Syamsu

Subbagian Alergi Imunologi

Bagian Ilmu Penyakit Dalam FK UNHAS
Makassar
The case no. 1
Emma is a 38-year-old woman who has had asthma since infancy.
She was occasionally admitted to hospital in childhood, but her
asthma became less troublesome in adolescence.
She continued to need regular low-dose inhaled corticosteroids.
She reported a marked worsening of her symptoms after the birth of
her first child. In the past 3 years, she has used inhaled combination
therapy in the form of fixed-dose salmeterol (50 mg) and fluticasone
(500 mg), taken twice daily, and has still needed quick-relief
bronchodilators on average 2 or 3 times per day.
She awakens with asthma symptoms about once a week and is
unable to participate in fitness classes because of wheezing.
Over the past year, Emma has had 4 exacerbations for which
prednisone therapy was required. One of the exacerbations was
sufficiently severe to require a visit to an emergency department,
but she was not admitted to hospital.
Question :
1. Is it diagnosis true Bronchial asthma ?
2. How about level of severity and Control status
3. What are the cause of refractory in this
patients ?
4. What are suggest in the management this
patient?
PENDAHULUAN

Asma merupakan kata sederhana mengungkap sindrom

yang heterogen dan sangat kompleks.

Predisposisi yang sangat banyak, jalur kejadian yang

bervariasi, jenis dan jumlah sitokin yang terlibat sangat
banyak. serta respon terhadap pengobatan sangat
bervariasi masih perlu telaah
Faktor pencetus beraneka ragam dan pemberat cukup
banyak.
Phenotypic heterogeneity of asthma
♣Allergic vs Non-allergic
♣Early-onset vs Late-onset
♣Severity (resistance to treatment)
♣Aspirin intolerance
♣Occupation
♣Environment
♣Exercise-induced
♣Exacerbation-prone
♣Eosinophilic vs Neutrophilic
♣Menses-related
 Component Classification of Asthma Severity (>12 yrs)
of Persistent
Intermittent
Severity Mild Moderate Severe
>2 d/wk Throughout
Symptoms <2 d/wk Daily
but not daily the day
Nighttime >1x/wk but
<2 d/mo 3-4x/mo Often 7x/wk
Impairment

awakening not nightly

>2 d/wk
but not daily & Several times
SABA use <2 d/wk Daily
not >1x on any per day
day
Interference Extremely
with activity
NONE Minor limitation Some limitation
limited
• Normal FEV1 • FEV1 : >80% • FEV1: >60% but • FEV1: <60%
between predicted <80% predicted
exacerbations
Lung • FEV1/FVC: normal • FEV1/FVC:
• FEV1: >80%
function predicted
• FEV1/FVC: reduced 5%
• FEV1/FVC: reduced 5%
normal
Exacerbations
RISK requiring oral
0-1/yr ≥2/yr
steroids Consider severity and interval since last exacerbation as
they may fluctuate over time in any severity category
Recommended Step 1 Step 2 Step 3 Step 4 or 5
TERMINOLOGY
Names for difficult asthma
 Severe refractory asthma
 Difficult to control asthma
 Brittle asthma
 Severe asthma
 Therapy-resistant asthma
 Steroid-dependent asthma
 NSAID hypersensitivity asthma
 Poorly controlled asthma
 Irreversible asthma
When is a severe acute episode happening?
• Limited ability to speak
• Pulsus paradoxus > 25mmHg
• Pulse >110/min
• RR >25-30/min
• Flow rates <50% predicted
• O2 saturation <91-92%
• Some consider flow rates < 35% predicted
to be life-threatening
 CLINICAL DANGER SIGNS

Use of accessory muscle of respiration

Brief fragmented speech
Inability to lie spine
Profound diaphoresis
Agitation
Severe symptoms that fail to improve initial emergency
department

•Life threatening airway obstruction can STILL OCCUR

when there signs are not present
 DON’T EVEN WAIT IF :

1. Inability to :
a. Maintain respiratory effort
b. Cyanosis
c. Depressed mental status
2. All three foreshadow imminent respiratory arrest
3. DON’T WAIT INTUBATE
 DIAGNOSIS
Hx : Prior intubation for asthma attack
Pex: Alteration of consciousness, fatigue, upright posture,
diaphoresis, accessory muscle breathing,
tachycardia, tachypnea, pulsus paradoxus
IMPORTANT : look in the mouth : obstruction may be
in the upper airway (epiglottis, angioedema)
No. GEN POLIMORFISME BERHUBUNGAN DENGAN PUSTAKA
FENOTIP
1 Interleukin 4 C-589T FEV1 < 50 % Nat Immunol. 2010 July;
(IL-4) Asma fatal atau hampir fatal 11(7): 577–584
2 Interleukin 4 reseptor-ɑ (IL-4RA) Q576R Obstruksi saluran napas berat Nat Immunol. 2010 July;
11(7): 577–584
3. Adrenergic reseptor ß2 (ADR-ß2) R16G Asma malam Respir Res. 2008; 9(1): 4.
Asma tergantung steroid The
Tak terkait asma fatal Pharmacogenomics
Journal (2001) 1, 27–
37
4 Adrenergic reseptor ß2 (ADR-ß2) A16G Resisten terhadap tiotropium bromida Allergy Asthma Immunol
Res. 2010 July;2(3):177-
182.
5 Tumor Necrosis Factor ɑ (TNF-ɑ) A-308G Asma berat The Pharmacogenomics
Tak terkait asma fatal Journal (2006) 6, 311–326.
6 Leukotriene-C4 A-444C Asma Intoleran Aspirin Curr Opin Pulm
Synthase (LTC4S) Med. 2009;15(1):57-62.
7 cysteinyl leukotriene receptor 1 C-945T dan T927C Resiten terhadap antileukotrin Curr Opin Pulm
((CYSLTR1) Med. 2009;15(1):57-62
8 Theophylline metabolism (CYP G-2964T Theophylline intoxication J Manag Care Pharm.
IA2) 2007;13(6):497-505
9 Interleukine 13 (IL-13) C-1112T Resisten terhadap antileukotrin Nat Rev Immunol 2008 ,
8:169-182
10. glucocorticoid receptor (NR3C1) D641V, G679S, V729I, Resisten terhadap steroid Allergy Asthma Immunol
and I747M Terkait asma fatal pd negro Res. 2010 July;2(3):177-
182.
11. Corticotropin releasing hormone GAT Resistensi terhadap steroid Curr Opin Pulm
receptor 1 (CRHR1) Med. 2009;15(1):57-62.
Sel mast
Makrofag
Eosinofil
Limfosit T
Neutrofil
Bronkokonstriksi
Basofil Eksudasi plasma
Trombosit Hipersekresi mukus
MEDIATOR
Hiperresponsif sal.napas
Sel neuron
Perubahan struktur
Sel epitel
Miofibroblast Histamin
Sel endotel
Sel otot polos Lipid mediator
Sitokin
Peptida
Faktor pertumbuhan
 Airway obstruction

Uneven ventilation
Hyperinflation

Work of breathing

Wasted ventilation V/Q mismatching

VO2 ,VCO2

Hypoxemia, hypercapnia

Respiratory acidosis
Metabolic acidosis
 Lung Immunological External
Prenatal morphogenesis
Fetal lung
development environment

Birth Vulnerable Neonatal lung Immunological development

airway structure (Th1 and Th2 cells)
External environment
(viruses, allergens, tobacco smoke)
Virus -related Atopy Atopy
wheeze
Tissue remodeling Airway inflammation

Bronchial Hyperresponsiveness Persistent inflammation

(BHR)
Age 3-5 years ASTHMA

Viruses, allergens,
BHR tobacco smoke,
PUBERTY “Epithelial-mesenchymal trophic unit” air pollution,
Injury, repair, remodelling exercise,
cold air, irritants

Adulthood PERSISTENT ASTHMA

Natural history of asthma

NATURAL HISTORY OF ASTHMA
Gbr 2. Inflammatory
Mediators and cell
types in the
pathogenesis of
airway remodeling in
asthmatic patients.
Asthma associa-
ted inflammation
primarily involves Th2
and Th17 pathway.
MCP1, Monocytes
chemoatractan
Protein 1; MIP-1a,
Macrophage
Inflammatory protein
1a
Fig 3.Mechanisms of airway
remodeling In asthmatic patients.
Asthma associated
Inflammatory mediators exert
their effects on different cell types
in the lung, leading to fibrosis,
excess mucus production,
angiogenesis, and increased
airway smooth muscle mass. MIP-
1a, Macrophage Inflammatory
Protein 1a
 attack
Asthma: attack

---------------------------------------------------------------------- attack

symptoms

---------------------------------------------------------------------- MPI

Asthma time
Trigger
Trigger
“heavy”
MPI:
Single
combination
mild
minimal
persistent inflammation
i
SEVERITY OF ASTHMA EXACERBATION

GINA 2006 28
Criteria for administration of omalizumab
• Age > 12 years
• Positive result on skin testing or in vivo reactivity to at least one
perennial aeroallergen
• Baseline immunoglobulin E levels of 30–700 IU/mL
• Weight 20–150 kg
• Calculated dose of omalizumab < 750 mg
• Severe or inadequately controlled asthma, as defined by
frequent exacerbations or the need for daily or frequent oral
corticosteroids, despite appropriate environmental control,
smoking cessation, patient education and consistent therapy
with inhaled corticosteroid at a minimum daily dose of 500 μg of
fluticasone or equivalent plus adjunctive therapy
TABLE 3. DISEASES ASSOCIATED WITH ASTHMA
• Allergic bronchopulmonary aspergillosi
• Hyperventilation/panic disorder
• Eosinophilic pneumonia
• Carcinoid syndrome
• Churg-Strauss syndrome
• Thyrotoxicosis
• 1-Antitrypsin deficiency
• Obstructive sleep apnea
• Vocal cord dysfunction
• Obesity
1. Confirm diagnosis
a. Ensure careful detailed history has been taken and full
examination performed.
b. Spirometry. Perform full inspiratory and expiratory loops if
possible. The expiratory loop may show small-medium
airways obstruction, but it may also be normal in children with
difficult asthma who do not yet have fixed airway
remodelling. Change in spirometry may occur in some children
simply on repeated expiratory forced manoeuvres. Spirometry
may also point to other pathology, eg. large airway pathology.
c. Perform reversibility test: calculate difference between FEV1
pre and post 400 micrograms salbutamol via large volume
spacer. An increase of 12% is significant.
d. A peak flow diary may be useful in some children to show
trends.
e. Ensure that trials of appropriate therapies have already been
tried, e.g. leukotriene receptor antagonist (montelukast),
long acting beta agonist (salmeterol or formoterol).
f. If not already done, switch separate inhalers to a combination
device, e.g. Seretide or Symbicort. Consider use of Symbicort as
a reliever device if appropriate.
g. Measure exhaled Nitric Oxide (eNO). This can be measured by
the BRI Pulmonary function testing (PFT) lab or by us once we
have our own equipment. A raised eNO (>20 ppb) is associated
with airway inflammation in asthma, and it usually falls if a
child is taking inhaled corticosteroids.
h. Consider arranging induced sputum examination.
i. Sometimes arranging an admission for a few days is useful to
observe symptoms, assess compliance in hospital, and record
serial spirometry.
j. Establish response to oral steroid therapy Consider the use of
long term low dose (preferably alternate day) steroid therapy.
k. Specific written advice about steroid replacement in the event
of a severe intercurrent illness should be part of the
management plan for children treated with ≥800 micrograms
per day of BDP or equivalent
2. Reasons for treatment failure
a. Inappropriate delivery devices: assess technique and modify
device use / choice if necessary.
b. Poor adherence: ask for their perception of compliance,
quantify number & type of prescriptions, concentrate on
education, use adherence chart. Consider a trial of
intramuscular triamcinolone (80mg as a single dose, 40mg in
<5 yrs).
c. Environmental factors: identify environmental allergens and
quantify allergy using skin prick or RAST testing. Suggest
allergen avoidance or removal strategies; provide opportunity
and help for smoking cessation (patients and family).
d. Psychosocial problems: attempt to identify factors, if
appropriate, consider referral to psychology service.
3. Consider alternative diagnoses or possible precipitating factors
a. Cystic fibrosis
b. Primary ciliary dyskinesia
c. Vocal cord dysfunction
d. Obliterative bronchiolitis
e. Bronchiectasis
f. Inhaled foreign body
g. Vascular ring / tracheobronchomalacia
h. Gastro-oesophageal reflux
i. Recurrent aspiration
j. Immunodeficiency
k. Congenital lung abnormalities
l. Congenital heart disease
Consider the following investigations
a. CXR
b. CT thorax (e.g. if interstitial lung disease or obliterative
bronchiolitis suspected)
c. Total IgE, specific IgE, skin prick testing
d. Immune function: IgG, IgA, IgM; (also consider as appropriate:
IgG subclasses, complement concentrations, neutrophil
function, antibody response (against tetanus, Hib,
Pneumococcus))
e. Sweat test
f. Barium swallow
g. pH study
h. Nasal brushing for ciliary beat frequency / ultra-structure
i. Flexible bronchoscopy
j. Micro-laryngoscopy
k. EchocardiographyC
TABLE 3
ENVIRONMENTAL FACTORS THAT COULD
PLAY A ROLE IN REFRACTORY ASTHMA
-------------------------------------------------------------------------
1. Tobacco smoke
a. In utero
b. Environmental
2. Allergen sensitization
3. Viral infections
4. Occupational agents
5. Air pollutants
6. Stress
Difficult Asthma Clinic

Diagnosis
of Asthma Referred to DAC
excluded
and Confirm Diagnosis
discharged

Identify and Manage Aggravating Factors

Control
Control Achieved
Achieved and
and Optimise Asthma Management Skills Discharged
Discharged
Control Control
Achieved
Trial Add on Therapies NOT
1
and 2
Achieved
Discharged 3 and remain
or remain under the
under DAC care of DAC
Other drugs as additional
 Other anti inlammation : methotrexate,
gold salt, cyclosporine, anti TNF
 Anti leukotrine : zafirlukast, montelukast
 Anti IgE : omalizumab
 Cytokine modulator
 Bronchothermoplasty
Table 1: Other treatments for severe asthma
Therapy or therapeutic Mode of Dosage Quality evidence, Cost Principal adverse effects
agent administration level
Methotrexate oral 5-25 mg/wk I $ Anemia, diarrhea, nausea,
single fibrosis, pulmonary toxicity
opportunistic infection

Cyclosporin A oral 3 mg/kg twice I $$$ Hypertension, renal failure,

with target serum hypertrichosis, parasthesia
concent 150 mg/L

Auranofin (gold salt) Oral 3 mg twice daily II-2 $$ Urticaria, stomatitis, leukopenia,
thrombocytopenia, proteinuria
Intravenous Intravenous 4 doses (1g/kg BW) I $$$ Aseptic meningitis syndrome,
Immunoglobulin first 2 doses on Thromboembolic events, renal-
consecutive days, impairment, hemolytic anemia
subsequent doses
once every 4 wks
Diaminodiphenyl Oral 100 mg twice daily II-2 $ Methemoglobinemia, hypersensitivity
sulfone (dapsone) reactions, agranulocytosis,
peripheral neuritis, psychosis
Hydroxychloroquine Oral 300–400 mg/d II-2 $ Hypersensitivity, liver and
renal toxicity, blood dyscrasias
Anti-interleukin-5 Intravenous 750 mg, given II-2 NA Local reaction at injection site
monthly
Anti-interleukin 12 Subcutaneous Weekly injections of II-2 NA Local reaction at injection site
increasing dose: 0.1,
0.25, 0.5 μg/kg

Bronchial Invasive Several serial sessions II-2 NA Short term increase in cough and
Thermoplasty bronchoscopic wheeze
procedure
CMAJ • JANUARY 12, 2010 • 182(1)