

MoherD et al.

Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement

Lancet

(1999)

CatesC

Spacers and nebulizers for the delivery of β-agonists in non-life-threatening acute asthma

Respir Med

(2003)

Castro-RodriguezJA et al.

β-Agonists via metered-dose inhaler with pacer vs. nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: a systematic review with meta-analysis

J Pediatr

(2004)

RodrigoGJ et al.

Acute asthma in adults: a review

Chest

(2004)

RodrigoG et al.

Corticosteroids in the emergency department therapy of adult acute asthma treatment: an evidence-based evaluation

Chest

(1999)

RoweBH et al.

Early emergency department treatment of acute asthma with systemic corticosteroids

Cochrane Database of Systematic Reviews

(2001)

BarnesPJ et al.

How do corticosteroids work in asthma?

Ann Inter Med

(2003)

LoselR et al.

Nongenomic actions of steroid hormones

Nat Rev Cell Biol

(2003)

EdmondsML et al.

Early use of inhaled corticosteroids in the emergency department treatment of acute asthma

Cochrane Database of Systematic Review

(2003)

ForesiA et al.

Inhaled corticosteroids and leukotriene modifiers in the acute treatment of asthma exacerbations

Curr Opin Pulm Med

(2003)

SelyeH

Correlations between the chemical structure and the pharmacological actions of the steroids

Endocrinology

(1942)

KleinK et al.

Kinisch-experimentelle Utersuchungen uber den Einfluβ von Aldosteron auf Hamodynamik und Gerinnung: Z Kreisl

Forsch

(1963)

TillmannHC et al.

Delayed genomic and acute nongenomic action of glucocorticosteroids in seasonal allergic rhinitis

Eur J Clin Invest

(2004)

Cited by (103)

As-Needed Use of Short-Acting β<inf>2</inf>-Agonists Alone Versus As-Needed Use of Short-Acting β<inf>2</inf>-Agonists Plus Inhaled Corticosteroids in Pediatric Patients With Mild Intermittent (Step 1) Asthma: A Cost-Effectiveness Analysis
2022, Journal of Allergy and Clinical Immunology: In Practice
Although the efficacy of the as-needed use of short-acting β₂-agonists (SABAs) plus inhaled corticosteroids (ICS) for treating children with mild intermittent asthma has been demonstrated, evidence of its cost-effectiveness is scarce.
The aim of the present study was to compare the cost-effectiveness of the as-needed use of SABAs alone versus the as-needed use of SABAs plus ICS in children 5 to 11 years old with mild intermittent (step 1) asthma but suffering from an exacerbation of asthma symptoms.
A decision-analysis model was adapted. Effectiveness parameters were obtained from a randomized clinical trial. Cost data were obtained from hospital bills and from the national manual of drug prices in Colombia. The study was carried out from the perspective of the national health care system in Colombia. The main outcome of the model was a first course of prednisone for an asthma exacerbation (AE).
Compared with the use of SABAs alone, the as-needed use of SABAs plus ICS was associated with lower overall treatment costs (US$17.99 vs US$27.94 mean cost per patient) and a higher probability of a lack of a requirement for a first course of prednisone (0.6500 vs 0.5100), thus showing dominance.
In Colombia, compared with the use of albuterol alone, the use of beclomethasone dipropionate added to albuterol as needed for symptom relief is cost-effective in children 5 to 11 years old with mild intermittent (step 1) asthma, because it involves a higher probability of a lack of a requirement for prednisone for AE at lower total treatment costs.
Inhaled Corticosteroids in Acute Asthma: A Systemic Review and Meta-Analysis
2020, Journal of Allergy and Clinical Immunology: In Practice
Asthma exacerbations are a common and important cause of attendance at emergency departments (ED) and subsequent hospital admissions. Despite previous reviews reporting that in acute settings the risk of hospital admission is reduced with the use of high doses of inhaled corticosteroids (ICS), this evidence has not changed clinical practice.
To estimate the efficacy of ICS in the treatment of acute asthma in ED.
Randomized controlled trials were identified using PubMed, The Cochrane Library, and EMBASE. The primary outcome was hospital admission rates. The primary comparison was between administration of ICS in addition to systemic corticosteroids (SCS) and to SCS alone. Secondary comparisons were ICS alone compared with SCS alone and ICS compared with placebo.
There were 25 studies involving 2733 participants. For the primary comparison, ICS in addition to SCS reduced the risk of hospital admission compared with SCS; fixed-effects odds ratio (95% confidence interval) 0.73 (0.57-0.94). Lung function was poorly reported. There was moderate evidence of an improvement in clinical scores and vital signs with ICS in addition to SCS. Relatively few studies reported adverse events.
There is moderate evidence that high doses of ICS, in addition to SCS, reduce the risk of hospital admission in ED treatment of moderate-to-severe asthma exacerbations. Further research is required to determine their optimal role in both ED and outpatient settings.
Asthma Exacerbations: Pathogenesis, Prevention, and Treatment
2017, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
The administration of high-dose ICS for asthma exacerbations should be reserved for patients with mild or intermittent asthma and those unable to tolerate OCS because of side effects such as diabetes or psychiatric effects. A systematic review analyzed 8 studies comparing the efficacy of ICS with placebo in acute asthma exacerbations and found that ICS appeared superior to placebo, especially when given at high doses, that is, >1 mg of budesonide or fluticasone.123 However, patients in these studies were heterogeneous in severity, ICS dose and administration frequency, and outcomes measured.
Guideline-based management of asthma focuses on disease severity and choosing the appropriate medical therapy to control symptoms and reduce the risk of exacerbations. However, irrespective of asthma severity and often despite optimal medical therapy, patients may experience acute exacerbations of symptoms and a loss of disease control. Asthma exacerbations are most commonly triggered by viral respiratory infections, particularly with human rhinovirus. Given the importance of these events to asthma morbidity and health care costs, we will review common inciting factors for asthma exacerbations and approaches to prevent and treat these events.
Monoclonal antibody therapy for the treatment of asthma and chronic obstructive pulmonary disease with eosinophilic inflammation
2017, Pharmacology and Therapeutics
Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala® (mepolizumab; anti-interleukin [IL]-5) and Cinquair® (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils.
The efficacy of single-high dose inhaled corticosteroid versus oral prednisone treatment on exhaled leukotriene and 8-isoprostane levels in mild to moderate asthmatic children with asthma exacerbation
2016, Allergologia et Immunopathologia
Citation Excerpt :
Multiple factors may play a role in the clinical efficacy of high dose ICS. ICS can have two different effects on acute asthma patients: (1) the classic anti-inflammatory or genomic action, involving the modification of gene expression, occurring within hours or days; and (2) the non-genomic action, with a rapid onset in minutes, but of shorter duration.40 Kumar et al. showed that inhaled FP induced vasoconstriction in the airway mucosa within 30 min and was of short duration (90 min).41
The anti-inflammatory effect of high-dose inhaled corticosteroids (ICS) in children with asthma exacerbation is unknown. We aimed to investigate the efficacy of single-high dose ICS versus oral prednisone treatment followed by a course of six day high-dose ICS or oral prednisone (P) treatment on the concentrations of Cys-LTs and 8-isoprostane levels in the exhaled breath condensate (EBC) of children with asthma exacerbation.
Ninety-four children with moderate–severe asthma exacerbation were evaluated with asthma scores, peak expiratory flow rate (PEF), forced expiratory volume in first second (FEV1) and exhaled Cys-LT and 8-isoprostane levels before and after treatment. EBC was collected from 52 patients before and four hours after treatment with inhaled fluticasone propionate (FP) (4000 μg) or P and after six days of treatment with FP-1000 μg/day or P. Cys-LTs and 8-isoprostane concentrations were determined using a specific immunoassay kit.
Both single high-dose FP (n = 59) and p (n = 35) treatment resulted in a significant improvement in asthma score (p < 0.0001), PEF (p < 0.0001), and FEV1 (p < 0.0001). Cys-LT concentration in the EBC decreased significantly both after the initial treatment (p = 0.001), and at the end of the six-day period in the FP group (p < 0.0001). 8-Isoprostane concentration was lower only after six days of treatment with FP-1000 μg/day in the FP group (p = 0.023). There was a significant decrease in exhaled Cys-LTs after four hours (p = 0.012) and six days of P treatment (p = 0.018) in children with asthma exacerbation.
High-dose ICS treatment may be useful in the treatment of children with asthma exacerbation. The effects start as early as after four hours. The suppression of Cys-LTs production contributes to the early effects. Suppression of both Cys-LTs and oxidants may favourably contribute to the effects observed later.
Nebulized fluticasone propionate, a viable alternative to systemic route in the management of childhood moderate asthma attack: A double-blind, double-dummy study
2015, Respiratory Medicine
In this study, we compared the clinical and immunological efficacy of nebulized corticosteroid (CS) to systemic route during treatment of moderate asthma attack in children.
In this randomized, placebo-controlled, double-blind, double-dummy, prospective study, 81 children aged 12 months to 16 years experiencing asthma attack randomized into two treatment groups to receive, either; nebulized fluticasone propionate (n = 39, 2000 mcg/day) or oral methylprednisolone (n = 41, 1 mg/kg/day). Pulmonary index scores (PIS) were assessed at admission and at 1st, 4th, 8th, 12th, 24th, 48th hours, as well as, on day 7 and peak expiratory flow (PEF) at baseline and at the 7th day. Daily symptom and medication scores were recorded for all subjects. Immunological studies included phytohemagglutinin induced peripheral blood mononuclear cells culture supernatant for cytokine responses and CD4(+) CD25(+) FOXP3(+) T regulatory cell (T reg) percentage at baseline and day 7.
The changes in PIS and PEF were similar in both treatment groups, with a significant improvement in both values at the 7th day, when compared to baseline. In both groups, significant reductions in symptom and medication scores were observed during the treatment period with no significant difference between the groups. At day 7 of intervention, phytohemagglutinin induced IL-4 level was significantly decreased only in the nebulized group compared to baseline (p = 0.01). Evaluation of cytokine responses by means of fold increase (stimulated (S)/unstimulated (US) ratio) revealed a significant reduction in IL-4, IL-5 and IL-17 only in nebulized group (p = 0.01, 0.01, 0.02; respectively). The fold increase value of IL-5 was significantly lower at 7th day in nebulized group when compared to systemic one (p = 0.02). At 7th day, although in both treatment groups the percentage of T reg cells was suppressed, it remained significantly higher in the nebule one when compared to systemic route (p = 0.04).
In the management of moderate acute asthma attack, nebulized CS (2000 mcg daily) was found to be as effective as systemic route with regard to clinical improvement. In addition, immunological parameters were more in favor of nebulized route which may imply a salutary effect of local CS usage.

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Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

The author has no financial or other potential conflicts of interest.

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Chest

Original ResearchRapid Effects of Inhaled Corticosteroids in Acute Asthma: An Evidence-Based Evaluation

Background

Objective

Methods

Results

Conclusions

Section snippets

Genomic Effects of CS

Rapid Nongenomic Effects of CS

Materials and Methods

Results

Discussion

Am J Emerg Med

J Pediatr

Eur J Pharmacol

Cell

Control Clin Trials

Control Clin Trials

Ann Emerg Med

J Allergy Clin Immunol

Ann Emerg Med

J Pediatr

Chest

Lancet

Respir Med

J Pediatr

Acute asthma in adults: a review

Chest

Corticosteroids in the emergency department therapy of adult acute asthma treatment: an evidence-based evaluation

Chest

Early emergency department treatment of acute asthma with systemic corticosteroids

Cochrane Database of Systematic Reviews

How do corticosteroids work in asthma?

Ann Inter Med

Nongenomic actions of steroid hormones

Nat Rev Cell Biol

Early use of inhaled corticosteroids in the emergency department treatment of acute asthma

Cochrane Database of Systematic Review

Inhaled corticosteroids and leukotriene modifiers in the acute treatment of asthma exacerbations

Curr Opin Pulm Med

Correlations between the chemical structure and the pharmacological actions of the steroids

Endocrinology

Kinisch-experimentelle Utersuchungen uber den Einfluβ von Aldosteron auf Hamodynamik und Gerinnung: Z Kreisl

Forsch

Delayed genomic and acute nongenomic action of glucocorticosteroids in seasonal allergic rhinitis

Eur J Clin Invest

Original Research
Rapid Effects of Inhaled Corticosteroids in Acute Asthma: An Evidence-Based Evaluation