1. Acute severe asthma: recent advances
Vaidehi Kaza, Venkata Bandi and Kalpalatha K. Guntupalli
Purpose of review Introduction
Acute severe asthma is challenging to the clinician both in The spectrum of asthma presentation can range from
terms of recognition and appropriate treatment. About 30% mild to severe. At times it is a very difficult disease to
of these episodes need admission to the medical intensive treat. Asthmatic attacks can be managed in most patients
care unit with a mortality of 8%. Relapse rates vary from 7 to with intensification of baseline therapy. There is, how-
15% depending on how well the patient is managed. The ever, a subgroup of patients with acute severe asthma
purpose of this review is to discuss recent advances in (ASA) that do not respond to conventional therapy and
identification of risk factors, pathophysiology and progress rapidly to respiratory failure. ASA is a distinct
management of acute severe asthma. entity, and the identification of this subtype of asthma,
Recent findings differentiation from other conditions and appropriate
Although the exact mechanism for acute severe asthma is treatment is important. The purpose of the current
unclear, some that are implicated include inflammation, review is to identify the key concepts in the diagnosis,
airway remodeling and downregulation of b-receptors. pathology, management, outcome and prognosis of ASA.
None of the environmental factors have been clearly related
to the development of near fatal attacks. Genetic Epidemiology
polymorphisms have been associated with severe asthma. Based on the 2004 National Health Interview Survey
Lack of steroid responsiveness has been linked to severe sample, an estimated 30.2 million Americans, or 104.7 per
asthma attacks. Chemokines and basement membrane 1000 persons, have been diagnosed with asthma within
changes characteristic of severe asthma are reported in a their lifetime. The annual economic cost of asthma is
few studies. Lack of symptom perception in a certain group $16.1 billion [1]. With the implementation of guideline-
of patients with acute severe asthma leads to delayed based therapy (National Asthma Education and Preven-
interventions. Specific treatment modalities and ventilator tion Program and Global Initiative for Asthma), a rise in
management is reviewed. outpatient visits, fall in inpatient hospitalizations and
Summary improving outcomes is reported. Table 1 outlines the
Severe asthma is a phenotype of asthma with variable latest asthma mortality data.
pathology and clinical presentation. Early recognition and
timely intervention is needed to prevent significant mortality Severe refractory asthma causes increased morbidity,
and morbidity. leading to significant health and economic consequences.
A cross-sectional study from Europe estimated direct and
Keywords indirect costs of ASA, and found that the total annual cost
acute severe asthma, management of acute severe per patient for ASA was 4.8 times that of mild asthma [2].
asthma, phenotypes of asthma
Definition
Curr Opin Pulm Med 13:1–7. ß 2007 Lippincott Williams & Wilkins. There have been a number of national and international
guidelines and workshops that have attempted to define
Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Texas,
USA ASA, incorporating symptoms, signs, clinical presentation
Correspondence to Kalpalatha K. Guntupalli, MD, Professor of Medicine, and use of high-dose steroids [3,4]. The European
Pulmonary Critical Care Medicine, Baylor College of Medicine Houston, TX 77030, Respiratory Society Task Force has incorporated the
USA
Tel: +1 713 873 2468; fax: +1 713 790 9576; e-mail: kkg@bcm.edu common term ‘difficult/therapy-resistant asthma’ for all
such cases [5]. The features of difficult/therapy-resistant
Current Opinion in Pulmonary Medicine 2007, 13:1–7
asthma are outlined in Table 2.
Abbreviations
ASA acute severe asthma The American Thoracic Society sponsored an Expert
PEEP positive end expiratory pressure
Panel Workshop on ‘refractory asthma’ to identify
important issues in severe refractory asthma and devel-
ß 2007 Lippincott Williams & Wilkins
1070-5287
oped a consensus definition [6]. The American Thoracic
Society definition is based on a combination of major and
minor criteria. It aims to identify subjects with
inadequate asthma control despite appropriate treatment
with corticosteroids – the true patient with refractory
1
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2. 2 Asthma
Table 1 Asthma death rates (modified from [1]) Factors contributing to severe asthma
Number of deaths in 2003 4009 Significant risk factors affecting the severity in asthma are
Gender-specific death rates females > males (1.8 : 1) discussed below.
Ethnicity and death rates African American 2.7
per 100 000
white 1.2 Environmental exposure
Hispanic 1.3 Allergen exposure is an important environmental risk
Mortality in 1999 1.7 factor for asthma development and exacerbation. Atopy
Mortality in 2003 1.4
Reduction in mortality 12% decrease compared is considered a risk factor for severe asthma in childhood.
to 1999 The European Network for Understanding Mechanisms
for Severe Asthma has shown that in contrast to children,
Table 2 European Respiratory Society Task Force definition for atopy may be a less important factor in adult asthma
‘difficult/therapy-resistant asthma’ (modified from [5]) patients [10]. Thirty-five percent of adult patients pre-
1. Poorly controlled with chronic symptoms senting to the emergency room with asthma exacerbation
2. Episodic exacerbations are current smokers. Cigarette smoking can decrease
3. Persistent and variable airways obstruction responsiveness to steroids and worsen asthma control
4. Continued requirement for short acting b2-agonists despite
inhaled corticosteroids [11]. Persistence of infectious agents such as Mycoplasma
5. Requiring courses or regular doses of oral corticosteroids for [12] and Chlamydia may play a role in worsening of asthma
control of asthma control. Ten Brinke et al. [13], from a cross-sectional
6. Asthma control uninfluenced by corticosteroid therapy
7. Diagnosis reconfirmed, features of difficult to treat and study, theorize that recurrent or chronic infection with
adherence to therapy are reconfirmed Chlamydiae pneumoniae might promote persistent airflow
limitation in adult nonatopic asthmatic patients.
asthma. Using this definition, subjects with severe refrac- Exposure to Alternaria spores has been identified as a
tory asthma must meet one of two major criteria as well as cause of ASA attacks in young patients with asthma [14].
two of seven minor criteria (see Table 3). Exposure to air pollutants can contribute to severe
asthma. Late-onset severe asthma and worsening of
Physiology of severe asthma asthma in an adult patient should raise the suspicion of
Refractory asthma encompasses a wide variation in occupational asthma which requires additional diagnostic
clinical symptoms and natural history. Some patients testing [15,16]. Aspirin intolerance was an important risk
have highly labile disease, with wide swings in peak factor in the European Network for Understanding
flows and rapid decompensation due to known or Mechanisms for Severe Asthma study. Patients with
unknown stimuli, while others are more chronically aspirin-intolerant asthma usually respond well to treat-
and severely obstructed [7,8]. The mechanisms interfer- ment with cysteinyl leukotriene receptor antagonists
ing with adequate bronchodilator response in patients such as montelukast [17].
with ASA are not clear; however, some interesting con-
cepts include ‘irreversibility’ of airflow obstruction due to Genetic factors
factors such as downregulation of b-receptors, inflam- Genetic polymorphisms are associated with severity of
mation and airway remodeling [9]. asthma. Interleukin-4 is a major cytokine responsible for
B cell class switching from IgM to IgE. The interleukin-4
Table 3 American Thoracic Society severe refractory asthma gene is linked to the IgE level. The IL4Ã-589T allele was
definition (modified from [6]) noted to be a risk factor for life-threatening asthma and
Major characteristics the IL4RAÃ576R allele a risk factor for decreased lung
In order to achieve control to a level of mild–moderate function in asthmatics [18]. Transforming growth factor-
persistent asthma b1 has been implicated in subepithelial fibrosis and
1. Treatment with continuous or near continuous
(greater than 50% of year) oral corticosteroids airway remodeling in ASA. Polymorphisms in the trans-
2. Requirement of high-dose inhaled steroids forming growth factor-b1 candidate gene were found to
Minor characteristics be related to asthma severity [19]. Genetics can deter-
1. Requirement for daily treatment with a controller medication
in addition to inhaled corticosteroids mine response to standard medications. A retrospective
2. Asthma symptoms requiring short-acting b-agonist use genotype-stratified study found that the B16-Arg/Arg
on a daily or near-daily basis allele at the 16th amino acid residue of the b2-adrenergic
3. Persistent airway obstruction (FEV1 < 80% predicted;
diurnal peak expiratory flow > 20%) receptor is associated with deterioration in pulmonary
4. One or more urgent care visit for asthma per year function with routine use of b-agonist medication [20]. A
5. Three or more oral steroid ‘bursts’ per year genotype-stratified randomized, placebo-controlled,
6. Prompt deterioration with less than 20% reduction in
oral or inhaled corticosteroid dose crossover trial in patients with mild asthma confirmed
7. Near-fatal asthma event in the past the above findings. The authors recommend devising
Definition of refractory asthma requires one or both major criteria and two and testing alternate asthma management strategies that
minor criteria. limit b-agonist use in the Arg/Arg genotype [21]. The
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3. Acute severe asthma Kaza et al. 3
Table 4 Chromosomes linked to inflammation in asthma [26] cystic fibrosis – conditions that will not respond to
Chromosome 5q31 modulate interleukin-4, -5 and -13, steroids. Significant variability to inhaled corticosteroid
and granulocyte macrophage responsiveness is noticed in patients with moderate
colony stimulating factor
Chromosome 6 major histocompatibility complex
persistent asthma [30]. FEV1 predicted, blood and
class I and II genes; expression sputum eosinophil levels prior to inhaled corticosteroids,
of tumor necrosis factor-a and higher response rate to short-acting bronchodilators
Chromosome 13q14 contains major atopy locus, linked to are factors associated with responsiveness to inhaled
total serum IgA levels
corticosteroids [31]. Glucocorticoids exert their effects
by binding to glucocorticoid receptor and translocating to
ADAM33 gene on chromosome 20p13 was identified as a the nucleus. Nocturnal asthma is associated with
susceptibility gene for asthma and is also implicated in decreased glucocorticoid receptor binding affinity at
chronic obstructive lung disease. ADAM33 protein night [32]. Glucocorticoid receptor abnormalities are a
levels correlate inversely with the FEV1-predicted and possible mechanism for glucocorticoid-insensitive
soluble ADAM33 levels increase in bronchoalveolar asthma. Reversible cytokine-induced reduction in glu-
lavage fluid significantly in proportion to asthma severity cocorticoid receptor binding affinity and reduction in
[22]. Tumor necrosis factor-a expression in the airway glucocorticoid receptor number are some of the proposed
was related to severity of asthma [23,24]. The levels of mechanisms for glucocorticoid insensitivity [33].
expression of the tumor necrosis factor-a gene and protein
were higher in patients with refractory asthma than in the Pathobiology of acute severe asthma
airways of control subjects or patients with mild asthma. The airway remodelling that occurs due to various
Treatment with the tumor necrosis factor-a antagonist chemokines has been studied extensively. A few of them
etanercept was shown to improve bronchial hyperrespon- are reviewed below.
siveness, FEV1 and asthma-related quality-of-life scores
[23,25]. Chromosomes linked to inflammatory responses Chemokines in severe asthma
seen in asthma are outlined in Table 4 [26]. Chemokines, especially eotaxin and the monocyte che-
moattractant proteins, are potent eosinophil chemoattrac-
Other risk factors for severe asthma tants that are important in severe asthma [34]. Increased
Risk factors for death from asthma are elaborated in expression of interleukin-11 by bronchial mucosa and
Table 5 [4,27,28]. airway epithelial cells is associated with structural remo-
deling and increasing severity of asthma [35]. Airways of
Corticosteroid responsiveness in severe asthma patients with severe asthma reveal infiltration by neu-
Corticosteroid-resistant asthma is defined as a failure to trophils, eosinophils, degranulated mast cells, sub-base-
improve lung function by more than 15% after treatment ment membrane thickening, loss of epithelial cell integ-
with high doses of prednisolone (30–40 mg daily) for rity and occlusion of the bronchial lumen by mucus.
2 weeks [29]. In addition, it is important to establish the Hyperplasia and hypertrophy of bronchial smooth muscle
diagnosis of asthma and exclude other causes, such as and hyperplasia of goblet cells were also present [36].
vocal cord dysfunction, congestive heart failure and
Airway remodeling in severe asthma
Table 5 Risk factors for death in patients with acute severe Pathologic studies of endobronchial biopsies of patients
asthma (modified from [4,27,28])
with asthma have demonstrated wide variability. No
1. History of sudden severe exacerbations difference was noted in subepithelial basement mem-
2. Prior asthma exacerbation requiring intubation and mechanical
ventilation brane thickness among patients with mild asthma as
3. Prior admission to intensive care unit compared to those with severe asthma [37]. Collagen
4. Two or more hospitalizations for asthma exacerbations in the deposition in large airway biopsies of mild, moderate
past year
5. Three or more emergency care visits for asthma exacerbation and severe asthmatics, as well as normal control subjects,
in the past year was evaluated to determine if the amount of collagen
6. Hospitalization or emergency care visit for asthma within the deposition increased among asthma patients of increasing
past month
7. Use of more than two canisters per month of inhaled short severity. Although these results confirmed thickening of
acting b2-agonist the subepithelial basement membrane in asthmatics
8. Current use or recent withdrawal from systemic corticosteroids compared with normal subjects, no significant differences
9. Difficulty perceiving airflow obstruction or its severity
10. Other comorbidity; cardiovascular, chronic obstructive in collagen deposition between very severe and milder
pulmonary disease forms of asthma existed, suggesting that, at the level of
11. Psychological problems or psychiatric disease the large airway, the amount of collagen deposition may
12. Low socioeconomic status
13. Urban/inner-city residence not predict the clinical severity of disease. A similar study
14. Illicit drug use analyzing asthmatic subjects of varying age group and
15. Sensitivity to Alternaria duration has shown that there is no association between
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4. 4 Asthma
Table 6 Clinical characteristics based on eosinophils in the presence is, however, associated with an increase in
airway [40] transforming growth factor-b cells, matrix metallopro-
Eosinophils Eosinophils teinase-9 in bronchoalveolar lavage fluid and tissue
present absent
basement membrane, as well as lower lung function
Sub-basement membrane thickened thin [41].
Subepithelial fibrosis present absent
Airway collapse higher lower
(loss of elastic recoil)
Phenotypes of severe asthma based on clinical presen-
Respiratory failure high low tation are provided in Table 7.
Clinical evaluation
subepithelial basement membrane thickness and age of Clinical evaluation of severe asthma involves prompt
onset or duration of asthma [38]. identification of the symptoms, physical signs and early
diagnostic evaluation.
Phenotypes in asthma
Duration of asthma and the cell subtypes contibuting to Symptoms
the pathogenesis of asthma severity are the key determi- Common symptoms of severe asthma are dyspnea, cough
nants of the phenotypes described as below. and wheezing; however, the presentation is variable.
Dyspnea is absent in about 18% of cases [42]. Wheezing
Early- and late-onset asthma is a poor indicator of functional impairment. It often
Development of asthma may be early in childhood or late increases or decreases as the obstruction varies [43].
in adulthood. Early- and late-onset asthmatic groups Symptom perception is also highly variable. There is a
differ in their allergic responses, with higher positive certain subset of asthmatics that have poor perception of
skin tests in the early-onset group. Symptom perception symptoms despite severe airway obstruction at presen-
along with lung function was worse in late-onset asthma. tation [28,44].
Finally, the early-onset asthma group had higher periph-
eral eosinophils, while the late-onset group had higher Physical signs
lymphocytes [39]. The physical signs encountered are tachypnea, tachycar-
dia, wheeze, hyperinflation, accessory muscle use, pulsus
Phenotypes based on the presence or absence of paradoxus, diaphoresis, cyanosis and obtundation. The
airway eosinophils presence of these signs is also highly variable [42].
The majority of patients with severe asthma have eosi-
nophils in the airways. These patients have increased Diagnostic tests
numbers of CD3þ, CD4þ and CD8þ T cells, and a higher An episode of acute asthma is characterized by hyperin-
number of exacerbations and near fatal events [40]. flation of the lungs on chest radiography. In addition,
Table 6 summarizes clinical characteristics based on there is abnormal distribution of ventilation, perfusion
eosinophil presence in the airway [40]. and altered gas exchange [40]. Abnormalities in pulmon-
ary function tests include markedly decreased FEV1 or
Neutrophilic phenotypes the peak expiratory flow rate. Hyperinflation increases
In certain other phenotypes, there is neutrophilia along the work of breathing. As dynamic hyperinflation
with eosinophilia. The mechanisms or the clinical increases, auto positive end expiratory pressure (PEEP)
implications for neutrophilia are not always clear. Their increases.
At some point, deflation can no longer remain passive and
Table 7 Phenotypes of acute severe asthma based on clinical the expiratory muscles are actively engaged in achieving
presentation [61] expiration. Ultimately, the accessory muscles of respir-
Type1 Type 2 (sudden ation also become active. Blood gas analyses reveal
(Slow progressive) asphyxic asthma) respiratory alkalosis, hypoxemia and hypocarbia. Typical
Duration of prolonged, slow rapid onset of asthma attacks are not characterized by hypoxemia and
symptoms onset and late arrival symptoms ad sudden marked arterial desaturations. Hypercarbia occurs in 10%
for medical care deterioration of cases needing emergency care. Hypercapnic patients
Prevalence 80–85% 15–20%
Airway excess mucus empty airways have greater airway obstruction, respiratory rate and
secretions plugging pulsus paradoxus than non-hypercapnic patients [42].
Perception of early late Findings of a quiet chest on auscultation, inability to
symptoms
Inflammation eosinophils neutrophils talk and cyanosis suggest the presence of hypercapnia.
Response to slow rapid Normocarbia should also be viewed as impending respir-
treatment atory failure that should be treated aggressively.
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5. Acute severe asthma Kaza et al. 5
Table 8 Differential diagnosis of acute severe asthma (modified Anticholinergics
from [5]) Acetylcholine stimulates muscarinic receptors M1–M3
1. Obliterative bronchiolitis leading to bronchoconstriction and mucus hypersecretion
2. Vocal cord dysfunction
3. Cystic fibrosis
[49]. An increase in M1 or M3 receptor activity and a
4. Bronchiectasis reduction in M2 activity lead to bronchoconstriction. M2
5. Endobronchial lesion receptors are impaired in acute asthma by eosinophil
6. Inhaled foreign body major basic protein, reactive oxygen radicals and neur-
7. Recurrent aspiration
8. Intermittent congestive heart failure aminidases. The available anticholinergics have slow
9. Tracheobronchomalacia onset of action and are used as second-line agents,
10. Upper airway obstruction
11. Allergic bronchopulmonary aspergillosis
especially in those patients with resistance to b2-agonists
12. Pulmonary eosinophilic syndromes [42]. Their role in severe asthma is not clear and needs
further assessment. A recent meta-analysis failed to sup-
port the use of ipratropium in ASA [42].
Differential diagnosis Methylxanthines
Differential diagnosis of ASA is outlined in Table 8. The current data does not support routine use of methyl-
xanthines (aminophylline and theophylline) in ASA [50].
Mortality and morbidity from acute severe
asthma Corticosteroids
The critical component of ASA is rapid assessment of the Corticosteroids are the main stay of treatment of severe
patient. It is essential to monitor progress with objective asthma. A meta-analysis of randomized control trials on
testing. Ignoring assessment of severity of obstruction or the effects of early emergency department treatment
relying excessively on gas exchange leads to poor out- with systemic corticosteroids reported improved lung
come [42]. Deaths from ASA are higher in African Amer- function and reduced admissions [51]. There is no
icans compared to whites [1,45]. Deaths from acute reported difference between the use of intravenous
episodes are rare and are associated with the phenotype and oral steroids [52]. As many as 25% of patients with
of rapidly fatal disease. These events usually occur at difficult-to-control asthma may be ‘steroid resistant’ [53].
work or home where there is little time to prevent any This is defined as a failure to improve morning pre-
rapid decline in clinical course. Deaths due to ASA were bronchodilator FEV1 15% after 14 days of 30–40 mg
12% lower in 2004 than 1999 [1]. of prednisone in association with the presence of a
significant bronchodilator response [53].
Management of acute severe asthma
The initial step in the management of these patients is to Heliox
stabilize them as rapidly as possible, ensure adequate Heliox, a blend of helium (80%) and oxygen (20%),
oxygenation and minimize side-effects. After the acute reduces the work of breathing and improves ventilation
episode resolves, the residual deficits can be addressed by reducing turbulent airflow [54]. Heliox-driven aero-
with appropriate outpatient regimens. On discharge, solized nebulization has a better deposition pattern [55].
objective monitoring of lung function, a written action The effects of heliox are, however, transient. Two recent
plan with clear instructions and a review of medications systematic reviews did not find enough evidence to
with instructions on their use is required [4]. Follow-up recommend its routine use in emergency department
with a primary care provider within 1 week is highly for ASA [56,57].
desirable.
Magnesium sulfate
Specific treatments A systematic review of the use of magnesium sulfate
The reader is referred to the National Institutes of Health published in 2000 failed to find evidence to support its
Global Initiative for Asthma guidelines, which clearly routine use for ASA [58].
outline management plans for monitoring as well as
treatment of the acute exacerbations [3]. Mechanical ventilation
Progressive exhaustion and patient fatigue despite
b-Agonists maximal therapy together with or without altered level
Short-acting b2-adrenergic agonists are the first line of of consciousness are indications for intubation. Noninva-
action. They have rapid onset of action, and provide more sive ventilation has been tried in small clinical trials with
bronchodilatation than methylxanthines and anticholi- some success. Further, larger studies are needed before
nergics [42,46]. Albuterol is a racemic mixture containing noninvasive ventilation can be recommended routinely
equal quantities of (R)- and (S)-isomers, with (R)-albu- in the management of ASA with respiratory fatigue.
terol providing the greatest bronchodilation [47,48]. Noninvasive ventilation can be used with caution and
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6. 6 Asthma
10 European Network for Understanding Mechanisms of Severe Asthma. The
that decision should not delay intubation, if one is ENFUMOSA cross-sectional European multicentre study of the clinical
required immediately [59]. The main aim of mechanical phenotype of chronic severe asthma. Eur Respir J 2003; 22:470–477.
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asthmatic adults presenting to 64 emergency departments. Chest 2003;
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and auto PEEP are crucial to the ventilatory management 12 Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae
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13 Ten Brinke A, Van Dissel JT, Sterk PJ, et al. Persistent airflow limitation in adult-
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and hyperventilation [60]. In patients who are spon- 14 O’Hollaren MT, Yunginger JW, Offord KP, et al. Exposure to an aeroallergen
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