The phenotypes of

bronchial asthma
• Asthma is a chronic inflammatory
disease of the airways. The chronic
inflammation occurring in the bronchial
system causes the bronchi to become
hypersensitive. Upon the slightest
irritant stimulus, the smooth muscles
of the bronchial wall contract
spastically, the mucous membrane
swells, the cross-section of the
bronchi narrows, and thick, sticky
mucus obstructs the passage of air
• Bronchospasm is predominantly a
reversible respiratory disorder;
however, in some patients, irreversible
airway remodeling develops. This is
an irreversible process characterized
by hypertrophy of airway smooth
muscles, thickening of the bronchial
wall, fibrosis, and increased mucus
production by epithelial goblet cells
 The non-eosinophilic
group can be further
In 1947, it was subdivided based on the
discovered that it could percentage of
be divided into at least granulocytes in the
Based on the cellular
two distinct subgroups. sample, which include
composition of
Extrinsic, also known as neutrophil (≥64%
inflammation, it can be
Initially thought to be a atopic/allergic, and neutrophil cell ratio),
categorized into
homogeneous diseases intrinsic asthma (non- mixed granular (both
eosinophilic (>3%
allergic asthma). eosinophil and
eosinophil cell ratio) and
Approximately 50% of neutrophil cell counts
non-eosinophilic
asthmatics can be elevated), and
classified into the paucigranular (neither
allergic asthma group eosinophil nor
neutrophil cell counts
increased)
• Asthma is an extremely heterogeneous group
of diseases, and the previous classification of
intrinsic and extrinsic asthma has been replaced
by endotypic and phenotypic definitions
• Endotypes refer to distinct pathomechanisms
underlying the disease, while phenotypes
encompass demographic characteristics,
clinical features, lung function, and
inflammation, allowing us to describe different
groups of asthma
• Biomarkers such as blood and sputum
eosinophil levels, exhaled nitric oxide fraction,
serum immunoglobulin E, and serum periostin
identify different asthma phenotypes
• With the increasing knowledge, we
have learned more about the
immunomechanisms regulating IgE
and the function of eosinophils and
neutrophils. It has been revealed that
chronically activated T helper cells are
at the core of asthma
• In terms of endotypes, we can
distinguish between Th2-high and Th2-
low or non-Th2 types of asthma. Th2-
high endotype is characterized by
eosinophilic airway inflammation, while
the Th2-low endotype is generally
associated with neutrophilic or
paucigranulocytic airway inflammation
• In childhood, asthma most commonly develops due to some allergen and/or physical activity, often
followed by spontaneous remission in late childhood or early adulthood. Allergen-induced asthma is
typically associated with other atopic diseases, high IgE levels, and eosinophilic inflammation, which
respond well to corticosteroid and anti-IgE therapies
• Late-onset eosinophilic asthma is often therapy-resistant and one of the most severe asthma subtypes.
Despite showing relatively mild and atypical symptoms, it is associated with persistent airway
obstruction and severe exacerbations. Therefore, early recognition is crucial, as these patients are
generally older, leading to frequent misdiagnosis of chronic obstructive pulmonary disease (COPD),
which has different treatment strategies than eosinophilic asthma. In this category, there is often an
increase in eosinophil levels in the blood and sputum, high levels of exhaled nitric oxide, resistance to
corticosteroid therapy, but a good response to dupilumab and mepolizumab
• Late-onset asthma is often associated with aspirin-exacerbated respiratory disease (AERD), creating
a clinical tetrad consisting of nasal polyposis, eosinophilic asthma, chronic rhinosinusitis, and
sensitivity to COX-1 (cyclooxygenase) inhibitors. COX-1 inhibitors can be aspirin-containing
preparations or other non-steroidal anti-inflammatory drugs (NSAIDs), the entry of which into the
body induces upper and lower airway responses in AERD patients, leading to rhinitis, conjunctivitis,
bronchospasm, or laryngospasm
• Very late-onset asthma primarily affects women (71%) and has an average age of around 50 years. In
this subtype of asthma, patients with both Th2 and non-Th2 predominance backgrounds are found.
With aging, the lung loses elasticity, and lung function declines, but the underlying mechanisms remain
largely unexplored. One of the suggested causes is that in the older generation, there is an increased
content of induced sputum neutrophil granulocytes due to Th1 and Th17 inflammation
• Non-T2 asthma primarily affects the adult population, and a significant portion of the underlying
pathomechanisms remains unexplored. Patients often show resistance to corticosteroid treatment and require
alternative therapeutic approaches, such as the use of macrolide antibiotics, theophylline, LABA or LAMA
medications, with smoking cessation being particularly important.
• Non-T2 asthma is associated with the activation of Th1 and/or Th17 cells, leading to an imbalance in the
Th1/Treg equilibrium. The triggering factors for severe non-eosinophilic asthma can include obesity, smoking,
and abnormalities affecting smooth muscles, with rare instances of atypical bacterial infections.
• There are several explanations for the connection between obesity and asthma. During obesity, there are
changes in lung functional capacity, which have secondary effects on airway smooth muscles. Additionally,
obesity is associated with systemic inflammation, which can favor the development of asthma. Steroid
treatment following an asthma diagnosis can have adverse effects as it hinders weight loss in these patients,
further worsening obesity symptoms. For this reason, it is not always clear whether obesity leads to the
development of asthma symptoms or if persistent asthma symptoms and increased steroid dosages following
exacerbations lead to obesity
• Cigarette smoke is presumed to not be directly related to the pathomechanism of asthma development, but it
is associated with severe asthma, frequent exacerbations, and declining lung function. Active smoking reduces
the expression of histone deacetylase 2, resulting in reduced glucocorticoid sensitivity. Cigarette smoke
damages the cilia lining the airways' mucous membrane, leading to mucus retention and the stagnation of
irritants in the airways, causing harm
• In the paucigranulocytic asthma group mediated by smooth muscles, patients do not show an increase in
eosinophil or neutrophil cell counts in induced sputum or blood samples. Therefore, inflammation-based
therapies are ineffective in their case. Inhaled corticosteroids have limited impact on airway inflammatory
markers, potentially defining them as a 'steroid-resistant' phenotype, necessitating the exploration of alternative
therapies. In this case, airway obstruction occurs independently of inflammation and may be caused by tissue
hypertrophy of the airway smooth muscle
STANDAR
TREATMENT

• Asthma can be classified as controlled,

partially controlled, or uncontrolled. Its
treatment consists of five steps, and the
severity determines the level of maintenance
therapy required for control.
• It is considered severe when the fourth or
fifth therapeutic step is necessary to achieve
control or when it remains uncontrolled even
with these measures. Within the latter
category, a distinction is made between
difficult-to-treat asthma (when treatment is
unsuccessful due to secondary factors such
as comorbidities or lack of patient adherence)
and true therapy-refractory asthma