4/7/2017 Severe asthma phenotypes - UpToDate

Author: Sally Wenzel, MD

Section Editor: Peter J Barnes, DM, DSc, FRCP, FRS
Deputy Editor: Helen Hollingsworth, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2017. | This topic last updated: Jun 27, 2016.

INTRODUCTION Asthma is defined and diagnosed through a combination of clinical symptoms and
physiologic abnormalities, generally without reliance upon pathologic or biologic markers. However, the
physiologic definition of asthma is relatively nonspecific, consisting of airway hyperreactivity and airflow
limitation during expiration, which is variable and/or reversible with bronchodilators. In most asthma
patients, the presence of bronchial hyperreactivity is never objectively confirmed.

The data suggesting that multiple phenotypes exist within the classification of "severe asthma" are
reviewed here. Details regarding the classification, evaluation, diagnosis, and treatment of severe
asthma are provided separately. (See "An overview of asthma management" and "Evaluation of severe
asthma in adolescents and adults" and "Diagnosis of asthma in adolescents and adults" and "Treatment
of severe asthma in adolescents and adults" and "Mechanisms and clinical implications of glucocorticoid
resistance in asthma".)

DEFINITION OF SEVERE ASTHMA The diagnosis of asthma is based upon the presence or history
of symptoms consistent with asthma (most commonly episodic cough, wheezing, or dyspnea) provoked
by typical triggers, combined with the demonstration of variable expiratory airflow obstruction. After
confirming a diagnosis of asthma and addressing comorbidities, severe asthma is that which requires
treatment with high dose inhaled glucocorticoids plus a second controller and/or systemic glucocorticoids
to prevent asthma from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy [1].

RATIONALE FOR CHARACTERIZING ASTHMA PHENOTYPES Patients with severe asthma

present with a variety of clinical histories, physiologic changes (beyond changes in forced expiratory
volume in one second [FEV1]), and airway inflammation, suggesting that severe asthma is not a single
disease or is a single process that produces widely varying host responses. Patients with severe asthma
may have manifested severe disease all their life, developed progressively more severe disease over
time, or may never have had asthma (to the best of their recollection) until some point in their adult life,
after which the disease progressed at a rapid pace [2]. Some patients with severe asthma have a clearly
defined atopic history, while others give little indication of an allergic component.

In addition to the variability in clinical features, patients with asthma do not respond in a uniform fashion
to asthma medications, particularly glucocorticoids and other nonspecific anti-inflammatory/cytotoxic
medications. It is hoped that exploration of asthma phenotypes will translate into improved
understanding of asthma pathophysiology and optimized medication selection [1,3].

SEVERE ASTHMA PHENOTYPES Among patients who meet the definition of severe asthma (table
1), a variety of clinical presentations, physiological characteristics, and responses to therapy are evident
[1,2,4,5]. Disease characteristics (phenotypes) that are most commonly used to differentiate patients with
severe asthma are described in this section. However, substantial overlap exists; as an example, adult
onset asthma does not exclude atopy, although it makes it less likely.

In order to characterize the various presentations of severe asthma, two statistical cluster analyses were
performed on patients participating in the Severe Asthma Research Program (SARP), including those
with mild, moderate, and severe asthma [2]. The first cluster analysis only utilized clinical and physiologic
data [2], while the second analysis also included bronchoscopic and inflammatory variables [6]. While

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 1/9
4/7/2017 Severe asthma phenotypes - UpToDate

similar, some differences were noted. Both cluster analyses identified childhood onset, generally allergic
asthma from mild to severe, and very severe asthma with a mixed inflammatory process. The
inflammatory clusters also identified a very distinct group with adult onset disease and nasal polyposis.
(See 'Hypereosinophilic adult onset asthma and aspirin exacerbated respiratory disease' below.)

The following sections describe characteristics that have been identified (with greater or lesser
frequency) among patients with severe asthma and potential ramifications in terms of treatment choices.

Childhood onset allergic asthma Data from case series of patients with severe asthma suggest that
childhood-onset (before the age of 12) versus later onset (after age 12) distinguishes two distinct
subgroups [2,7-9]. Childhood-onset asthma represents a relatively homogeneous group of patients, often
with a strong allergic history and family history of asthma. In contrast, adult-onset asthmatics are a very
mixed group of patients.

Adult onset atopic asthma Among patients with adult onset asthma, those with severe disease are
less likely to be atopic (34 percent) than those with mild-to-moderate persistent asthma (52 percent) [10].
While only applicable to a minority of severe asthma patients, atopic/allergic asthma can arise in
adulthood, often in patients with a history of allergic rhinitis in childhood. Identifying the presence of
atopy has implications for selection of therapy and potentially for environmental modifications (eg, dust
mite mitigation). (See "Trigger control to enhance asthma management".)

As an example, treatment with the monoclonal antibody to IgE (omalizumab) is indicated for patients with
severe asthma, elevated IgE levels (eg, 35 to 700 international units/mL), and positive allergy skin tests
to perennial allergens. Treatment with omalizumab can reduce the frequency of exacerbations and
reduces the inhaled glucocorticoid requirement [11,12]. As only about 30 percent of allergic asthmatics
appear to respond to omalizumab, it remains to be determined whether there is a specific subphenotype
of allergic asthma that responds better than others. (See "Anti-IgE therapy".)

Adult onset nonatopic asthma Many patients with adult onset asthma describe the onset of asthma
symptoms following a viral illness, occupational exposure, or the ingestion of aspirin, while such histories
are less frequent among those with childhood-onset asthma. In adult-onset asthma, an allergic
component may be more difficult to confirm, as significantly fewer asthmatics with onset of disease after
the age of 12 demonstrate positive allergy skin tests or specific allergic symptoms compared to early
onset [13,14].

Hypereosinophilic adult onset asthma and aspirin exacerbated respiratory disease Patients
with adult onset eosinophilic asthma typically require systemic glucocorticoids to maintain control of their
asthma and often early in the course of disease [6-8,10]. They are less likely to be atopic/allergic but
have high levels of blood and tissue eosinophils, as well as high levels of exhaled nitric oxide. These
findings are often seen in association with severe sinus disease, nasal polyposis, and in a minority,
aspirin exacerbated respiratory disease (AERD).

AERD refers to the combination of asthma, chronic rhinosinusitis (CRS) with nasal polyposis, and acute
upper and lower respiratory tract reactions to ingestion of aspirin (acetylsalicylic acid, ASA) and other
cyclooxygenase-1 (COX-1) inhibiting nonsteroidal antiinflammatory drugs (NSAIDs). (See "Aspirin-
exacerbated respiratory disease".)

AERD is good example of the complex overlap between the various phenotypes of severe asthma, as
illustrated by the following observations. Peripheral blood eosinophilia occurs in approximately 50
percent of patients with AERD, although not all patients with eosinophilic asthma have AERD.
Depending on the case series, between 30 and 70 percent of patients with AERD are atopic.

Patients with AERD have a baseline dysregulation of arachidonic acid metabolism with over-production
of leukotrienes C4, D4, and E4, which are potent bronchoconstrictors and promoters of airway
inflammation. In the presence of COX-1 inhibitors such as aspirin (ASA) and NSAIDs, COX-1 inhibition

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 2/9
4/7/2017 Severe asthma phenotypes - UpToDate

leads to a further increase in production of leukotrienes C4, D4, and E4. Leukotriene modifying agents
(eg, montelukast, zafirlukast, zileuton) are used to address the underlying dysregulation of leukotriene
production and also protect patients from severe exacerbations due to accidental NSAID exposure. (See
"Aspirin-exacerbated respiratory disease", section on 'Abnormalities in AERD'.)

Aspirin desensitization can be helpful in patients with AERD (with primary benefits in the upper airway),
although it is not used in all patients, often for safety concerns. (See "Aspirin-exacerbated respiratory
disease: NSAID challenge and desensitization".)

Agents targeting Type 2 lymphocyte inflammation may also have a role in treating nasal polyposis and
AERD. In a preliminary study, a monoclonal antibody (dupilumab) to the interleukin (IL)-4 receptor alpha
subunit (IL-R4A), which inhibits the activity of the Type 2 cytokines IL-4 and -13, reduced polyp scores in
patients with chronic sinusitis and nasal polyposis (50 percent had asthma) [15]. Smaller studies of anti-
IL-5 and anti-IgE in this population also showed modest efficacy [16,17]. (See "Investigational agents for
asthma", section on 'Biologic agents' and "Anti-IgE therapy".)

Not all patients with adult onset hypereosinophilic asthma have nasal polyps or AERD. However, they
are often refractory to inhaled therapy alone. Early studies with anti-IL-5 monoclonal antibodies suggest
that patients with hypereosinophilic adult onset asthma may respond favorably to anti-IL-5 directed
therapy, including an improved ability to taper oral glucocorticoids [18-20]. (See "Investigational agents
for asthma", section on 'Anti-IL-5 monoclonal antibodies'.)

Asthmatic granulomatosis Some patients with severe asthma have granulomatous inflammation on
lung biopsy. It is not known whether this inflammation is an intercurrent disease process, a consequence
of therapy, or different asthma phenotype. In a case series that included 19 patients with severe asthma
who underwent video-assisted lung biopsy, 10 were found to have interstitial non-necrotizing granulomas
with asthma-like submucosal inflammation and mucus plugging in the small airways, and without
evidence of hypersensitivity pneumonitis [21]. Peripheral blood eosinophilia was present in most, and the
fraction of exhaled nitric oxide (FENO) was elevated. Atopy was present in 6 of 10. Computed
tomography was abnormal in some patients, and a large majority had a family history of autoimmune
disease. (See "Evaluation of severe asthma in adolescents and adults", section on 'Conditions that
mimic asthma'.)

CLINICAL CHARACTERISTICS ASSOCIATED WITH SEVERE ASTHMA Certain clinical

characteristics have been identified that are associated with severe asthma but do not define a particular
phenotype.

Glucocorticoid resistance By definition, most severe asthmatics receive oral or high doses of
inhaled glucocorticoids. Thus, most severe asthma has an element of GC resistance. However, even
with these very potent anti-inflammatory drugs, the response to therapy is often variable [22]. In some
patients with severe asthma, the response appears to be shifted, so that although a response occurs, it
requires extremely high doses. These patients would appear to be "glucocorticoid-dependent." In others,
even high doses of glucocorticoids may lead to little or no response, or even worsening. These patients
may be truly glucocorticoid-resistant, but are likely in a minority. (See "Mechanisms and clinical
implications of glucocorticoid resistance in asthma".)

Many, if not most studies of glucocorticoid resistance have been done in moderate rather than severe
asthmatics, and extrapolation from those results is often difficult [23,24]. Some severe asthmatics may
not demonstrate an improvement with glucocorticoids on a chronic basis, but may demonstrate
improvement with glucocorticoids during a period of exacerbation. This difference in the acute versus
chronic response has not been studied to date. In addition, patients with persistent sputum eosinophilia
appear to respond better to high dose glucocorticoid therapy than those with no evidence for eosinophilia
[25]. Thus, GC resistance is a rather vague term. Generally this term has been replaced with more
specific phenotypes below.

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 3/9
4/7/2017 Severe asthma phenotypes - UpToDate

Exacerbation frequency Some patients with severe asthma have frequent episodes of extreme
airflow limitation (brittle asthma), while others do not [26]. No consistent definition of "frequent
exacerbation" has been agreed upon, but more than two or three exacerbations during a year is
commonly used [1]. Approximately 30 percent of patients with severe asthma meet this definition of
frequent exacerbations [27]. Patients with frequent exacerbations tend to have greater peripheral airway
obstruction on pulmonary function tests, persistent eosinophilia in blood and bronchoalveolar lavage,
and more comorbidities (eg, chronic rhinosinusitis, recurrent respiratory infections, obesity, obstructive
sleep apnea, and psychosocial issues) [6,28,29].

Among patients enrolled in the Severe Asthma Research Program (SARP), frequent exacerbations were
associated with persistent eosinophilic inflammation in peripheral blood and bronchoalveolar lavage
despite high doses of systemic glucocorticoids [6]. However, similar to GC resistant asthma, the
characteristic of frequent exacerbations may be due to multiple different and unrelated factors, like
smoking, obesity, and psychologic factors. Therefore, this clinical phenotype has generally been
replaced with the phenotypes below.

Asthma associated with obesity Several studies have identified an increased prevalence of asthma
among obese individuals compared with those of normal weight, although the exact reason for the
association is not known. In a Dutch cohort, the prevalence of obesity (body mass index 30 kg/m2)
among a cohort with severe asthma was 21 percent [30]; in a similar cohort in the United Kingdom, the
prevalence of obesity was 48 percent [31]. The risk of obesity-associated asthma is higher for women
than men and among nonatopic individuals than atopic. Asthma associated with obesity is often more
difficult to control and less likely to respond to traditional asthma therapy.

Despite the association of obesity and asthma, studies addressing the role of weight loss for severe
asthma are limited and improved asthma control has not been consistently demonstrated [32].

Perimenopausal onset asthma Onset of asthma within a year of a woman's last menstrual period
may define a separate asthma phenotype [13,14]. In a case series, induced sputum from 40 women with
menopause onset asthma showed a higher percentage of neutrophils and slightly lower percentage of
eosinophils compared with sputum from 35 women with premenopausal onset asthma [14]. None of the
women with menopausal onset asthma were atopic, while 76 percent of the premenopausal asthma
onset group were atopic. Whether menopausal onset asthma is different from adult onset asthma in men
requires additional study. Whether menopausal onset asthma is different from adult onset asthma in men
requires additional study. How much overlap there is with the adult onset less atopic, generally obese
women from the cluster analysis of the Severe Asthma Research Program population remains to be
determined, but a large percentage of that population was also post-menopausal [2].

PHENOTYPING BASED ON BIOMARKERS OF INFLAMMATION It is hoped that identifying

biomarkers for the various asthma phenotypes will aid the selection of therapies that are most likely to
work for individual patients.

Th2-like/Eosinophilic asthma Approximately 50 percent of severe asthma is associated with

persistent elevation in markers of Th2 (or more correctly Type 2) inflammation, likely arising from residual
elevations in the Type 2 cytokines interleukin (IL)-4, 5, and 13. Data for this arise from the Severe
Asthma Research Program (SARP), as well as clinical trials of antibodies directed towards these
cytokines [18,33-36].

As noted above, in severe asthma, the eosinophilic phenotype appears more common among late onset
asthma than childhood onset, which is more typically associated with atopy (see 'Severe asthma
phenotypes' above). However, data from clinical trials suggest that levels of eosinophils between 200
and 300/microL or fraction of exhaled nitric oxide (FENO) levels above 20 ppb support an underlying
active Type 2 immune process, which will respond to Type 2 specific therapy [19,33]. The ideal method
for assessing Type 2 inflammation is not known [37]. Sputum eosinophilia predicts airway eosinophilia,

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 4/9
4/7/2017 Severe asthma phenotypes - UpToDate

but is a time consuming test and observer dependent. Statistical associations have been noted between
sputum eosinophilia and peripheral blood eosinophil counts, FENO, and serum periostin, but the
accuracy of these biomarkers for predicting sputum eosinophilia is imperfect [38,39]. The European
Respiratory Society/American Thoracic Society guidelines suggest that treatment of severe asthma be
guided by clinical criteria and sputum eosinophil counts (performed in centers experienced in this
technique) rather than by clinical criteria alone [1].

Peripheral blood eosinophils appear to be good predictors of response to Type-2 targeted therapy as
shown in studies of the monoclonal antibodies to IL-5 (ie, mepolizumab and reslizumab) and also anti-IL-
4RA [15,19,20,40]. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5
therapy' and "Investigational agents for asthma", section on 'Anti-lL-4 receptor alpha subunit antibody'.)

Fraction of exhaled nitric oxide Measurement of FENO has been used as a biomarker for Type-2
inflammation. Increased FENO levels (eg, greater than 50 ppb in adults or greater than 35 ppb in
children) correlate with eosinophilic airway inflammation and responsiveness to inhaled glucocorticoids.
In a study of bronchial brushings and sputum obtained from subjects with severe asthma, mild/moderate
asthma (on or off inhaled glucocorticoids), and healthy controls, expression of inducible nitric oxide
synthetase (iNOS), the enzyme which generates exhaled NO, differentiated severe asthma from the
other groups better than FENO, arginase2 mRNA/protein, or nitrotyrosine (NT) protein [41]. In a separate
study from SARP, FENO was a better predictor of systemic glucocorticoid use among patients with severe
asthma than forced expiratory volume in one second (FEV1) [42]. FENO is also consistently decreased in
response to IL-4/-13 targeted therapies suggesting that at least a portion of the FENO is driven by these
cytokines. However, a number of other factors have been identified that affect FENO values, such as age,
sex, atopy, and cigarette smoking, making it an imperfect biomarker for guiding therapeutic decisions.
Thus, the European Respiratory Society/American Thoracic Society guidelines suggest against using
FENO to guide treatment decisions in severe asthma [1]. (See "Exhaled nitric oxide analysis and
applications", section on 'Clinical use in asthma'.)

Periostin Periostin is an extracellular matrix protein, encoded by the gene POSTN, which is also
induced by IL-4 and IL-13 in airway epithelial cells and lung fibroblasts. Microarray studies of airway
epithelium have shown a greater than four-fold increase in POSTN transcripts among patients with
asthma compared with healthy controls [43]. The three-gene signature of periostin, chloride channel
accessory 1 (CLCA1), and serpin beta2 (SERPINB2) in airway brushings was found to separate asthma
into subgroups of T helper lymphocyte-2 (Th2)-high (mediated by IL-4, IL-5, and IL-13) or Th2-low
endotypes [44].

Serum periostin is also a marker of Th2 associated airway inflammation and a better predictor of airway
eosinophilia than blood eosinophil counts or FENO [45] in glucocorticoid nave patients. However, its
utility in more severe disease and children is less clear. In one study, a subgroup analysis suggested that
subjects with high initial peripheral blood periostin levels had a greater response to lebrikizumab than the
low-periostin group. This study is described separately. (See "Investigational agents for asthma", section
on 'Anti-IL-13 antibodies'.)

It is hypothesized that airway histopathology varies among subgroups differentiated by response to

treatment, although this has not been fully studied. For example, patients with elevations in Type 2
biomarkers (blood eosinophils, periostin and FENO) have been evaluated for response to Type 2 directed
biologic therapies for severe asthma, with studies suggesting that patients with airway or sputum
eosinophilia are more likely to respond to glucocorticoid therapy. Thus, patients with severe asthma and
ongoing Type 2 inflammation, despite treatment with inhaled and even oral glucocorticoids, may benefit
from some of the biologic therapies targeting this pathway [18,19,33,34,46]. (See "Investigational agents
for asthma", section on 'Anti-IL-5 monoclonal antibodies' and "Investigational agents for asthma", section
on 'Anti-lL-4 receptor alpha subunit antibody'.)

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 5/9
4/7/2017 Severe asthma phenotypes - UpToDate

Neutrophilic asthma The existence of a neutrophilic asthma phenotype (eg, 40 to 60 percent

neutrophils in induced sputum) is controversial [47-49]. The specificity of neutrophilic inflammation for a
particular subtype of asthma is complicated by the many confounding factors that can contribute to
neutrophilia in sputum, including the use of inhaled glucocorticoids, air pollution, respiratory infection,
sensitization to aspergillus, and gastroesophageal disease. In one study, sputum neutrophilia was
associated with pre and post-bronchodilator FEV1, suggesting that neutrophilic airway inflammation may
have a role in persistent airflow limitation in asthma [50].

Analysis of patients in SARP identified two subgroups with moderate-to-severe asthma and frequent
health care use despite treatment with high doses of inhaled or oral glucocorticoids; one of these
subgroups also had reduced lung function [2,6,51]. The majority (>83 percent) of those with reduced
lung function (cluster 5, described above) had sputum neutrophilia alone or in combination with sputum
eosinophilia. (See 'Rationale for characterizing asthma phenotypes' above.)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Severe
asthma".)

SUMMARY

A consensus definition of severe asthma requires that patients have needed therapy with high dose
inhaled glucocorticoid and a long-acting beta agonist (LABA) or leukotriene modifier/theophylline for
the previous year and/or have needed systemic glucocorticoids for 50 percent or more of year to
prevent asthma from becoming uncontrolled; other conditions must have been excluded, and
exacerbating factors treated (table 1). (See 'Definition of severe asthma' above.)

Severe asthma is likely to represent a heterogeneous population. This heterogeneity is obvious to

clinicians who treat asthma routinely and notice that responses to therapy vary among patients.
(See 'Severe asthma phenotypes' above.)

Characteristics that appear to differentiate subgroups or "phenotypes" of severe asthma include

age, gender, age of asthma onset, atopic status, obesity, exacerbation frequency, eosinophilia,
aspirin exacerbated respiratory disease, and glucocorticoid resistance, although substantial overlap
exists among these. (See 'Severe asthma phenotypes' above.)

A better understanding of asthma phenotypes has the potential to lead to improved treatment of this
group of patients. As examples, patients with atopic severe asthma may appear more likely to
benefit from anti-IgE therapy (omalizumab) and those with adult onset, eosinophilic disease with or
without aspirin exacerbated respiratory disease may benefit from therapy with anti-interleukin
(IL)-5/IL-5R antibodies or IL-4RA antibodies as well as leukotriene modifiers and aspirin
desensitization. (See 'Severe asthma phenotypes' above.)

It is hoped that identifying biomarkers for asthma phenotypes will improve the selection of therapies
that are most likely to work for individual patients. Ideally, biomarkers would be reproducible,
accurate, and accessible noninvasively. International guidelines suggest that treatment of severe
asthma be guided by clinical criteria and sputum eosinophil counts (performed in centers
experienced in this technique) rather than by clinical criteria alone. On the other hand, guidelines
advise against using fraction of exhaled nitric oxide (FENO) to guide treatment decisions in severe
asthma due to uncertain benefits. Other biomarkers that are being evaluated include sputum
neutrophil levels and serum periostin. (See 'Phenotyping based on biomarkers of inflammation'
above.)

Use of UpToDate is subject to the Subscription and License Agreement.

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 6/9
4/7/2017 Severe asthma phenotypes - UpToDate

REFERENCES

1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation
and treatment of severe asthma. Eur Respir J 2014; 43:343.
2. Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster
analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010; 181:315.
3. Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and
allergic disease: the next steps toward personalized care. J Allergy Clin Immunol 2015; 135:299.
4. Newby C, Heaney LG, Menzies-Gow A, et al. Statistical cluster analysis of the British Thoracic
Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PLoS One
2014; 9:e102987.
5. Bourdin A, Molinari N, Vachier I, et al. Prognostic value of cluster analysis of severe asthma
phenotypes. J Allergy Clin Immunol 2014; 134:1043.
6. Wu W, Bleecker E, Moore W, et al. Unsupervised phenotyping of Severe Asthma Research
Program participants using expanded lung data. J Allergy Clin Immunol 2014; 133:1280.
7. Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes: role of age at
onset and eosinophilic inflammation. J Allergy Clin Immunol 2004; 113:101.
8. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir
Crit Care Med 2008; 178:218.
9. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided
pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.
Am J Respir Crit Care Med 1999; 160:1001.
10. Amelink M, de Groot JC, de Nijs SB, et al. Severe adult-onset asthma: A distinct phenotype. J
Allergy Clin Immunol 2013; 132:336.
11. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with
severe persistent asthma who are inadequately controlled despite best available therapy (GINA
2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309.
12. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal
antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184.
13. van den Berge M, Heijink HI, van Oosterhout AJ, Postma DS. The role of female sex hormones in
the development and severity of allergic and non-allergic asthma. Clin Exp Allergy 2009; 39:1477.
14. Foschino Barbaro MP, Costa VR, Resta O, et al. Menopausal asthma: a new biological phenotype?
Allergy 2010; 65:1306.
15. Bachert C, Mannent L, Naclerio RM, et al. Effect of Subcutaneous Dupilumab on Nasal Polyp
Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial. JAMA
2016; 315:469.
16. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a
treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011; 128:989.
17. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic patients
with nasal polyps and asthma. J Allergy Clin Immunol 2013; 131:110.
18. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory
eosinophilic asthma. N Engl J Med 2009; 360:973.
19. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a
multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380:651.
20. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in
eosinophilic asthma. N Engl J Med 2014; 371:1189.

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 7/9
4/7/2017 Severe asthma phenotypes - UpToDate

21. Wenzel SE, Vitari CA, Shende M, et al. Asthmatic granulomatosis: a novel disease with asthmatic
and granulomatous features. Am J Respir Crit Care Med 2012; 186:501.
22. Chipps BE, Szefler SJ, Simons FE, et al. Demographic and clinical characteristics of children and
adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol 2007; 119:1156.
23. Sher ER, Leung DY, Surs W, et al. Steroid-resistant asthma. Cellular mechanisms contributing to
inadequate response to glucocorticoid therapy. J Clin Invest 1994; 93:33.
24. Adcock IM, Lane SJ, Brown CR, et al. Differences in binding of glucocorticoid receptor to DNA in
steroid-resistant asthma. J Immunol 1995; 154:3500.
25. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts:
a randomised controlled trial. Lancet 2002; 360:1715.
26. Ayres JG, Miles JF, Barnes PJ. Brittle asthma. Thorax 1998; 53:315.
27. Kupczyk M, ten Brinke A, Sterk PJ, et al. Frequent exacerbators--a distinct phenotype of severe
asthma. Clin Exp Allergy 2014; 44:212.
28. in 't Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are
associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;
161:1902.
29. ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat
asthma. Eur Respir J 2005; 26:812.
30. van Veen IH, Ten Brinke A, Sterk PJ, et al. Airway inflammation in obese and nonobese patients
with difficult-to-treat asthma. Allergy 2008; 63:570.
31. Gibeon D, Batuwita K, Osmond M, et al. Obesity-associated severe asthma represents a distinct
clinical phenotype: analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort
according to BMI. Chest 2013; 143:406.
32. Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database Syst Rev
2012; :CD009339.
33. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J
Med 2011; 365:1088.
34. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil
levels. N Engl J Med 2013; 368:2455.
35. Fajt ML, Gelhaus SL, Freeman B, et al. Prostaglandin D pathway upregulation: relation to asthma
severity, control, and TH2 inflammation. J Allergy Clin Immunol 2013; 131:1504.
36. Muraro A, Lemanske RF Jr, Hellings PW, et al. Precision medicine in patients with allergic
diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy
of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J
Allergy Clin Immunol 2016; 137:1347.
37. Korevaar DA, Westerhof GA, Wang J, et al. Diagnostic accuracy of minimally invasive markers for
detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir
Med 2015; 3:290.
38. Hastie AT, Moore WC, Li H, et al. Biomarker surrogates do not accurately predict sputum eosinophil
and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 2013; 132:72.
39. Wagener AH, de Nijs SB, Lutter R, et al. External validation of blood eosinophils, FE(NO) and
serum periostin as surrogates for sputum eosinophils in asthma. Thorax 2015; 70:115.
40. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with
elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised,
placebo-controlled, phase 3 trials. Lancet Respir Med 2015; 3:355.

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 8/9
4/7/2017 Severe asthma phenotypes - UpToDate

41. Yamamoto M, Tochino Y, Chibana K, et al. Nitric oxide and related enzymes in asthma: relation to
severity, enzyme function and inflammation. Clin Exp Allergy 2012; 42:760.
42. Wysocki K, Park SY, Bleecker E, et al. Characterization of factors associated with systemic
corticosteroid use in severe asthma: data from the Severe Asthma Research Program. J Allergy
Clin Immunol 2014; 133:915.
43. Woodruff PG, Boushey HA, Dolganov GM, et al. Genome-wide profiling identifies epithelial cell
genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci
U S A 2007; 104:15858.
44. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major
subphenotypes of asthma. Am J Respir Crit Care Med 2009; 180:388.
45. Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway
inflammation in asthmatic patients. J Allergy Clin Immunol 2012; 130:647.
46. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor
monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised
dose-ranging study. Lancet Respir Med 2014; 2:879.
47. Cowan DC, Cowan JO, Palmay R, et al. Effects of steroid therapy on inflammatory cell subtypes in
asthma. Thorax 2010; 65:384.
48. Hastie AT, Moore WC, Meyers DA, et al. Analyses of asthma severity phenotypes and inflammatory
proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010; 125:1028.
49. Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013;
25:755.
50. Shaw DE, Berry MA, Hargadon B, et al. Association between neutrophilic airway inflammation and
airflow limitation in adults with asthma. Chest 2007; 132:1871.
51. Moore WC, Hastie AT, Li X, et al. Sputum neutrophil counts are associated with more severe
asthma phenotypes using cluster analysis. J Allergy Clin Immunol 2014; 133:1557.

Topic 544 Version 12.0

https://www.uptodate.com/contents/severe-asthma-phenotypes?source=search_result&search=asma%20grave&selectedTitle=2~150 9/9