Slide Severe Respiratory Tract Allergy_IPACI 2025[1]

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ALERGI IMUNOLOGI DKI JAKARTA
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9 Indonesian Pediatric & Clinical Immunology Meeting 2024
“Moving Toward High Evidence Practice on Pediatric Allergy and Clinical Immunology Care”
8-10 Juni 2024, Ritz Carlton, Jakarta
Management of Severe
Respiratory Tract Allergy
Wisnu Barlianto
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SEVERE ASTHMA
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What is asthma
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined
by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough,
that vary over time and in intensity, together with variable expiratory airflow limitation. Airflow
limitation may later become persistent.
How is asthma diagnosed

The diagnosis of asthma is based on the history of characteristic symptom patterns and evidence of
variable expiratory airflow limitation. This should be documented from bronchodilator reversibility
testing or other tests.
GINA, 2023
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The asthma management cycle for personalized asthma care
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GINA 2023 Box 3-2 GINA, 2023

© Global Initiative for Asthma, www.ginasthma.org
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Box 6-6 © Global Initiative for Asthma, www.ginasthma.org

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Box 3-13 © Global Initiative for Asthma, www.ginasthma.org

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*Anti-inflammatory reliever (AIR) Box 3-12 © Global Initiative for Asthma, www.ginasthma.org
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What is difficult to treat asthma

asthma that is uncontrolled despite prescribing of medium- or high-dose ICS with a second controller
(usually a LABA) or with maintenance OCS, or that requires high-dose treatment to maintain good
symptom control and reduce the risk of exacerbation. It is associated with poor control due to an
incorrect diagnosis or associated comorbidities, poor medication adherence, psychological or
environmental factors
What is severa asthma
Asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller
(and/or systemic corticosteroid) to prevent it from becoming “uncontrolled” or remains “uncontrolled“
despite this therapy.
GINA, 2023
IPACI
Proportion of adults have difficult-to-treat or severe asthma
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GINA, 2023
IPACI
Prevalence of mild-to-moderate and severe asthma in children
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Sex Age
Children aged 0-5 years Total Males Females 0-1 2-3 4-5
Mild-to-moderate asthma 4413.2 4788.1 4021.2 3458.5 4674.9 5052.7

(4396.4-4430.0) (4763.7-4812.6) (3998.3-4044.3) (3432.1-3485.0) (4645.4-4704.5) (5022.0-5083.7)
Severe asthma 11.0 12.7 9.3 7.1 8.8 16.9

(10.2-11.9) (11.4-14.0) (8.2-10.5) (6.0-8.5) (7.6-10.2) (15.2-18.9)
Sex Age
Children aged 6-11 years Total
Males Females 6-7 8-9 10-11
Mild-to-moderate asthma 2545.2 2831.3 2244.8 3349.6 2496.9 1829.9

(2532.9-2557.5) (2813.2-2849.5) (2228.2-2261.4) (3324.9-3374.4) (2475.9-2518.2) (1812.1-1848.0)
Severe asthma 22.8 25.7 19.7 23.3 24.1 21.0

(21.6-24.0) (24.0-27.5) (18.1-21.3) (21.2-25.4) (22.1-26.3) (19.1-23.0)
Data are presented as prevalence (95% confidence interval) per 100.000 individual. The 95% confidence intervals (Cis) were
calculated using the Wilson confidence interval for a binomial distribution.
Kimura Y et al. Allergy. 2024;00:1–5.

IPACI
Treatment algorithm for severe asthma
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1. Assure diagnosis 2. Classify severity and type 3. Treat and prevent
Hamelmann. Allergy. 2019;74:2280–2282

1. Assure Diagnosis IPACI
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Diagnosis other than SA, e.g. :

Asthma ? no • Anatomic abnomartilies • Gastro-esopaphageal reflux GERD
• Bronchiectasis • Immunodeficiency WHO-criteria for severe asrhma:
• Cardicvascular disease • Interstitial lung disease (EAE) • Untreated severe asthma - diagnosis
• Ciliary dysfunction (PCD) • Psychogenic breathing problems not confirmed
yes • COPD • Recurrent obstructive bronchitis
• Difficult-to-treat asthma -
• Cystic fibrosis (CF) • Vocal cord dysfunction (VCD)
suboptimal treatment
Comor- Treat comorbidities, e.g. :
yes
• Allergic rhinitis • Treatment-resistant severe asthma -
bidities ? • Chornic sinusitis poor control
• Obesity
yes
*ERS-criteria for severe asthma :
Adhe- no Secure treatment adherence : 1. Chronic-obstructive symptoms - most
rence ? • Inhalation training days during last 3 months

• Asthma education for parents and patients
2. High treatment level - oral CS
yes daily/every 2nd day for control
3. Acute severe asthma attascks - >2
Treat- no Adjust according to guidelines :
hospital adminissions or OCS in last year
ment • GINA
• Natlional guidelines
yes
VS
Severe asthma Difficult-to-treat asthma*
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Overview of pulmonary and extrapulmonary comorbidities in severe asthma,

in adults and children.
Ronco L et al. 2022 Front. Pediatr. 10:932366

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Allergic rhinitis
Allergic rhinitis (AR) is considered a major risk factor for asthma onset and uncontrolled or moderate-to-
severe AR can significantly affect asthma control, being associated with more frequent wheeze attacks.
Interactions between the upper and lower respiratory tracts are well known as they share anatomical,
functional, pathogenic and immunological patterns, so that allergic airway disease represents a
continuum of a single inflammatory process
Chronic rhinosinusitis
It has been demonstrated to be associated with impaired asthma control and increased exacerbation
frequency, in a common ground due to a systemic cyclic inflammatory response, which is not only by
contiguity between upper and lower airways, but it is the result of a complex interplay among several
immunological mechanisms both inside and outside the respiratory system
GINA, 2023
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Obesity
Obesity is known to be an aggravating factor of many pulmonary conditions, through effects on lung
mechanical function and altered immunological and inflammatory state. This is due to high excessive
ventilator response for metabolic demands and chronic mild inflammation caused by augmented
proinflammatory cytokines such as leptin and reduced anti-inflammatory ones (adipokine) from the
adipose tissue
Gastro esophageal reflux disease
GERD is thought to enhance bronchoconstriction through vagal nerve stimulation and micro aspiration
of small amount of gastric and duodenal contents that irritate and damage the airways leading to
release of inflammatory cells and mediators.
GINA, 2023
2. Classify severity and type IPACI
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Measure :
1. Level of lung function : 3. Level of treatment :
5. Level and type of
1. FVC/FEV1 1. ICS dose
inflammation, if
2. FEV1 2. OCS
applicable :
3. MEF25 3. LABA
1. IgE serum level
4. PEF 4. LTRA
2. Specific
5. Reversibility 5. LAMA
sensitization
2. Level of control : 6. Biologicals
3. Eosinophils in PB
1. ACT 4. Level of instability/ 4. FeNO WHO-criteria for severe asrhma (3) :
2. ACQ • Untreated severe asthma - diagnosis
future risk : 5. Induced sputum
not confirmed
1. No. of exacerbatios 6. BAL fluid
• Difficult-to-treat asthma -
2. No. of hospital admissions 7. Bronchial biopsy
suboptimal treatment
3. No. of unscheduled visits
• Treatment-resistant severe asthma -
4. Exacerbation score
poor control
Severity and type of SA

3. Treat and prevent IPACI
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SA* ? no Assure diagnosis and classify :

Algoritma part 1 & 2
yes
Uncon- Remain at current treatment level :

no
trolled ? Control at reguler intervals
yes
Step-up therapy according yo guidelines :
• Preferentially no mono-therapy with high-dose ICS
• In patients >6 years of age on high-dose ICS/LABA: try add-on LAMA
• Assess symptoms, lung function, level of control after 4-6 weeks
Uncont- no Remain at current treatment level :

Criteria for asthma control in children and
rolled ? Control at reguler intervals
adolescentts (4) :
yes 1. No symptoms or use rescue medication
Step-up therapy according yo guidelines : 2. Normal daily activities
1. Use biological according to inflammatory profile :
1. In patients >6 years with severe allergic asthma : add-on mepolizumab 3. Normal lung function
2. In patients >6/12 years with eosinophilic asthma : add-on mepolizumab
(reslizumab/dupilumab)
2. Avoid use of systemic corticosteroids for longer period (>1 week)
3. Assess symptoms, lung function, level of control after 4-6 weeks Hamelmann. Allergy. 2019;74:2280–2282
Monoclonal antibodies (mAbs) effective in the treatment of patients IPACI
with severe asthma
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Varricchi G, Ferri S, Pepys J, et al. Allergy. 2022;77:3538-3552

Algorithm for assessment and choice of a biologic for children and IPACI
adolescents with severe asthma
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Allergic asthma if evience of sensitization to ≥ 1

parennial aeroallergen and total IgE 30-1300 IU/mL (6-11
years) or 30-700 IU/mL (12+ years)
Difficult to control asthma
Nonallergic asthma if NO evidence of sensitization Confirm diagnosis, adherence, inhaler technique,
to ≥ 1 parennial aeroallergen, or total IgE <30, environment exposures, comorbidities
or >1300 IU/mL (6-11 years) or >700 IU/mL (12+ years)
Nonbiologic step-ups
*Consider coexisting disorder
• OMA – chronic idiopathic urticaria
• MEPO – HES, CRSwNP, EGPA
• DUPI – atopic dermatitis, CRSwNP, EoE Severe uncontrolled asthma
Phenotyping – blood EOS, FeNO, tIgE & sIgE/skin test, lung function
Blood EOS <150 cells/µL Blood EOS 150-1500 cells/µL Blood EOS >1500 cells/µL
Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

Phenotyping – blood EOS, FENO, tIgE & sIgE/skin test, lung function
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FENO <20 ppb FENO ≥20 ppb
Allergic asthma Nonallergic asthma Allergic asthma Nonallergic asthma
DUPI*,
OMA* NONE Or OMA* DUPI*, 6-11 YEARS
OMA*, DUPI*, DUPI*,

Or TEZ TEZ OMA*, Or TEZ 12+ YEARS
Or TEZ

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FENO <20 ppb FENO ≥20 ppb
Allergic asthma Nonallergic asthma Allergic asthma Nonallergic asthma
DUPI*, DUPI*, DUPI*, DUPI*,

6-11 YEARS MEPO*, MEPO* MEPO*, MEPO*
Or OMA* Or OMA*
BENRA, BENRA, BENRA, BENRA,

DUPI*, DUPI*, DUPI*, DUPI*,
12+ YEARS MEPO*, MEPO*, MEPO*, MEPO*,
OMA*, Or TEZ OMA*, Or TEZ
Or TEZ Or TEZ

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Rule out other causes of eosinophilia
Allergic asthma Nonallergic asthma
MEPO*,
6-11 YEARS Or OMA* MEPO*
BENRA, BENRA,
12+ YEARS MEPO*, MEPO*,
OMA*, Or TEZ
Or TEZ

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Summary of biologics approved for children and adolescents with asthma ≥6 years IPACI
Meeting
Characteristic Omalizumab Mepolizumab Dupilumab

Therapeutic target Anti-IgE Anti–IL-5 Anti–IL-4Ra
Mechanism of action Binds to free IgE, inhibits binding to FcεRI on Binds to free/circulating IL-5, thereby inhibiting Binds to IL-4Ra, blocking the downstream effects
mast cells, basophils, and plasmacytoid interaction with its Receptor of both IL-4 and IL-13
dendritic cells; FcεRII on dendritic
cells and Eosinophils
Indications Moderate-severe allergic asthma; nasal Severe asthma with an eosinophilic phenotype; Moderate-severe asthma with an eosinophilic
polyps; chronic RSwNP; EGPA; HES phenotype; moderate-severe atopic dermatitis;
chronic idiopathic Urticaria chronic RSwNP; eosinophilic Esophagitis
Dosing and frequency Based on total IgE & weight; 6-11 y: 40 mg every 4wk, ≥12 y: 100 mg every 4 6-11 y, ≤30 kg: 100 mg every 2 wk or
75-375 mg every 2-4 Wk Wk 300 mg every 4 wk, 6-11 y, >30 kg: 200
mg every 2 wk, ≥12 y: 200 mg or 300
mg every 2 wk
Route of administration SQ
Home administration Yes
Administration device(s) Prefilled syringe or lyophilized powder single- Prefilled syringe or Autoinjector Prefilled syringe or prefilled pen
use vial
IgE range 6-11 y: 30-1300 kU/L NA
≥12 y: 30-700 kU/L
Eosinophil count NA ≥150/µL ≥150-300/µL
Maximum 1500/µL

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Summary of biologics approved for children and adolescents with asthma ≥12 years IPACI
Meeting
Characteristic Benralizumab Tezepelumab

Therapeutic target Anti–IL-5Ra Anti–TSLP
Mechanism of action Binds to the IL-5Ra chain, resulting in rapid Binds to TSLP, thereby inhibiting interaction with
depletion of eosinophils via antibody- its receptor
dependent cellular Cytotoxicity
Indications Severe asthma with an eosinophilic Add-on maintenance treatment in severe
phenotype asthma
Dosing and frequency 30 mg every 4 wk 210 mg every 4 wk
Route of administration SQ
Home administration Yes No
Administration device(s) Prefilled syringe or Autoinjector Prefilled syringe
IgE range NA
Eosinophil count ≥300/µL NA
EGPA, Eosinophilic granulomatosis with polyangiitis; HES, hypereosinophilic syndrome; NA, not applicable; RSwNP, rhinosinusitis with nasal polyposis;
SQ, subcutaneous; TSLP, thymic stromal lymphopoietin

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Adverse effect profiles of biologics for asthma IPACI
Meeting
Biologic agent Common adverse reactions Agent-specific adverse reactions/safety Rare agent-specific adverse
concern reactions/safety concern
Omalizumab Injection-site reactions Serum sickness, hypereosinophilic Anaphylaxis (black box
conditions (EGPA) warning)
Mepolizumab Injection-site reactions Helminthic infections, hypereosinophilic Hypersensitivity reactions,
conditions (EGPA) herpes zoster infection
Dupilumab Injection-site reactions, Transient eosinophilia, helminthic Hypersensitivity reactions
URI/nasopharyngitis infection, conjunctivitis (with atopic
dermatitis)
Benralizumab Injection-site reactions, Helminthic infections Hypersensitivity reactions
nasopharyngitis
Tezepelumab Injection-site reactions, Pharyngitis, arthralgia, back pain,
nasopharyngitis, hypersensitivity reactions
URI, headache

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ALLERGIC RHINITIS
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Diagnosis
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nasal congestion
Diagnosis of rhinitis is suggested by
the presence of rhinorrhea (anterior and posterior)
1 or more of the following symptoms sneezing
itching
Rhinitis can be classified by pathogenic mechanisms, as allergic (AR) or nonallergic (NAR),

and differentiated from conditions that have overlapping symptoms of rhinitis.
Dykewicz MS et al. Journal of Allergy and Clinical Immunology 2020

IPACI
Classification of etiologies rhinitis in children
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Rhinitis in
childhood
Non allergic Infectious

Allergic rhinitis
rhinitis rhinitis
Idiopathic (non
Structural
allergic without
abnormalities
eosinophilia)
Roberts G et al. Allergy 2013;68:1102–1116

IPACI
Classification of rhinitis causation in children
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Roberts G et al. Allergy 2013;68:1102–1116

IPACI
Pathophysiology
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Okubo K et al., Japanese guidelines for allergic rhinitis 2020. Allergology International
IPACI
Physical examination of patient presenting with symptoms
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compatible with rhinitis
General • facial pallor, elongated facies, preferred mouth breathing, and any evidence of
systemic disease.
observation
• Excessive lacrimation, erythema, and swelling of the bulbar and/or palpebral

conjunctiva, cobblestoning of the tarsal conjunctiva, swelling or dermatitis of outer
Eyes eyelids, Dennie-Morgan lines, or venous stasis below the lower eyelids (‘‘allergic
shiners,’’ which may occur in AR or NAR).
• Reduced patency of nasal valve; transverse external crease; external deformity

such as saddle nose, septal deviation or perforation, spurs, ulcers, perforation,
Nose prominent vessels, or excoriation; nasal turbinate hypertrophy, edema, pallor or
erythema, and crusting; discharge (amount, color, consistency), and nasal polyps

IPACI
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Ears • Tympanic membrane dullness, erythema, retraction, perforation, reduced or increased mobility,
and air-fluid levels.
• Halitosis, dental malocclusion or high arched palate associated with chronic mouth breathing,
Oropharynx tonsillar or AH, cobblestoning of the oropharyngeal wall, pharyngeal postnasal discharge,
temporomandibular joint pain or clicking with occlusion, furrowing, coating, or ulceration of
tongue or buccal mucosa.
Neck • Lymphadenopathy, or tenderness, thyroid enlargement or nodule.

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• Signs of asthma such as wheezing or other abnormal or

Chest diminished sounds by auscultation.
Skin • Rashes, especially eczematous or urticarial (distribution and

description), or dermatographism.
Other organ
• When history or general observation indicate these should
system be included.

CLASSIFICATION AND TREATMENT OPTION
Klimek et al. Allergo J Int (2019) 28:255–276

IPACI
Next-generation ARIA guidelines 2020
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Bousquet et al. J Allergy Clin Immunol. 2020

IPACI
Next-generation ARIA guidelines 2020
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Bousquet et al. J Allergy Clin Immunol. 2020

IPACI
Intermitten allergic rhinitis
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pharmacologic treatment
age 12 and older
Dykewicz MS et al. Journal of Allergy

and Clinical Immunology 2020
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Intermitten allergic rhinitis

pharmacologic treatment
age 12 and older
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Dykewicz MS et al. Journal of Allergy

and Clinical Immunology 2020
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Most of the meds listed in the algorithm are approved for use in children < age 12
Comparative trials have, for the most part, been limited to those 12 years of age
The principles of treatment of children are the same as for adults, but special care must be
given to dosage adjustment, adverse effects, and long-term safety
Most pharmacologic treatments for AR are approved for children down to age 5 years,
and many down to age 2 years or even younger

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Review of pharmacotherapy classes for rhinitis
Oral antihistamine We recommend against prescribing a first- Strength of

generation antihistamine and are in favor of a recommendation : Strong
(Recommendation 6) second-generation antihistamine when prescribing
an oral antihistamine for the treatment of AR.
Oral leukotriene receptor We suggest that the clinician not select the oral Conditional
antagonist leukotriene receptor antagonist (LTRA) montelukast
for the initial treatment of AR due to reduced
(Recommendation 7) efficacy when compared with that of other agents.

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Systemic corticosteroids We suggest that for the treatment of very severe or Strength of
intractable AR, the clinician may consider a short recommendation:
(recommendation 9,10) course (5-7 days) of oral corticosteroids. Conditional
We suggest that for the treatment
of very severe or intractable AR, the clinician not
prescribe a depot parenteral corticosteroid for AR
due to the potential risks of systemic and local
corticosteroid side effects.
Intranasal antihistamin We recommend that the clinician offer INAH as a Conditional
first-line option for patients with intermittent AR
(recommendation 13)

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Intranasal corticosteroids We recommend that when choosing monotherapy for Strength of recommendation :
(IRecommendation 14) persistent AR, INCS be the preferred medication. Strong
Intranasal decongestants We suggest that the use of intranasal decongestants be Conditional
(Recommendation 16) short term and used for intermittent or episodic therapy of
nasal congestion.
Oral decongestan We suggest that oral decongestant agents be used with Conditional
(Recommendation 18) caution in older adults and children younger than 4 years
old, and in patients of any age who have a history of cardiac
arrhythmia, angina pectoris, cerebrovascular disease,
uncontrolled hypertension, bladder outlet obstruction,
glaucoma, hyperthyroidism, or Tourette syndrome.

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UKK CABANG

How is asthma diagnosed

GINA 2023 Box 3-2 GINA, 2023

Box 6-6 © Global Initiative for Asthma, www.ginasthma.org

Box 3-13 © Global Initiative for Asthma, www.ginasthma.org

What is difficult to treat asthma

Mild-to-moderate asthma 4413.2 4788.1 4021.2 3458.5 4674.9 5052.7

Severe asthma 11.0 12.7 9.3 7.1 8.8 16.9

Mild-to-moderate asthma 2545.2 2831.3 2244.8 3349.6 2496.9 1829.9

Severe asthma 22.8 25.7 19.7 23.3 24.1 21.0

Kimura Y et al. Allergy. 2024;00:1–5.

1. Assure diagnosis 2. Classify severity and type 3. Treat and prevent

Hamelmann. Allergy. 2019;74:2280–2282

Diagnosis other than SA, e.g. :

Adhe- no Secure treatment adherence : 1. Chronic-obstructive symptoms - most

rence ? • Inhalation training days during last 3 months

Overview of pulmonary and extrapulmonary comorbidities in severe asthma,

Ronco L et al. 2022 Front. Pediatr. 10:932366

Severity and type of SA

SA* ? no Assure diagnosis and classify :

Uncon- Remain at current treatment level :

Uncont- no Remain at current treatment level :

Varricchi G, Ferri S, Pepys J, et al. Allergy. 2022;77:3538-3552

Allergic asthma if evience of sensitization to ≥ 1

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

FENO <20 ppb FENO ≥20 ppb

Allergic asthma Nonallergic asthma Allergic asthma Nonallergic asthma

OMA*, DUPI*, DUPI*,

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

FENO <20 ppb FENO ≥20 ppb

Allergic asthma Nonallergic asthma Allergic asthma Nonallergic asthma

DUPI*, DUPI*, DUPI*, DUPI*,

BENRA, BENRA, BENRA, BENRA,

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

Rule out other causes of eosinophilia

Allergic asthma Nonallergic asthma

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

Characteristic Omalizumab Mepolizumab Dupilumab

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

Characteristic Benralizumab Tezepelumab

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

Bacharier LB. J Allergy Clin Immunol 2023;151:581-9

1 or more of the following symptoms sneezing

Rhinitis can be classified by pathogenic mechanisms, as allergic (AR) or nonallergic (NAR),

Dykewicz MS et al. Journal of Allergy and Clinical Immunology 2020

Non allergic Infectious

Roberts G et al. Allergy 2013;68:1102–1116

Roberts G et al. Allergy 2013;68:1102–1116

compatible with rhinitis

• Excessive lacrimation, erythema, and swelling of the bulbar and/or palpebral

• Reduced patency of nasal valve; transverse external crease; external deformity

Dykewicz MS et al. Journal of Allergy and Clinical Immunology 2020

compatible with rhinitis

Neck • Lymphadenopathy, or tenderness, thyroid enlargement or nodule.

Dykewicz MS et al. Journal of Allergy and Clinical Immunology 2020

compatible with rhinitis

• Signs of asthma such as wheezing or other abnormal or

Skin • Rashes, especially eczematous or urticarial (distribution and

Dykewicz MS et al. Journal of Allergy and Clinical Immunology 2020

Klimek et al. Allergo J Int (2019) 28:255–276

Bousquet et al. J Allergy Clin Immunol. 2020

Bousquet et al. J Allergy Clin Immunol. 2020

Dykewicz MS et al. Journal of Allergy

Intermitten allergic rhinitis

OMA, DUPI, DUPI*,

DUPI, DUPI, DUPI, DUPI,