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Diagnosis and Management of Severe Asthma


Kian Fan Chung, MD, DSc, FRCP1,2

1 Department of Respiratory Medicine, Airways Disease, National Address for correspondence Kian Fan Chung, MD, DSc, FRCP,
Heart & Lung Institute, Imperial College London, United Kingdom Department of Respiratory Medicine, National Heart & Lung Institute,
2 Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, Imperial College London, Dovehouse St, London SW3 6LY,
London, United Kingdom United Kingdom (e-mail: f.chung@imperial.ac.uk).

Semin Respir Crit Care Med 2018;39:91–99.

Abstract Severe therapy-resistant asthma has been defined as “asthma which requires treatment
with high dose inhaled corticosteroids (ICSs) plus a second controller (and/or systemic
corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncon-
trolled’ despite this therapy”. Patients who usually present with ‘difficult-to-treat
asthma’ should first be assessed to determine whether he/she has asthma with the

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exclusion of other diagnoses and if so, whether the asthma can be classified as severe
therapy-resistant. This necessitates an assessment of adherence to medications,
Keywords confounding factors, and comorbidities. Increasingly, management of severe ther-
► severe asthma apy-resistant asthma will be helped by the determination of phenotypes to optimize
► difficult-to-treat responses to existing and new therapies. Severe asthma patients are usually on a
asthma combination of high dose ICS and long-acting β-agonist (LABA) and, in addition, are
► phenotyping often on a maintenance dose of oral corticosteroids. Phenotyping can be informed by
► management of measuring blood eosinophil counts and the level of nitric oxide in exhaled breath, and
asthma the use of sputum granulocytic counts. Severe allergic asthma and severe eosinophilic
► severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic
asthma therapies currently available, namely anti-immunoglobulin E (IgE) and anti-interleukin
► neutrophilic asthma (IL)-5 antibodies, respectively. Further progress will be realized with the definition of
► T2-high noneosinophilic or non-T2 phenotypes. It will be important for patients with severe
► T2-low asthma to be ultimately investigated and managed in specialized severe asthma
► exhaled nitric oxide centers.

Despite the establishment of guidelines for its management, not respond to existing therapies. Therefore, severe asthma is
over the past 20 years asthma still remains a problem in terms recognized as a major unmet need with a high personal and
of its management. It has also been recognized that not all social impact, as well as a high burden on health care resources.
patients are responsive to currently available treatments. This One of the first definitions that recognized these different
in part may be due to the fact that a lot of heterogeneity of possibilities was the one that was developed by the World
asthma is now recognized in terms of gene-environment Health Organization (WHO) Consultation on Severe Asthma1
interactions, pathophysiological mechanisms, environmental where it rested on the definition of asthma control given by the
exposures, comorbidities, and underlying disease severity. American Thoracic Society (ATS)/European Respiratory Society
There are also other additional factors such as poor health (ERS) Task Force on asthma control and its severity.2 Thus,
care access and care received, psychosocial factors, and re- severe asthma was defined by the level of current clinical
sponsiveness of disease to therapy. Thus, there could be many control and risks as “Uncontrolled asthma which can result in
reasons why a patient’s asthma can become difficult-to-treat, risk of frequent severe exacerbations (or death) and/or adverse
from not receiving the right treatment or not being able to reactions to medications and/or chronic morbidity (including
obtain the right treatment, to having a type of asthma that does impaired lung function or reduced lung growth in children).”

Issue Theme Evolving Concepts in Copyright © 2018 by Thieme Medical DOI https://doi.org/
Asthma; Guest Editor: Paul M. O’Byrne, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0037-1607391.
MB, FRCP(C), FRSC New York, NY 10001, USA. ISSN 1069-3424.
Tel: +1(212) 584-4662.
92 Severe Asthma Chung

The WHO global definition further recognized three groups of costeroids, and level of obesity.8 Clearly, there is a need for a
severe asthma: (1) untreated severe asthma representing more concerted effort worldwide to measure accurately, the
patients who cannot receive treatment for their asthma be- impact of difficult-to-control/severe asthma.
cause they cannot afford the treatments or do not have access
to such treatments, as may occur in underdeveloped countries
From Difficult-to-treat Asthma to Severe
(2) difficult-to-treat severe asthma in patients who are treated
Therapy-resistant Asthma
for their asthma but are not responsive to the treatments for
many reasons including not being adherent to treatments or In patients who usually present with difficult-to-control
not taking the right treatments, and (3) treatment-resistant asthma in primary care and on referral to secondary or tertiary
severe asthma where control is not achieved despite the care, a diagnosis of severe therapy-resistant asthma may
highest level of recommended treatment and asthma for ultimately be made. Thus, in many “difficult-to-control”
which control can be maintained only with the highest level asthma patients, establishing appropriate diagnosis and/or
of recommended treatment. The definitions of severe asthma treatment of confounders through an evaluation protocol
under the European Respiratory Society (ERS) (1999),3 Amer- may lead to improvement in their condition. Therefore, it is
ican Thoracic Society (ATS) (2000),4 and the joint ERS-ATS recommended that such patients have their asthma diagnosis
(2014),5 task forces have all focused on severe asthma patients confirmed, evaluated, and managed by an asthma specialist for
as being treatment-resistant or therapy-resistant. The latest more than 3 months, with increasing preference for this to be
Global Initiative for Asthma (GINA) guidelines has also recog- done within a severe asthma specialist center.
nized the difficult-to-treat asthma category that needs Currently, as defined, severe therapy-resistant asthma is

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special attention in specialized clinics (http://ginasthma.org/ about asthma that is not controlled adequately by current
2017-gina-report-global-strategy-for-asthma-management- treatments used at Steps 4 and 5 of the GINA guidelines,
and-prevention/). global strategy for asthma management and prevention,
updated 2016, available from: http://www.ginasthma.org/
(accessed on 12/01/2017). The ERS/ATS guidelines published
Prevalence of Difficult-to-treat Asthma or
in 2014 defined severe asthma as: When a diagnosis of
Therapy-resistant Asthma
asthma is confirmed and comorbidities have been addressed,
Asthma is a global health problem that affects around 300 severe asthma is defined as “asthma which requires treat-
million people of all ages and ethnic groups with an estimated ment with high dose inhaled corticosteroids (ICSs) plus
death rate of 250,000 each year as a direct result of asthma. In a second controller (and/or systemic corticosteroids) to
addition, there is a high degree of chronic morbidity posed by prevent it from becoming ‘uncontrolled’ or which remains
chronic symptoms of cough, breathlessness, and also by the ‘uncontrolled’ despite this therapy.”5 This definition implies
occurrence of exacerbations. Difficult-to-control asthma has that a diagnosis of asthma has been established with the
been reported to be prevalent in 17.4% of asthmatics in exclusion of other diagnoses that may masquerade under the
the Netherlands but with only one-fifth of these (3.6% of the guise of asthma and that comorbidities have been addressed,
asthmatic population) having severe refractory asthma as and therefore, the clinical management of severe asthma
defined by difficult-to-control asthma, who are adherent starts with attention to the issue of diagnosis and comorbid-
to treatment with the correct inhaler technique.6 In the ities; in addition, in terms of the therapy-resistant asthma, it
United Kingdom (UK), severe difficult-to-control asthma has is important that the patient is being adequately treated and
been estimated to be prevalent in 140 patients/million popula- that he/she is compliant to the prescribed treatments.3
tion with an annual incidence of 14 patients/million. These Another difficult issue that may arise in terms of the diag-
diverse estimates of prevalence and incidence of severe asthma nosis of asthma is the condition recently labeled as the
indicate the difficulties in obtaining reliable figures. Asthma-COPD (Chronic Obstructive Pulmonary Disease)
People suffering from both difficult-to-control and severe overlap syndrome when a patient has the defining charac-
therapy-resistant asthma represent an important economic teristics of COPD, namely, incompletely reversible airflow
burden. In Europe, the economic costs of asthma consisting of limitation, in addition to features of asthma.9 The ERS/ATS
direct costs, such as hospital care and medication, and indirect severe asthma guidelines recommend three stages in reach-
costs, such as time lost from work, range from 509 Euros for ing the diagnosis of severe asthma, with the first stage being
controlled asthma to 2,281 Euros for uncontrolled asthma per the confirmation of the diagnosis of asthma and identifica-
patient.7 Using these figures, it has been calculated that the tion of difficult-to-treat asthma, the second stage being the
costs of asthma for the whole of Europe would be 21 billion differentiation of severe asthma from milder asthma, and the
Euros for 2014 for asthmatics aged between 16 and 54 years. In final stage being the determination as to whether the severe
the United States (U.S.), the total costs of $56 billion has been asthma is controlled or uncontrolled.5
reported for asthma in 2015 (www.aafa.org/page/cost-of-
asthma-on-society.aspx). In the UK, the economic costs for
Systematic Assessment of Severe Asthma
severe refractory asthma have been estimated to be between
£2,912 to £4,217 per patient per year, with the predictors of There is a great need for a systematic assessment of patients
these costs being influenced by the degree of airflow obstruc- with difficult-to-treat asthma and the steps involved in this
tion, the location of care, the use of maintenance oral corti- assessment are listed in ►Table 1. A high prevalence of

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Severe Asthma Chung 93

Table 1 Systematic assessment of difficult-to-treat/severe therapy- one second [FEV1 of 68% of predicted]) and experienced 2.5
resistant asthma exacerbations on average in the previous year.12 In the US
Severe Asthma Research Program (SARP), severe asthma was
1. Confirmation of asthma diagnosis: Lung function also characterized by abnormal lung function that is respon-
variability; Bronchial provocation test sive to bronchodilators, a history of sino-pulmonary infections,
2. Exclude other conditions masquerading as asthma persistent symptoms, and increased health care utilization.13
3. Assess severity of disease: Poor symptom control, From the UK Difficult Asthma National Registry, 93% of severe
airflow obstruction, frequent exacerbations, asthma subjects had comorbidities related to taking systemic
life-threatening severe exacerbations corticosteroid exposure, such as Type II diabetes, osteoporosis,
4. Optimization of treatment according to national and dyspepsia.14 These comorbidities independently impact a
guidelines broad spectrum of outcomes in difficult asthma patients and
5. Assess adherence to therapy the use of a validated questionnaire to screen for six common
comorbidities associated with difficult asthma has been
6. Adaptation and using self-management plans
shown to be useful in increasing their.15,16 Systematic evalua-
7. Identification and avoidance of trigger factors
tion of these conditions is essential in difficult-to-treat asthma.
8. Assessment and management of comorbidities Multidimensional assessment of severe asthma may lead
9. Phenotyping according to clinic-physiologic- to improved outcomes following the assessment of airway
inflammatory parameters function, comorbidities, and risk factors, indicating that
10. Individualization of management plan some of the traits may be treated with a good response.17

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In patients referred with difficult asthma from respiratory
specialists, a structured approach coupled with targeted
alternative or additional diagnoses, psychiatric illness, or comorbidity interventions has been shown to improve
nonconcordance with therapies, together with a higher num- control of key comorbidities and to enhance asthma out-
ber of comorbidities has been reported in an earlier series comes.18 In the UK Difficult Asthma National Registry, the
(►Table 2).10 In another cohort, the reasons for receiving benefits of a systematic assessment of patients with severe
systematic assessment for difficult asthma varied from experi- asthma include an improvement in quality of life and
encing poor symptom control, frequent exacerbations, poor asthma control, with a reduction in health care use and
lung function, patient factors, and diagnostic uncertainty.11 In steroid burden.19 There was also an improvement in lung
the U-BIOPRED severe asthma cohort, upper airway symp- function with a reduction in rescue courses of oral steroids,
toms, increased sleepiness with increased anxiety and depres- with the most frequent therapeutic intervention being the
sion, and with the presence of nasal polyps in 25% of subjects use of maintenance oral corticosteroids and steroid-sparing
together with gastroesophageal reflux disease in up to 46% of interventions.20
subjects, were comorbid features. These patients also had
chronic airflow obstruction (forced expiratory volume at
Adherence to Treatment
Table 2 Comorbidities and associated conditions with severe Nonadherence to prescribed medications for asthma repre-
therapy-resistant asthma sents an important factor in patients presenting with diffi-
cult-to-treat asthma. This has been recognized, particularly
1. Vocal cord dysfunction for the use of inhaled and oral corticosteroid therapy,10,21
2. Dysfunctional breathing and has been reported to be 30 to 70% of prescribed medica-
3. Rhinosinusitis tion. Using an analysis of prescription records from general
practice, 35% of severe asthma patients attending a difficult
4. Nasal polyps
asthma service in the UK were found to be nonadherent to
5. Obstructive sleep apnea combination ICS and long-acting β-agonist (LABA) inha-
6. Gastroesophageal disease lers,21 and 65.2% of patients in another study were reported
7. Anxiety to be nonadherent, defined as less than 80% filling of ICS
prescriptions.22 For oral corticosteroid therapy, adherence,
8. Depression
based on measurement of serum prednisolone and cortisol
9. Obesity/overweight levels, varied from 33% to 45% in two centers specializing in
10. Corticosteroid side effects: osteoporosis, severe asthma management.10,21 The reasons for nonadher-
obesity, diabetes ence are complex and are not always evident. Patients may
11. Chronic obstructive pulmonary disease have concerns about the side-effects of the therapy, parti-
12. Bronchopulmonary aspergillosis cularly with high dose of inhaled or oral corticosteroids, and
may also feel that the medication is not working with asthma
13. Bronchiectasis
control perceived to be unchanged despite taking these
14. Eosinophilic conditions (eosinophilic granulomatosis treatments. Poorly adherent asthma patients have been
with angiitis, bronchopulmonary aspergillosis,
associated with poorer control of asthma,21 with an in-
hypereosinophilic syndrome)
creased frequency of exacerbations and hospitalisation,23

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94 Severe Asthma Chung

supporting the view that this results from inadequate reason for this is that there has been better delineation of
treatment. the eosinophilic phenotype and the use of clinically-acces-
A test based on the suppression of fractional exhaled sible biomarkers. Use of biomarkers such as blood eosinophil
nitric oxide (FeNO) levels has been used to identify non- count and FeNO are now being recommended for use in the
adherence to ICS in a difficult asthma population,24 but assessment of patients with asthma, and in particular for
electronic counters that can be attached or built within an severe asthma. The presence of eosinophilia and high FeNO
inhaler represent a direct and less obtrusive method of can be indicative of a good response to ICS therapy, although
assessing adherence.25,26 With these electronic devices, it less so for oral corticosteroid therapy.34 Another important
is possible to monitor whether any improvement in adher- reason for defining this phenotype is because of the recent
ence to inhaled therapies can lead to an improvement in availability of anti-interleukin (IL)-5 antibody therapies that
asthma control. Alternatively, in some patients, their non- are aimed at severe eosinophilic asthma patients. In addition,
adherence may have been engendered by a true lack of effect the introduction of anti-immunoglobulin E (IgE) therapy has
of these drugs in controlling asthma in a severe therapy- led to the definition of a severe allergic asthma phenotype.
resistant asthma patient. Therefore, in the management and evaluation of patients
with severe asthma, it is recommended that patients with
severe asthma be phenotyped, according to whether they
Clinical Phenotypes of Severe Asthma
have allergic or eosinophilic asthma.
Severe asthma is a heterogeneous condition that can present
with various clinical phenotypes underlined by diverse

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The Severe Eosinophilic Asthma Phenotype
molecular mechanisms that may be driving these different
phenotypes.27,28 Phenotyping is becoming an important step Eosinophilia is now recognized as an important feature of
in the evaluation of the patients with severe asthma as this is asthma. In fact, sputum eosinophilia is found in under half of
likely to help in choosing appropriate treatments.29 Pheno- all patients with asthma and both blood and sputum eosi-
types of asthma have been identified according to causal or nophilia are associated with more severe disease, worse
triggering factors such as allergen-induced or aspirin-in- control, and worse prognosis.35 The resulting effects of
duced, to the type of airflow obstruction, to the severity eosinophilic airway inflammation include air trapping, wor-
and response to treatments, to radiological findings, and to sening of symptoms, frequent exacerbations, and impact on
the nature of airway inflammation.29,30 Use of statistical quality of life. Adult-onset asthma patients with a high blood
unbiased clustering approaches has identified patients with eosinophil count ( 0.3  109 per L) have a distinct pheno-
airflow obstruction and activity of disease, patients with type of severe asthma with frequent exacerbations and poor
early age of onset of disease with an atopic background, and a prognosis.36 Persistent airflow limitation and distal inflam-
more severe group of asthma patients associated with adult- mation with air trapping are seen in these patients, together
onset disease and active disease.13,31 with chronic rhinosinusitis and nasal polyposis.37
In the U-BIOPRED cohort of severe asthma, three clusters A recent Consensus group defined severe eosinophilic
of severe asthma were characterized by a cluster of patients asthma by a set of major criteria38 that included (i) a diagnosis
with well-controlled moderate-to-severe asthma and with of severe asthma according to the ERS/ATS severe asthma
three clusters of severe asthma: (i) late-onset severe asthma guidelines, (ii) high-load eosinophilic disease (persistent blood
with a history of smoking and chronic airflow obstruction, or sputum eosinophilia detected on  2 occasions), (iii) frequent
(ii) nonsmoking severe asthma with chronic airflow obstruc- exacerbations (  2 per year), (iv) dependence (continuous or
tion, and (ii) obese female patients with frequent exacerba- intermittent) on oral corticosteroids to achieve asthma control.
tions but with normal lung function.32 In the SARP cohort, The minor criteria included: (i) late onset of disease, (ii) upper
cluster analysis has led to the definition of phenotypes of airway disease (i.e., chronic rhinosinusitis, often with nasal
early onset atopic asthma of mild to moderate severity, of polyposis), (iii) fixed airflow obstruction, (iv) air trapping/
obese late onset nonatopic asthma female patients with presence of mucus plugs.
frequent exacerbations, and of those with severe airflow In asthma, molecular phenotyping on the basis of gene
obstruction with use of oral corticosteroid therapy.33 expression has started.39 One mechanism underlying eosino-
In the Leicester cohort that used sputum eosinophilia as a philic asthma, referred to as T-helper cell type 2 (Th2)- or
marker of eosinophilic asthma, there was discordance be- T2-high characterized by expression of genes stimulated by
tween symptoms and presence of sputum eosinophilia.31 exposure to the Th2 cytokine, interleukin (IL)-13, in airway
One cluster was that of an early-onset, symptom-predomi- epithelial cells, has been widely recognized.40 Mild asthmatic
nant group with minimal eosinophilic disease, with a high patients with Th2-high expression had evidence of eosinophil
prevalence of obesity and female gender, while the other inflammation in blood and sputum, responded well to ICS
cluster consisted of an eosinophilic inflammation-predomi- therapy, and formed 50% of the mild asthmatic population. In
nant group with few symptoms, late-onset disease, and a patients with severe asthma, the prevalence of Th2-high is likely
greater proportion of males, with a high prevalence of to be lower, being 37% in nonsmoking severe asthma and 25% in
rhinosinusitis, aspirin sensitivity, and exacerbations. moderate asthma.41 The Th2-high asthma defines a severe
There are compelling reasons for undertaking a pheno- eosinophilic asthmatic as one who experiences frequent severe
typic exercise in patients with severe asthma. The main exacerbations.42 Therefore, the severe eosinophilic patient can

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Severe Asthma Chung 95

be described as a Th2- or T2-high asthma phenotype. Such monitoring metabolic consequences such as development of
patients may respond well to anti-IL5 therapies (see forth- fatty liver or the metabolic syndrome are important.55
coming sections). There has been no efficacious approach to reducing the
dose or replacing the oral maintenance dose of prednisolone.
The use of sputum eosinophil counts which has been re-
Neutrophilic Severe Asthma Phenotype
commended by the ERS/ATS guidelines may help toward
The neutrophilic noneosinophilic asthma phenotype remains adjusting to the lowest dose of prednisone or prednisolone
less well-defined and 50% of patients with symptomatic needed.56 Low levels of sputum or blood eosinophil counts
asthma are reported to have this inflammatory phenotype indicate a noneosinophilic phenotype that is likely to be less
with high neutrophil counts in sputum ranging from 40% to responsive to oral corticosteroid therapy, and therefore
76% of sputum cells. Sputum neutrophilia has been associated corticosteroids can be down-titrated. On the other hand,
with severe asthma, corticosteroid insensitivity, and chronic the blood eosinophil count may increase as a result of down-
airflow obstruction,43–46 and is sometimes observed during titration of the oral corticosteroid dosage, in which case this
acute exacerbations.47 Sputum neutrophilic inflammation would represent a corticosteroid-sensitive but relatively-
associated with inflammasome activation that has been re- resistant eosinophilic asthma.
cently described, supports the presence of a neutrophilic The use of methotrexate as a steroid-reducing agent is not
phenotype of asthma,48 supporting the notion that neutrophil recommended by the ERS/ATS guidelines. On the other hand,
infiltration into the airways might be a crucial pathophysio- mepolizumab, the anti-IL5 antibody, reduced by 50% of the
logical process underlying severe asthma. Another possibility maintenance dose of oral corticosteroid in oral corticoster-

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is that increased airway neutrophilia may be the result of oid-dependent patients with severe eosinophilic asthma.57
infection, exposure to air pollutants, or treatment with corti- Similar results have been reported with the anti-IL-5Rα
costeroids, particularly oral corticosteroids,49 or might merely antibody, benralizumab.58 Therefore, these biologics target-
represent innocent bystanders. The recent failure of a neu- ing IL-5 may be useful steroid-sparing agents in steroid-
trophil target in the form of a CXCR2 antagonist in patients dependent severe eosinophilic asthma.
with asthma, with a high blood neutrophil count and low
eosinophil count50 would not lend support to the concept of
Molecular Phenotyping of Severe Asthma:
neutrophilic asthma, but it is likely that stratifying neutrophi-
T2-high and T2-low
lic asthma on the basis of blood cell counts is not accurate
enough. In neutrophilic asthma, an elevated gene expression of Phenotyping, according to the gene expression in airways
NLRP3, caspase-1 and IL-1β in sputum cells has been re- tissues is more likely to yield phenotypes based on potential
ported.51,52 The neutrophilic severe asthma phenotype may driving mechanisms.39 In the U-BIOPRED cohort, an unbiased
exist but needs validation. approach was taken to obtain molecular phenotypes of severe
asthma using an analysis of sputum transcriptomics data that
yielded three molecular phenotypes.48 One molecular pheno-
Relative Corticosteroid Insensitivity
type was characterized by immune receptors IL33R, CCR3, and
A poor therapeutic response to corticosteroid therapy is a TSLPR with enrichment of gene signatures for IL-13/Th2 and
hallmark of patients with severe asthma.53 Only 78% of innate lymphoid cell type 2 associated with high sputum
patients with mild-to-moderate asthma and 62% of those eosinophilia; these patients had severe asthma with oral
with moderate-to-severe asthma achieved good disease con- corticosteroid dependency, frequent exacerbations, and se-
trol with a combination of ICS and LABAs (fluticasone propio- vere airflow obstruction. The second cluster was characterized
nate and salmeterol).54 This is also observed in patients with by interferons, tumor necrosis factor-α- and inflammasome-
severe asthma who are on an established dose of oral corti- associated genes with the highest sputum neutrophilia, and
costeroids at Step 5. In the U-BIOPRED cohort, 50% of severe serum C-reactive protein levels. The third phenotype was
asthma patients were on oral corticosteroid therapy, and these characterized by genes of metabolic pathways, ubiquitination,
patients had a high prevalence of nasal polyps and of uncon- and mitochondrial function with paucigranulocytic inflam-
trolled asthma, a higher number of exacerbations compared mation and little airflow obstruction. This unbiased approach
with those not on oral corticosteroid maintenance.12 In addi- yielded one T2-high and two T2-low molecular phenotypes,
tion, markers of lung inflammation such as FeNO and sputum and also provided potential therapeutic targets. In addition,
eosinophils were raised, while blood eosinophil counts remain the value of examining sputum granulocytic inflammatory
suppressed, such that this group represents an eosinophilic cells as biomarkers for these molecular endotypes has been
corticosteroid-insensitive phenotype. emphasized.
Factors that could be underlying corticosteroid insensitivity
include cigarette smoking, bacterial infections, obesity, and
Current Management of Severe Asthma
deficiency of vitamin D.53 In addition, these patients continue
to experience side-effects from oral corticosteroid (CS) ther- The management of difficult-to-treat asthma represents the
apy. Comorbidities associated with oral CS therefore need most challenging aspect of asthma and has been addressed in
particular attention. Measures such as monitoring of bone the ERS/ATS guidelines on severe asthma.5 These guidelines
densitometry and use of anti-osteoporotic measures, and focused mainly on certain aspects of management, making

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96 Severe Asthma Chung

specific recommendations on the use of sputum eosinophil are more likely to respond to anti-IL5 or anti-IL5R antibody
count and exhaled nitric oxide to guide therapy, as well as treatment in terms of reduction in exacerbations and im-
reviewing treatment with anti-IgE antibody, methotrexate, provement in lung function.57,62–65
macrolide antibiotics, antifungal agents, and bronchial ther- Another utility of measuring blood eosinophil count aside
moplasty. The current version of GINA recommends that from supporting the diagnosis of severe eosinophilic asthma
difficult-to-treat asthma patients be referred for specialist is that the presence of a very high eosinophil count should
investigation and consideration of add-on treatment at Step raise the suspicion of other eosinophilic conditions that often
5, and has added new treatments such as long-acting cho- co-exist with asthma (could be considered as comorbidity),
linergic antagonist, tiotropium, at Step 4, and the anti-IgE such as Churg-Strauss syndrome or eosinophilic granuloma-
antibody, omalizumab and the anti-IL5 antibody, mepolizu- tosis with polyangiitis, eosinophilic pneumonia, allergic
mab or reslizumab, at Step 5. bronchopulmonary aspergillosis, and the hypereosinophilic
syndrome.
Total serum IgE level is used as a biomarker for identifying
Specialized Centers for Severe Asthma
those who are suitable to receive anti-IgE antibody, omali-
There is an increasing need for patients with severe asthma zumab treatment, but high levels of FeNO (> 19.5 parts per
to be managed in specialized asthma centers that deliver a billion) and high blood eosinophil counts (> 260/μL) have
multidisciplinary team approach and provide up-to-date been shown to be the predictive biomarkers of response (in
management protocols. Care in a specialized severe asthma terms of reduction in exacerbations).66
center should aim, in addition to managing comorbidities, to A low blood eosinophil count has been often taken as

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phenotyping asthma using biomarkers, and initiate novel reflecting a T2-low phenotype but this definition remains to
targeted therapies. In the National Health Service in the UK, be validated. In fact, biomarkers reflecting T2-low groups are
this process is led by a specialized commissioning process lacking due to lack of precision in identification on T2-low
with the identification of regional centers that provide all phenotypes.
aspects of service needs for the management of severe
asthma (https://www.england.nhs.uk/wp-content/uploads/
Long-acting Anticholinergics
2013/06/a14-respiratory-sev-asthma.pdf). With our in-
creasing understanding of the complexity of asthma pheno- The long-acting anticholinergic agent, tiotropium, which has
types and some of the basic pathways, and the introduction already been established as bronchodilator therapy for
of new therapies or management plans, the advantage of COPD, is now licensed as an additive bronchodilator therapy
having specialized severe asthma centers is to concentrate for patients with severe asthma. In addition to providing a
the experience and expertise of how to best integrate these small improvement in FEV1 when added on to ICS and LABA,
approaches into future treatment and management plans. and also to maintenance oral steroid therapy, there was a
small but significant reduction in time to exacerbation.67,68

Use of Current Biomarkers


Anti-IgE Therapy: Omalizumab
With the current knowledge of phenotypes (severe eosino-
philic asthma is the most identified) and biologic treatments The anti-IgE antibody, omalizumab, is an established treat-
targeted toward T2-high targets, the handful of biomarkers ment for severe allergic asthma at Step 5 of the GINA guide-
currently being used in the management of asthma are lines. A therapeutic trial of omalizumab should be considered
mostly indicative of T2-high asthma, namely blood eosino- in severe allergic asthma patients with uncontrolled asthma
phil count, serum IgE levels, levels of FeNO, and sputum despite optimal pharmacological and nonpharmacological
eosinophil count. management, and appropriate allergen avoidance, if their total
Tailoring of asthma treatment based on sputum eosino- serum IgE level is 30 to 700 IU/mL, with the possibility of
phils is effective in decreasing asthma exacerbations, while including those with levels up to 1300 IU/mL.5 The response to
use of FeNO levels was not effective in improving asthma treatment should be assessed by considering factors such as
outcomes in children and adults.59 Sputum-guided treat- quality of life, frequency of exacerbations, and health care use.
ment has been recommended for patients with moderate or If no improvement is seen after 4 months of omalizumab
severe asthma who are managed in centers experienced in treatment, continuation of treatment will likely not provide
this technique recommended by the ERS/ATS guidelines.5 benefit. A high blood eosinophil count and high FeNO con-
Usefulness of FeNO measurements has been provided for centration can predict if those patients are likely to benefit
assessing adherence to corticosteroid therapy but this re- from a reduction in exacerbations.66
mains to be validated.24
The level of blood eosinophil count has been shown to
Anti-IL5 Antibody: Mepolizumab and
predict responsiveness to corticosteroid therapy.60 Blood
Reslizumab
eosinophil counts remain the best surrogate marker for
sputum eosinophil count in comparison to FeNO and serum The use of the anti-IL5 antibodies, mepolizumab, and reslizu-
periostin levels.61 Patients with eosinophilic moderate to mab, has been approved for use in patients with severe
severe asthma characterized by high blood eosinophil counts eosinophilic asthma at Step 5 of the GINA management

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Severe Asthma Chung 97

guidelines.69 These treatments will be appropriate for patients Conclusion


with severe asthma with a history of frequent exacerbations
who demonstrate high levels of blood eosinophil counts. They, With a greater understanding of the pathological processes
both reduce exacerbations risk and improve lung function.63,70 that has led to the development of the new biologic treat-
Mepolizumab also leads to a reduction in maintenance oral ments for severe asthma and the ability to phenotype
prednisolone dose in severe oral corticosteroid-dependent patients with severe asthma, remarkable progress has
eosinophilic asthma, associated with a significant reduction been made in the management of severe asthma. There is
in exacerbations,57 which might be useful in reducing the side- a lot more to learn about the biological pathways involved in
effects associated with maintenance oral corticosteroid ther- severe asthma, particularly concerning the T2-low pathways,
apy. Benralizumab, an anti-IL5R antibody, is another biologic and these patients are devoid of any targeted treatments.
treatment that should be approved soon for treating severe This makes it imperative that severe asthma/difficult-to-
eosinophilic asthma.65 treat asthma be managed through a uniform protocol in
With the availability of two T2-based targets, anti-IgE, and specialized centers that can offer a multi-disciplinary ap-
anti-IL5 antibodies, clinicians will need guidance as to which proach, provide accurate phenotyping, and the latest treat-
antibody to use first in patients with severe asthma who ments, in addition to continue research into the causative
qualify for both treatments. mechanism in individual severe asthma patients.39 Precision
or personalized medicine defined as tailoring of medical
treatment to the individual characteristics of each patient
Bronchial Thermoplasty
based on genetic, biomarker, phenotypic, or psychosocial

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Bronchial thermoplasty is an interventional procedure ad- characteristics is the ultimate way we would providing the
ministered through three bronchoscopic procedures with best treatments for patients with severe asthma.76
the application of intraluminal thermal energy to the air-
way wall, with the aim of ablating the airway smooth Financial Disclosure
muscle in the wall, although other structures such as base- K.F.C. reports personal fees from Advisory Board member-
ment membrane, epithelial cells, and nerves are also likely ship with GSK, Boehringer Ingelheim, Novartis, Astra-
to be affected.71 The limited data available in patients with Zeneca and Teva, personal fees from payments for lectures
severe asthma indicate a modest effect in improving asthma from Astra-Zeneca, Novartis and Merck, and grants for
quality of life and some reduction in asthma exacerbations.5 research to his institution from Merck and GSK, all in
The ERS/ATS guidelines on severe asthma highlighted the relation to asthma, COPD and cough.
very low confidence in the small amount of data available
with the unknown long-term consequences of this invasive Acknowledgment
approach, and a lack of understanding as to which patients K.F.C. is a Senior Investigator of the National Institute for
may benefit from this procedure.5 A recent report also Health Research of the United Kingdom National Health
indicates that in actual clinical practice, this procedure in Service.
patients with severe asthma resulted in a high number of
adverse events following the procedure. In 152 procedures,
11.8% resulted in emergency respiratory readmission and
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