(Chest. 2003;123:405S-410S.)
© 2003
American College of Chest Physicians
Severe/Fatal Asthma*
Sally Wenzel, MD, FCCP
* From the National Jewish Medical and Research Center, Denver, CO.
Correspondence to: Sally Wenzel, MD, FCCP, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: wenzels{at}njc.org
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Abstract
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Severe asthma is poorly understood clinically, physiologically, and pathologically. While milder forms of asthma are generally easily treated, more severe forms often remain refractory to the best current medical care. Although some patients with severe asthma have had severe disease for most of their lives, there appears to be a second group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental elements may be the most important in the development of severe disease. Physiologically, these patients often have airtrapping and may have loss of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, distal disease, and, in at least one third of patients, a different pathology. Treatment remains problematic and likely will remain so until a better understanding of this disease develops.
Key Words: asthma • inflammation • phenotypes • physiology • remodeling • treatment
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Introduction
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Severe or refractory asthma afflicts a small percentage (likely < 5%) of the population of patients who have asthma. However, as these patients remain difficult to treat and prone to severe exacerbations, they contribute disproportionately to the overall costs of asthma. The introduction of high-potency inhaled corticosteroids (CS) had a marked impact on the numbers of patients who were dependent on therapy with oral CS. However, beyond those medications, little further progress has been made in understanding the disease and improving its treatment.
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Definitions
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Severe persistent asthma has been defined in guidelines, but the definitions have been somewhat limited in scope and difficult to apply. Severe or "refractory" asthma was given a working definition by the workshop sponsored by the American Thoracic Society, the proceedings of which were published in 2000.1
This definition included one of two major criteria (ie, continuous high-dose inhaled CS or oral CS for > 50% of the previous year), with two of seven additional minor criteria required for diagnosis. The minor criteria included aspects of lung function, exacerbations, disease stability, and amount of additional medications. Patients also must have had compliance and exacerbating factors fully addressed. Although these definitions are a start (the author of this article was the chair of that workshop), the list of criteria still may not be definitive. For instance, it is not clear whether a stable patient with symptoms of asthma who is receiving therapy with a fluticasone/salmeterol combination (500/50) and has an FEV1 of 78% predicted truly has refractory asthma. Yet, the current definition would include that patient. Expanding the minor criteria requirements to three would likely improve the capture of those who fulfill the "spirit" of the definition, rather than the "letter" of the definition.
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Epidemiology
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Surprisingly little is known about the development of severe asthma. Do most patients with severe asthma have a life-altering event in childhood that irreversibly alters their lungs, from which they will never recover, or do they slowly but steadily decline over the years? Did those patients with a history of adult-onset disease actually have some level of asthma as children that was ignored, or do they have a more rapid decline in function once the asthma begins? None of these questions has been answered satisfactorily. Some information has come from the large cohort of asthma patients studied in Melbourne, Australia, which has been followed for 35 years.2
Those data suggest that if a person has reduced lung function in childhood, that person is likely to have reduced lung function in adulthood, as well, but that there is little "progressive decline" of the mean data. Interestingly, two studies3
4
from Europe have suggested that late-onset asthma is associated with a more rapid decline in lung function. In the database of > 100 patients with severe asthma who were seen at National Jewish Medical and Research Center (Denver, CO), approximately two thirds of patients had onset in childhood, and the remaining one third experienced onset after the age of 20 years.5
Whether there are distinct phenotypic differences in adult-onset vs childhood-onset asthma or severe asthma is not known.
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Risk Factors
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As is the case for many diseases, risk factors can be divided into genetic and environmental. Unfortunately, asthma itself is a disease involving multiple genes. Severe asthma is not likely to be different and is less well-studied. There are reports6
7
of relevant mutations in both the interleukin-4 gene or the interleukin-4 receptor, some of which have been linked to loss of lung function, and others to near-fatal events. Interestingly, two non-T helper (Th) type 2 factors also have been associated with severity of asthma, transforming growth factor (TGF)-ß1 and monocyte chemotactic protein-1, both of which can promote fibrotic reactions.8
9
Whether mutations of the receptors for the primary treatments for asthma (ß2 and glucocorticoid receptors [GRs]) decrease responsiveness to medications and influence outcomes is not yet clear.
Environmental factors include both allergen and tobacco exposure, with the strongest data for house dust mite, cockroach, and Alternaria exposures.10
11
12
Additionally, many patients will continue to smoke or own a cat despite being aware of the negative effects.13
Infection also may contribute to severe disease, with respiratory syncytial virus infections implicated in childhood, while pathogens like Mycoplasma and Chlamydia may play a role in adults.4
Although not precisely "environmental," additional "lung-external" factors may include obesity, gastroesophageal reflux disease, and chronic sinusitis. A large-scale epidemiologic study14
of patients with severe/difficult-to-treat asthma suggested that body mass index increases with increasing severity of disease and that 76% of that cohort of patients with severe disease were either overweight or obese. However, similar to gastroesophageal reflux disease and chronic sinusitis, the relationship of effective treatment of obesity to severity of disease is not clear.
Certainly another external factor related to severity of disease is compliance/adherence to medications. Studies15
have suggested that in children and adolescents instability of disease is related to adherence to therapy with CS. However, there are other patients in whom the current medications do not effectively treat the disease. In those patients, adherence to medication may be influenced by lack of responsiveness to medication, but further study is required in the population of patients with severe disease to determine the proportions of each. If the patient is receiving therapy with oral CS, the early-morning measurement of cortisol level can be helpful in determining compliance. If concern remains, then treatment trials with injectable long-acting steroids, such as depomethylprednisolone or triamcinolone, can be informative.16
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Physiologic Aspects
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Although the classic measure of airflow limitation, FEV1, has been commonly used to indicate the presence of severe disease, it is becoming clear that the correlation between FEV1 and disease symptoms is poor, at best.17
While airflow limitation is clearly part of the physiologic changes of severe asthma, it is likely to be only part of the picture. One prevalent theory regarding severe asthma is that it develops due to a progressive increase in airflow limitation, which is often presumed to be irreversible. Although this may be true in some patients, others may have severe airflow limitation at presentation, while others, primarily adults, may develop a more rapid decline in lung function over a 
10-year period of time.4
Finally, it is not clear whether these changes are truly irreversible. There may be irreversibility to current aggressive medical management, but that does not necessarily mean the lungs are in a fixed fibrotic state.
Changes in airway reactivity also play a role in the severity of asthma, but the correlations of a provocative concentration of a substance causing a 20% fall in FEV1 with disease severity, although present, are poor as well.18
Increased airway reactivity likely relates to the stability of airflow, and hence to variability in peak flow/FEV1. This instability may be an important aspect to the symptomatology of a subgroup of patients with severe asthma, in whom continuous airflow limitation may play a more minor role.19
As FEV1 and airway reactivity changes do not adequately explain disease severity, it is conceivable that other physiologic factors, such as changes in elastic recoil and/or small airway physiology, are also important. For years, it has been observed20
21
that the elastic recoil properties of the lung in asthma patients are not normal. It has been reported22
that general compliance is increased in patients with moderate persistent asthma. However, the precise pathologic mechanism behind the change is not clear. There are also suggestions that the airways (in addition to the parenchyma) may be more collapsible than are the airways in healthy individuals. The FVC/slow vital capacity ratio appeared to be decreased in a group of patients with severe asthma who had persistent eosinophilia.23
Those asthma patients also appear to be at a higher risk of near-fatal events than those with a more normal (1:1) ratio.
Various measures of small airway physiology have been developed. Unfortunately, there are no comprehensive studies of small airway physiology in patients with severe asthma. However, there is considerable evidence for airtrapping in patients with severe asthma, without associated hyperinflation. Residual volumes are routinely > 200% of predicted in severe asthma, with only modestly increased thoracic gas volumes.23
Whether this increase in residual volume is reflective of small airway disease is not known. None of the physiologic measures have been well-correlated with inflammatory or structural changes.
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Pathology of Severe Asthma
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Unlike many diseases, the pathology of asthma itself remains poorly understood, primarily due to limitations in tissue availability. With that in mind, the pathology of severe asthma is even more limited. Given the heterogeneity of the presentation and the physiology, it is likely that heterogeneity exists at the pathologic level as well.
Multiple different pathologic explanations for severe asthma certainly could exist. In this regard, it may be helpful to place these possible explanations into subgroups comprising four different general areas. These four areas include the following: (1) poor/altered response to standard medication (inhaled steroids/ß-agonists); (2) alterations in lung structure (remodeling); (3) different (more distal) location of the disease; and (4) a different underlying pathology. It is obvious that although these explanations are different, there are a considerable number of ways in which they may overlap as well.
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Poor/Altered Response to Medications
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Pathologic studies of severe asthma suggest that up to two thirds of patients with severe asthma have persistent tissue eosinophils, despite continued therapy with high-dose systemic steroids. In addition to high numbers of eosinophils, there are associated increases in T lymphocytes and markers for activation of a Th-2 pathway.23
This pattern of inflammation may be thought of as representing the classic form of steroid resistance, whereas a Th-2 pattern of inflammation persists despite the presence of high-dose steroid therapy. Numerous laboratories are working on the mechanisms underlying this lack of effect, with the possibilities including high levels of proinflammatory mediators sequestering the GR, diminished binding of the GR to the genome, or increased levels of an alternatively spliced GR (ie, GR-ß), which has lessened inhibitory capabilities.24
25
26
However, it is possible that other, non-Th-2, proeosinophilic factors are also playing a role in the process.
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Airway/Parenchymal Remodeling
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In the last 5 years, it has been suggested that the apparent progressive loss of lung function in more severe forms of asthma is due to structural or remodeling changes in the airways and perhaps the parenchyma as well. However, what the precise changes are remains unclear. Numerous structures have been implicated, including the subbasement membrane (SBM), epithelium, smooth muscle, nerves, and blood vessels. In general, there is a paucity of data on any of these structures in relation to disease severity.
Although the SBM has been reported23
to be thickened in asthma patients, the relationship to disease severity is unclear. Patients with severe asthma with persistent eosinophil levels had the thickest SBM when compared to those of healthy control subjects, patients with milder cases of asthma, and those without eosinophils. Interestingly, this thickened SBM was seen in association with high numbers of TGF-ß-positive cells in the submucosa.23
27
However, the absolute increase in thickness is small and is not likely to explain the increase in airflow limitation. It may, however, be a marker for abnormalities in composition, distribution, or quantity of extracellular matrix elements in other regions of the airway or parenchyma that are not as easily identified.
The epithelium is almost certainly abnormal in asthma patients. In asthmatic patients, there appears to be an increase in the ratio of goblet cells to ciliated epithelial cells. Mucus plugging of the small and medium airways may contribute to airflow limitation and air trapping in patients with severe asthma. Early studies28
29
suggested the following two pathways: epithelial growth factor receptor and TGF-ß1 and/or TGF-ß2 may be altered in asthma patients and may contribute to an inappropriate and inadequate repair process, augmenting goblet cell metaplasia and mucus production.
The amount (and perhaps phenotypes) of smooth muscle in the airways of patients with severe asthma also has been reported to be increased. Patients dying of status asthmaticus have been reported30
to have increased smooth muscle mass in the airways from the largest airways to nearly the smallest. Although a relationship of increased airway smooth muscle to severity of disease would seem to be logical, there are no studies that have been performed to evaluate that. The mechanisms driving the increased smooth muscle are not clear.
Relating any of these structural changes to functional changes has not been easy. As noted earlier, in addition to airflow limitation, airtrapping, hyperresponsiveness, and loss of elastic recoil/collapsibility may also be important. It is likely that alterations in the alveolar attachments to the airways and the airways themselves play a role in collapsibility, but issues of recoil remain less clear. Elastin levels have been shown to be abnormal (ie, decreased or disordered) in patients who have died of asthma. Furthermore, the numbers of proteolytic enzymes that alter elastin composition have been shown to be increased in several instances in asthma.31
32
It may be that changes in elastin composition, secondary to chronic inflammatory elements, contribute to the unique structural/functional relationships of patients with severe asthma.
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Altered Location of Disease
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Physiologic and pathologic data suggest that inflammatory changes exist in the lung periphery. Although the relationship to severity of disease remains unclear, autopsy studies33
34
have suggested that both increased inflammation and wall thickness may exist in patients who have died of asthma, as opposed to those with milder asthma and healthy control subjects. Studies35
36
of living asthma patients also have suggested that distal lung inflammation may be more important than proximal lung inflammation. These data have considerable implications for current drug therapy, as most inhaled medications are unlikely to reach the lung periphery in high amounts.37
Finally, structural and inflammatory changes in the small airway and parenchyma may interact to a greater degree in the small airways than the large airways due to the smaller general mass of the airway structure.
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A Different Underlying Disease
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The definition of asthma remains a purely physiologic one, with the concept of the need for inflammation having only recently been added and having been poorly defined. In that regard, asthma can be diagnosed on the basis of reversible airflow limitation and/or bronchial hyperresponsiveness. Numerous other diseases could meet these basic requirements and, therefore, could be confused with asthma. The observation that not all patients with severe asthma have continued eosinophilic inflammation but, rather, have neutrophil predominance or very little inflammation supports the idea that at least a subgroup of patients who are thought to have severe asthma may have a distinctly different disease.23
38
Other investigators39
also have found a predominance of neutrophils in some patients with more severe disease. The patients without eosinophils also do not appear to have the same degree of collapsibility and have less severe asthma attacks, also supporting a different presentation for this disease subtype. Interestingly, in a study40
of CT scans in patients with severe asthma vs those with bronchiolitis obliterans (BO), another disease causing severe airflow limitation, there were no changes on CT scans that were convincingly discriminating for BO vs asthma. As pathology is not always obtained for either severe asthma or BO, it is likely that some patients with severe asthma actually have BO. Whether other, less well-defined obstructive diseases also could masquerade as severe asthma requires further study.
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Treatment
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The treatment of severe asthma remains highly problematic. CS remain the drug of choice, likely because of their broad and nonspecific effects, and there are few alternatives in existence. Benefit may be seen in some cases with leukotriene modifiers, especially as a large percentage of patients with severe asthma may be aspirin-sensitive.41
Anti-IgE also appears to reduce hospitalizations in patients with more severe forms of asthma and may prove of benefit in some of these patients once it is available.42
Other forms of therapy, such as cyclosporine and methotrexate, have only limited applicability in this population. Until specific phenotypes of severe asthma can be better defined clinically, pathologically, and perhaps genetically, drug trials in this population will be unlikely to show considerable benefit due to the heterogeneity of the population.
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Footnotes
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Dr. Wenzel is a consultant to Genentech/Novartis.
Abbreviations: BO = bronchiolitis obliterans; CS = corticosteroids; GR = glucocorticoid receptor; SBM = subbasement membrane; TGF = transforming growth factor; Th = T helper
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- Burchard, EG, Silverman, EK, Rosenwasser, LJ, et al Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med 1999;160,919-922[Abstract/Free Full Text]
- Pulleyn, LJ, Newton, R, Adcock, IM, et al TGFbeta1 allele association with asthma severity. Hum Genet 2001;109,623-627[CrossRef][ISI][Medline]
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- Halonen, M, Stern, DA, Wright, AL, et al Alternaria as a major allergen for asthma in children raised in a desert environment. Am J Respir Crit Care Med 1997;155,1356-1361[Abstract]
- Rosenstreich, DL, Eggleston, P, Kattan, M, et al The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336,1356-1363[Abstract/Free Full Text]
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- Ogirala, RG, Sturm, TM, Aldrich, TK, et al Single, high-dose intramuscular triamcinolone acetonide versus weekly oral methotrexate in life-threatening asthma: a double-blind study. Am J Respir Crit Care Med 1995;152,1461-1466[Abstract]
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Abstract
Introduction
