S y a m s uSubbagian Alergi Imunologi

Bagian Ilmu Penyakit Dalam FK UNHASMakassar

The case no. 1Emma 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 status3. What are the cause of refractory in this

patients ?4. What are suggest in the management this

patient?

PENDAHULUAN

Asma merupakan kata sederhana mengungkap sindromyang heterogen dan sangat kompleks.

Predisposisi yang sangat banyak, jalur kejadian yang bervariasi, jenis dan jumlah sitokin yang terlibat sangatbanyak. serta respon terhadap pengobatan sangatbervariasi masih perlu telaahFaktor pencetus beraneka ragam dan pemberat cukupbanyak.

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

of

Severity

Classification of Asthma Severity (>12 yrs)

IntermittentPersistent

Mild Moderate Severe

Symptoms <2 d/wk>2 d/wk

but not dailyDaily

Throughout the day

Nighttime awakening

<2 d/mo 3-4x/mo>1x/wk but not nightly

Often 7x/wk

SABA use <2 d/wk

>2 d/wk

but not daily &

not >1x on any day

DailySeveral times

per day

Interference with activity

NONE Minor limitation Some limitationExtremely

limited

Lung function

• Normal FEV1

between

exacerbations

• FEV1: >80%

predicted

• FEV1/FVC:

normal

• FEV1 : >80%

predicted

• FEV1/FVC: normal

• FEV1: >60% but

<80% predicted

• FEV1/FVC:

reduced 5%

• FEV1: <60%

• FEV1/FVC:

reduced 5%

RISK Exacerbations requiring oral steroids

0-1/yr ≥2/yr

Consider severity and interval since last exacerbation as

they may fluctuate over time in any severity category

Recommended Treatment Step

Step 1 Step 2 Step 3 Step 4 or 5

Imp

air

me

nt

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 respirationBrief fragmented speechInability to lie spineProfound diaphoresisAgitationSevere symptoms that fail to improve initial emergency

department

•Life threatening airway obstruction can STILL OCCURwhen there signs are not present

DON’T EVEN WAIT IF :

1. Inability to :a. Maintain respiratory effortb. Cyanosisc. Depressed mental status

2. All three foreshadow imminent respiratory arrest3. DON’T WAIT INTUBATE

DIAGNOSIS

Hx : Prior intubation for asthma attackPex: Alteration of consciousness, fatigue, upright posture,

diaphoresis, accessory muscle breathing,tachycardia, tachypnea, pulsus paradoxusIMPORTANT : look in the mouth : obstruction may bein the upper airway (epiglottis, angioedema)

No. GEN POLIMORFISME BERHUBUNGAN DENGAN

FENOTIP

PUSTAKA

1 Interleukin 4

(IL-4)

C-589T FEV1 < 50 %

Asma fatal atau hampir fatal

Nat Immunol. 2010 July;

11(7): 577–5842 Interleukin 4 reseptor-ɑ (IL-4RA) Q576R Obstruksi saluran napas berat Nat Immunol. 2010 July;

11(7): 577–5843. Adrenergic reseptor ß2 (ADR-ß2) R16G Asma malam

Asma tergantung steroid

Tak terkait asma fatal

Respir Res. 2008; 9(1): 4.

The

Pharmacogenomics

Journal (2001) 1, 27–

374 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

Tak terkait asma fatal

The Pharmacogenomics

Journal (2006) 6, 311–326.

6 Leukotriene-C4

Synthase (LTC4S)

A-444C Asma Intoleran Aspirin Curr Opin Pulm

Med. 2009;15(1):57-62.

7 cysteinyl leukotriene receptor 1

((CYSLTR1)

C-945T dan T927C Resiten terhadap antileukotrin Curr Opin Pulm

Med. 2009;15(1):57-628 Theophylline metabolism (CYP

IA2)

G-2964T Theophylline intoxication J Manag Care Pharm.

2007;13(6):497-5059 Interleukine 13 (IL-13) C-1112T Resisten terhadap antileukotrin Nat Rev Immunol 2008 ,

8:169-182

10. glucocorticoid receptor (NR3C1) D641V, G679S, V729I,

and I747M

Resisten terhadap steroid

Terkait asma fatal pd negro

Allergy Asthma Immunol

Res. 2010 July;2(3):177-

182.11. Corticotropin releasing hormone

receptor 1 (CRHR1)

GAT Resistensi terhadap steroid Curr Opin Pulm

Med. 2009;15(1):57-62.

Sel mastMakrofagEosinofilLimfosit TNeutrofilBasofilTrombosit

Sel neuron

Sel epitelMiofibroblastSel endotelSel otot polos

MEDIATOR

BronkokonstriksiEksudasi plasma

Hipersekresi mukusHiperresponsif sal.napas

Perubahan struktur

HistaminLipid mediator

SitokinPeptida

Faktor pertumbuhan

Airway obstruction

HyperinflationUneven ventilation

Work of breathing

Wasted ventilation V/Q mismatchingVO2 ,VCO2

Hypoxemia, hypercapnia

Respiratory acidosisMetabolic acidosis

Lungmorphogenesis

Fetal lung Immunologicaldevelopment

ExternalenvironmentPrenatal

Neonatal lung

Tissue remodeling Airway inflammation

External environment(viruses, allergens, tobacco smoke)

Immunological development(Th1 and Th2 cells)

Vulnerableairway structure

AtopyVirus -related Atopywheeze

ASTHMA

Bronchial Hyperresponsiveness

(BHR)Persistent inflammation

Viruses, allergens,

tobacco smoke,

air pollution,

exercise,

cold air, irritants

“Epithelial-mesenchymal trophic unit”

Injury, repair, remodelling

BHR

PERSISTENT ASTHMAAdulthood

PUBERTY

Age 3-5 years

Birth

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

Asthma: attack

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

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

Asthma time

MPI:

minimalpersistent inflammationi

Trigger“heavy”

combination

attack

TriggerSingle mild

symptoms

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 oralcorticosteroids, despite appropriate environmental control,smoking cessation, patient education and consistent therapywith 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 diagnosisa. 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 withdifficult asthma who do not yet have fixed airway remodelling. Change in spirometry may occur in some children simply on repeated expiratory forced manoeuvres. Spirometrymay 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 bythe 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 eventof a severe intercurrent illness should be part of themanagement plan for children treated with ≥800 microgramsper day of BDP or equivalent

2. Reasons for treatment failurea. 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 oneducation, use adherence chart. Consider a trial ofintramuscular 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. Suggestallergen avoidance or removal strategies; provide opportunityand 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 fibrosisb. Primary ciliary dyskinesiac. Vocal cord dysfunctiond. Obliterative bronchiolitise. Bronchiectasisf. Inhaled foreign bodyg. Vascular ring / tracheobronchomalaciah. Gastro-oesophageal refluxi. Recurrent aspirationj. Immunodeficiencyk. Congenital lung abnormalitiesl. Congenital heart disease

Consider the following investigationsa. CXRb. CT thorax (e.g. if interstitial lung disease or obliterative

bronchiolitis suspected)c. Total IgE, specific IgE, skin prick testingd. Immune function: IgG, IgA, IgM; (also consider as appropriate:

IgG subclasses, complement concentrations, neutrophilfunction, antibody response (against tetanus, Hib, Pneumococcus))

e. Sweat testf. Barium swallow g. pH studyh. Nasal brushing for ciliary beat frequency / ultra-structurei. Flexible bronchoscopyj. Micro-laryngoscopyk. EchocardiographyC

TABLE 3ENVIRONMENTAL FACTORS THAT COULDPLAY A ROLE IN REFRACTORY ASTHMA-------------------------------------------------------------------------1. Tobacco smoke

a. In uterob. Environmental

2. Allergen sensitization3. Viral infections4. Occupational agents5. Air pollutants6. Stress

Difficult Asthma Clinic

Trial Add on Therapies

1

2

3

Optimise Asthma Management Skills

Identify and Manage Aggravating Factors

Confirm Diagnosis

Referred to DACDiagnosis

of Asthma

excluded

and

discharged

Control

Achieved

and

Discharged

Control

Achieved

and

Discharged

Control

Achieved

and

Discharged

or remain

under DAC

Control

NOT

Achieved

and remain

under the

care of DAC

Other drugs as additionalOther anti inlammation : methotrexate,

gold salt, cyclosporine, anti TNF Anti leukotrine : zafirlukast, montelukastAnti IgE : omalizumabCytokine modulator Bronchothermoplasty

Table 1: Other treatments for severe asthma

Therapy or therapeutic

agent

Mode of

administration

Dosage Quality evidence,

level

Cost Principal adverse effects

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, parasthesiaconcent 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)