Page 46 - Škrgat, Sabina, ed. 2022. Severe Asthma - Basic and Clinical Views. Koper: University of Primorska Press. Severe Asthma Forum, 1
P. 46
endotypes4 defined by the presence or absence ly clinical practice. Thus there is also a grow-
of T2 inflammatory processes has become ing understanding that problematic asthma is
severe asthma forum 1: severe asthma - basic and clinical views the central polarizing lens through which we seldom purely severe asthma in isolation but
view asthma pathophysiology. T2 inflamma- often part of a wider constellation of adverse
tion may be driven by either (CD4+) Type 2 health issues. Attempts to highlight this by
helper (Th2) lymphocytes or innate lymphoid adoption of specific terminology with discrete
cells group 2 (ILC2).5 Th2 lymphocytes pro- definitions for “difficult-to-treat (or difficult)
duce critical “asthma-genic” cytokines in- asthma” and “severe asthma” have been pro-
cluding interleukin (IL)-4, IL-5 and IL-13. posed as outlined by the Global Initiative for
IL-4 promotes IgE production by B lympho- the management of Asthma (GINA)13. Using
cytes, increases low-affinity CD23 (FCεRII) that perspective, difficult asthma describes
IgE receptor expression on B lymphocytes and asthma in which aggravating co-morbidi-
macrophages while directing class switching ties, inadequate treatment, suboptimal in-
of naïve CD4 T-helper lymphocytes to the T2 haler technique and/or poor adherence may
type.6 IL-13 shares a common receptor (IL- individually or collectively impede good asth-
4Rα) with IL-4 and shows similar effects in- ma control. This broad definition also encom-
cluding promoting IgE production and CD23 passes the subset of patients with truly severe
expression.7,8 IL-4 and IL-13 also induce gob- asthma that remain sub-optimally controlled
let cell metaplasia and MUC5AC produc- despite optimised treatment of both asthma
tion, driving mucus production too.8 IL-5 is and contributory factors13-17. Severe asthma
a key driver of eosinophilic processes, respon- has been defined by the ERS/ATS as asthma
sible for eosinophil migration into the asth- which requires treatment with guideline sug-
matic airway where they are a predominant gested medications for GINA steps 4–5 asth-
cell type in T2 disease.9 Eosinophils are now ma (high dose ICS & long acting beta agonist
commonly regarded as the prime target for a (LABA) or leukotriene modifier/theophyl-
range of evolving asthma treatment options line) for the previous year or systemic steroids
from newer inhaled corticosteroids (ICS) and for > 50% of the previous year to prevent it
other prophylactic medications to monoclonal from becoming ‘‘uncontrolled’’ or which re-
antibody biologic treatments. The last 5-years mains ‘‘uncontrolled” despite this therapy18.
have seen a proliferation of higher level bio- For this definition, uncontrolled asthma was
logic asthma treatments enter clinical practice defined as at least one of: poor symptom con-
globally with undoubted improvements in pa- trol (as measured by standard measures such
tient outcomes. These include agents such as as Asthma Control Questionnaire or Asth-
Omalizumab, Mepolizumab, Reslizumab, ma Control Test), frequent severe exacerba-
Benralizumab and Dupilumab. Yet not all tions (2 or more bursts of systemic steroids
patients respond well to biologic treatments10. for at least 3 days at a time in the past year),
Furthermore, recent studies have also shown serious exacerbation (at least 1 asthma hos-
that following a thorough characterization, pitalisation in the past year), or airflow lim-
most patients with more problematic asthma itation (pre-bronchodilator FEV1, Forced Ex-
fall into the T2 category of disease suggest- piratory Volume in 1 second <80% predicted
ing the need to look beyond that simple patho- alongside reduced FEV1/FVC [Forced Vital
physiological paradigm in the future11,12. Capacity] defined as less than the lower lim-
it of normal). In parallel there is increasing
As our understanding of the pathophysi- emphasis on thorough and holistic assessment
ology of more severe asthma has grown, so has of patients with more difficult asthma. With
our recognition of the context in which that such approaches it is becoming evident that
disease exists in patients encountered in dai-
of T2 inflammatory processes has become ing understanding that problematic asthma is
severe asthma forum 1: severe asthma - basic and clinical views the central polarizing lens through which we seldom purely severe asthma in isolation but
view asthma pathophysiology. T2 inflamma- often part of a wider constellation of adverse
tion may be driven by either (CD4+) Type 2 health issues. Attempts to highlight this by
helper (Th2) lymphocytes or innate lymphoid adoption of specific terminology with discrete
cells group 2 (ILC2).5 Th2 lymphocytes pro- definitions for “difficult-to-treat (or difficult)
duce critical “asthma-genic” cytokines in- asthma” and “severe asthma” have been pro-
cluding interleukin (IL)-4, IL-5 and IL-13. posed as outlined by the Global Initiative for
IL-4 promotes IgE production by B lympho- the management of Asthma (GINA)13. Using
cytes, increases low-affinity CD23 (FCεRII) that perspective, difficult asthma describes
IgE receptor expression on B lymphocytes and asthma in which aggravating co-morbidi-
macrophages while directing class switching ties, inadequate treatment, suboptimal in-
of naïve CD4 T-helper lymphocytes to the T2 haler technique and/or poor adherence may
type.6 IL-13 shares a common receptor (IL- individually or collectively impede good asth-
4Rα) with IL-4 and shows similar effects in- ma control. This broad definition also encom-
cluding promoting IgE production and CD23 passes the subset of patients with truly severe
expression.7,8 IL-4 and IL-13 also induce gob- asthma that remain sub-optimally controlled
let cell metaplasia and MUC5AC produc- despite optimised treatment of both asthma
tion, driving mucus production too.8 IL-5 is and contributory factors13-17. Severe asthma
a key driver of eosinophilic processes, respon- has been defined by the ERS/ATS as asthma
sible for eosinophil migration into the asth- which requires treatment with guideline sug-
matic airway where they are a predominant gested medications for GINA steps 4–5 asth-
cell type in T2 disease.9 Eosinophils are now ma (high dose ICS & long acting beta agonist
commonly regarded as the prime target for a (LABA) or leukotriene modifier/theophyl-
range of evolving asthma treatment options line) for the previous year or systemic steroids
from newer inhaled corticosteroids (ICS) and for > 50% of the previous year to prevent it
other prophylactic medications to monoclonal from becoming ‘‘uncontrolled’’ or which re-
antibody biologic treatments. The last 5-years mains ‘‘uncontrolled” despite this therapy18.
have seen a proliferation of higher level bio- For this definition, uncontrolled asthma was
logic asthma treatments enter clinical practice defined as at least one of: poor symptom con-
globally with undoubted improvements in pa- trol (as measured by standard measures such
tient outcomes. These include agents such as as Asthma Control Questionnaire or Asth-
Omalizumab, Mepolizumab, Reslizumab, ma Control Test), frequent severe exacerba-
Benralizumab and Dupilumab. Yet not all tions (2 or more bursts of systemic steroids
patients respond well to biologic treatments10. for at least 3 days at a time in the past year),
Furthermore, recent studies have also shown serious exacerbation (at least 1 asthma hos-
that following a thorough characterization, pitalisation in the past year), or airflow lim-
most patients with more problematic asthma itation (pre-bronchodilator FEV1, Forced Ex-
fall into the T2 category of disease suggest- piratory Volume in 1 second <80% predicted
ing the need to look beyond that simple patho- alongside reduced FEV1/FVC [Forced Vital
physiological paradigm in the future11,12. Capacity] defined as less than the lower lim-
it of normal). In parallel there is increasing
As our understanding of the pathophysi- emphasis on thorough and holistic assessment
ology of more severe asthma has grown, so has of patients with more difficult asthma. With
our recognition of the context in which that such approaches it is becoming evident that
disease exists in patients encountered in dai-
