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1. Acute severe asthma: recent advancesVaidehi 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 . 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 . asthma, phenotypes of asthma DeﬁnitionCurr 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 deﬁnePulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Texas,USA ASA, incorporating symptoms, signs, clinical presentationCorrespondence to Kalpalatha K. Guntupalli, MD, Professor of Medicine, and use of high-dose steroids [3,4]. The EuropeanPulmonary Critical Care Medicine, Baylor College of Medicine Houston, TX 77030, Respiratory Society Task Force has incorporated theUSATel: +1 713 873 2468; fax: +1 713 790 9576; e-mail: email@example.com common term ‘difﬁcult/therapy-resistant asthma’ for all such cases . The features of difﬁcult/therapy-resistantCurrent Opinion in Pulmonary Medicine 2007, 13:1–7 asthma are outlined in Table 2.AbbreviationsASA acute severe asthma The American Thoracic Society sponsored an ExpertPEEP positive end expiratory pressure Panel Workshop on ‘refractory asthma’ to identify important issues in severe refractory asthma and devel-ß 2007 Lippincott Williams & Wilkins1070-5287 oped a consensus deﬁnition . 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 1Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2 Asthma Table 1 Asthma death rates (modiﬁed from ) 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 ) patients . 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 . Persistence of infectious agents such as Mycoplasma 5. Requiring courses or regular doses of oral corticosteroids for  and Chlamydia may play a role in worsening of asthma control of asthma control. Ten Brinke et al. , 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 . 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 . 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 . 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 ) 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 . 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 . 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 . 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 . TheCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acute severe asthma Kaza et al. 3Table 4 Chromosomes linked to inﬂammation in asthma  cystic ﬁbrosis – conditions that will not respond toChromosome 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 factorChromosome 6 major histocompatibility complex persistent asthma . 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 bronchodilatorsChromosome 13q14 contains major atopy locus, linked to are factors associated with responsiveness to inhaled total serum IgA levels corticosteroids . Glucocorticoids exert their effects by binding to glucocorticoid receptor and translocating toADAM33 gene on chromosome 20p13 was identiﬁed as a the nucleus. Nocturnal asthma is associated withsusceptibility gene for asthma and is also implicated in decreased glucocorticoid receptor binding afﬁnity atchronic obstructive lung disease. ADAM33 protein night . Glucocorticoid receptor abnormalities are alevels correlate inversely with the FEV1-predicted and possible mechanism for glucocorticoid-insensitivesoluble 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. Tumor necrosis factor-a expression in the airway glucocorticoid receptor number are some of the proposedwas related to severity of asthma [23,24]. The levels of mechanisms for glucocorticoid insensitivity .expression of the tumor necrosis factor-a gene and proteinwere higher in patients with refractory asthma than in the Pathobiology of acute severe asthmaairways of control subjects or patients with mild asthma. The airway remodelling that occurs due to variousTreatment with the tumor necrosis factor-a antagonist chemokines has been studied extensively. A few of themetanercept 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 asthmaseen in asthma are outlined in Table 4 . 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 . IncreasedRisk factors for death from asthma are elaborated in expression of interleukin-11 by bronchial mucosa andTable 5 [4,27,28]. airway epithelial cells is associated with structural remo- deling and increasing severity of asthma . Airways ofCorticosteroid 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 . In addition, it is important to establish the Hyperplasia and hypertrophy of bronchial smooth musclediagnosis of asthma and exclude other causes, such as and hyperplasia of goblet cells were also present .vocal cord dysfunction, congestive heart failure and Airway remodeling in severe asthmaTable 5 Risk factors for death in patients with acute severe Pathologic studies of endobronchial biopsies of patientsasthma (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 . 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 severity10. Other comorbidity; cardiovascular, chronic obstructive in collagen deposition between very severe and milder pulmonary disease forms of asthma existed, suggesting that, at the level of11. Psychological problems or psychiatric disease the large airway, the amount of collagen deposition may12. Low socioeconomic status13. Urban/inner-city residence not predict the clinical severity of disease. A similar study14. Illicit drug use analyzing asthmatic subjects of varying age group and15. Sensitivity to Alternaria duration has shown that there is no association betweenCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
4 Asthma Table 6 Clinical characteristics based on eosinophils in the presence is, however, associated with an increase in airway  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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . and altered gas exchange . 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  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 . 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.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
Acute severe asthma Kaza et al. 5Table 8 Differential diagnosis of acute severe asthma (modiﬁed Anticholinergicsfrom ) Acetylcholine stimulates muscarinic receptors M1–M3 1. Obliterative bronchiolitis leading to bronchoconstriction and mucus hypersecretion 2. Vocal cord dysfunction 3. Cystic ﬁbrosis . 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 obstruction11. Allergic bronchopulmonary aspergillosis especially in those patients with resistance to b2-agonists12. Pulmonary eosinophilic syndromes . 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 .Differential diagnosis MethylxanthinesDifferential diagnosis of ASA is outlined in Table 8. The current data does not support routine use of methyl- xanthines (aminophylline and theophylline) in ASA .Mortality and morbidity from acute severeasthma CorticosteroidsThe critical component of ASA is rapid assessment of the Corticosteroids are the main stay of treatment of severepatient. It is essential to monitor progress with objective asthma. A meta-analysis of randomized control trials ontesting. Ignoring assessment of severity of obstruction or the effects of early emergency department treatmentrelying excessively on gas exchange leads to poor out- with systemic corticosteroids reported improved lungcome . Deaths from ASA are higher in African Amer- function and reduced admissions . There is noicans compared to whites [1,45]. Deaths from acute reported difference between the use of intravenousepisodes are rare and are associated with the phenotype and oral steroids . As many as 25% of patients withof rapidly fatal disease. These events usually occur at difﬁcult-to-control asthma may be ‘steroid resistant’ .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 mg12% lower in 2004 than 1999 . of prednisone in association with the presence of a signiﬁcant bronchodilator response .Management of acute severe asthmaThe initial step in the management of these patients is to Helioxstabilize 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 ventilationepisode resolves, the residual deﬁcits can be addressed by reducing turbulent airﬂow . Heliox-driven aero-with appropriate outpatient regimens. On discharge, solized nebulization has a better deposition pattern .objective monitoring of lung function, a written action The effects of heliox are, however, transient. Two recentplan with clear instructions and a review of medications systematic reviews did not ﬁnd enough evidence towith instructions on their use is required . Follow-up recommend its routine use in emergency departmentwith a primary care provider within 1 week is highly for ASA [56,57].desirable. Magnesium sulfateSpeciﬁc treatments A systematic review of the use of magnesium sulfateThe reader is referred to the National Institutes of Health published in 2000 failed to ﬁnd evidence to support itsGlobal Initiative for Asthma guidelines, which clearly routine use for ASA .outline management plans for monitoring as well astreatment of the acute exacerbations . Mechanical ventilation Progressive exhaustion and patient fatigue despiteb-Agonists maximal therapy together with or without altered levelShort-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 withbronchodilatation than methylxanthines and anticholi- some success. Further, larger studies are needed beforenergics [42,46]. Albuterol is a racemic mixture containing noninvasive ventilation can be recommended routinelyequal 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 andCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
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 . The main aim of mechanical phenotype of chronic severe asthma. Eur Respir J 2003; 22:470–477. ventilation is to support gas exchange until bronchodila- 11 Silverman RA, Boudreaux ED, Woodruff PG, et al. Cigarette smoking among asthmatic adults presenting to 64 emergency departments. Chest 2003; tors and steroids improve airﬂow. Avoiding hyperinﬂation 123:1472–1479. and auto PEEP are crucial to the ventilatory management 12 Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae of ASA. The volume-controlled mode is the preferred in the airways of adults with chronic asthma. Am J Respir Crit Care Med 1998; 158:998–1001. mode of ventilation. Pressure control is not an ideal mode 13 Ten Brinke A, Van Dissel JT, Sterk PJ, et al. Persistent airﬂow limitation in adult- for ASA due to ﬂuctuations in airway resistance and auto onset nonatopic asthma is associated with serologic evidence of Chlamydia PEEP levels, leading to variable tidal volumes, and hypo- pneumoniae infection. J Allergy Clin Immunol 2001; 107:449–454. and hyperventilation . In patients who are spon- 14 O’Hollaren MT, Yunginger JW, Offord KP, et al. Exposure to an aeroallergen as a possible precipitating factor in respiratory arrest in young patients with taneously breathing, addition of extrinsic PEEP improves asthma. N Engl J Med 1991; 324:359–363. patient ventilator synchrony and trigger sensitivity. 15 Malo JL. Asthma may be more severe if it is work-related. Am J Respir Crit Care Weaning in patients with asthma can be started once Med 2005; 172:406–407. the hyperinﬂation has resolved and the intrinsic PEEP is 16 Le MN, Siroux V, Pin I, et al. Asthma severity and exposure to occupational asthmogens. Am J Respir Crit Care Med 2005; 172:440–445. less than 5 cm. Weaning is usually rapid . Difﬁcult 17 Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin- weaning should raise the suspicion of myopathy from intolerant asthma by montelukast, a leukotriene antagonist: a randomized, corticosteroids or concomitant use of neuromuscular double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165:9–14. blocking agents. The mortality of ASA requiring intuba- 18 Sandford AJ, Chagani T, Zhu S, et al. Polymorphisms in the IL4, IL4RA, tion and mechanical ventilation has improved over the and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000; 106 past two decades, in large part due to improvements in (1 Pt 1):135–140. ventilatory management and care in the intensive care 19 Pulleyn LJ, Newton R, Adcock IM, Barnes PJ. TGFbeta1 allele association with asthma severity. Hum Genet 2001; 109:623–627. unit. There is also signiﬁcant reduction in barotrauma 20 Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the related to mechanical ventilation. beta2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162:75–80. Conclusion 21 Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratiﬁed, randomised, placebo-controlled Severe asthma has the potential to result in fatality if cross-over trial. Lancet 2004; 364:1505–1512. untreated and unrecognized. The various phenotypes 22 Holgate ST, Yang Y, Haitchi HM, et al. The genetics of asthma: ADAM33 as an for severe asthma need to be understood to make a example of a susceptibility gene. Proc Am Thorac Soc 2006; 3:440–443. 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