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Chronic Recurrent Cough and Chronic Recurrent Cough and Chronic Recurrent Cough and Chronic Recurrent Cough and

Childhood AsthmaChildhood AsthmaChildhood AsthmaChildhood Asthma

Helmi LubisHelmi LubisHelmi LubisHelmi Lubis

Ridwan M. DaulayRidwan M. DaulayRidwan M. DaulayRidwan M. Daulay

Wisman DalimuntheWisman DalimuntheWisman DalimuntheWisman Dalimunthe

Rini S. DaulayRini S. DaulayRini S. DaulayRini S. Daulay 1

Definition of cough

a sudden explosive expiratory maneuver that tends to clear materials from the airways and prevent aspiration of food or fluid

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Physiologic or pathologic?

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Cough

Physiologic Pathologic

Pathologic: �intensity, �frequency, cough characteristic, sputum

characteristic

Cough without receptor stimulation: psychogenic, habitual cough

Cough Model Reflex

Voluntary controlVoluntary controlVoluntary controlVoluntary control

of coughof coughof coughof cough

Placebo effectPlacebo effectPlacebo effectPlacebo effect

Exogenous opioidsExogenous opioidsExogenous opioidsExogenous opioids

Endogenous Endogenous Endogenous Endogenous

opioidsopioidsopioidsopioidsCough controlCough controlCough controlCough control

centrecentrecentrecentre

Respiratory area of brainstemRespiratory area of brainstemRespiratory area of brainstemRespiratory area of brainstem

+ve+ve+ve+ve ----veveveve

Cerebral cortexCerebral cortexCerebral cortexCerebral cortex

Vagus nerveVagus nerveVagus nerveVagus nerve

Sensation of Sensation of Sensation of Sensation of

irritationirritationirritationirritation

Airway irritationAirway irritationAirway irritationAirway irritation Respiratory musclesRespiratory musclesRespiratory musclesRespiratory muscles

COUGHCOUGHCOUGHCOUGH 4

Widdicombe J. Cough. Blackwell publishing 2003; 20

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Cough Reflex Arc

Vagal nerveVagal nerveVagal nerveVagal nerve

Trigeminal, FacialTrigeminal, FacialTrigeminal, FacialTrigeminal, Facial

Hippoglosus nerve, etcHippoglosus nerve, etcHippoglosus nerve, etcHippoglosus nerve, etc

Diaphragm; Diaphragm; Diaphragm; Diaphragm;

Intercostal, Intercostal, Intercostal, Intercostal,

Abdominal & lumbal Abdominal & lumbal Abdominal & lumbal Abdominal & lumbal

musclesmusclesmusclesmuscles

Respiratory tract musclesRespiratory tract musclesRespiratory tract musclesRespiratory tract muscles

Muscles involve in Muscles involve in Muscles involve in Muscles involve in respirationrespirationrespirationrespiration

Cough centerCough centerCough centerCough center EfferentEfferentEfferentEfferent EfectorEfectorEfectorEfector

MuscleMuscleMuscleMuscle,,,,

Larynx, trachea,Larynx, trachea,Larynx, trachea,Larynx, trachea,

and bronchusand bronchusand bronchusand bronchus

AfferentAfferentAfferentAfferent

Vagal nerve Vagal nerve Vagal nerve Vagal nerve

branchbranchbranchbranch

Distributed evenly Distributed evenly Distributed evenly Distributed evenly

in medulla near byin medulla near byin medulla near byin medulla near by

the respiratory the respiratory the respiratory the respiratory

center:center:center:center:

Under the higher Under the higher Under the higher Under the higher

control centercontrol centercontrol centercontrol center

ReceptorReceptorReceptorReceptor

LarynxLarynxLarynxLarynx

TracheaTracheaTracheaTrachea

BronchusBronchusBronchusBronchus

EarEarEarEar

GastricGastricGastricGastric

NoseNoseNoseNose

Sinus paranasalSinus paranasalSinus paranasalSinus paranasalTrigeminal nerveTrigeminal nerveTrigeminal nerveTrigeminal nerve

Nerve Phrenicus,Nerve Phrenicus,Nerve Phrenicus,Nerve Phrenicus,

Intercostal &Intercostal &Intercostal &Intercostal &

lumbarislumbarislumbarislumbaris

PharynxPharynxPharynxPharynxGlossopharyngealGlossopharyngealGlossopharyngealGlossopharyngeal

nervenervenervenerve

PericardiumPericardiumPericardiumPericardium

diaphragmdiaphragmdiaphragmdiaphragmNerve phrenicusNerve phrenicusNerve phrenicusNerve phrenicus

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Chang AB. Cough 2003;7:1-15.

How do we cough ?Inspiratory ExpiratoryCompressive

�Deep inspiration

(150-200% tidal

volume)

� Maximal dilation of

tracheo-bronchial tree

�Glottic closure 0.2’

�Contraction of

thoracic & abdminal

muscles vs fixed

diaphragm

����� Intrathoracic

pressure

� Expiratory muscles

contraction

� Sudden glottic

opening

�Explosive release of

intrathoracic air

Cloutier MM: Cough, in : Loughlin GM ed Resp dis in children, 1994

� Inspiratory muscles contractionInspiratory muscles contractionInspiratory muscles contractionInspiratory muscles contraction

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Figure 1. Diagrammatic representation of the changes of the following variables duringa representative cough: flow rate, volume, subglottic pressure and sound level.

McCool FD. Chest 2006;129:48S-53S.

1 2 3

0

10

2030

40

50

cmH2O

L/s

0.0

Airvolume

Subglotticpressure

Flow rates

1.0

2.03.0

4.0

5.0

6.0

positiveFlow phase

Min flowphase

Negative Flow phase

Inspiratoryphase

glottisclosure

Expiratory phase (explosive)

SoundMechanism of Cough

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�IPS(IDAI): Chronic Recurrent Cough or (Batuk Kronik Berulang / BKB)�Chronic: > 2 weeks AND/OR�Recurrent: > 3 episodes in 3 months

�BKB is not a final diagnosis, but lead to a group of diseases with the same manifestation

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Diagnosis of Asthma

“Cough and/or wheezing that:

•Hyperreactivity

•Nocturnal (variability)

•Reversibility

•Episodic

•“Atopic family”9

Inflammatory processes

Desquamation ofepithelium

Mucus plug

BasementMembranethickening

Neutrophil andeosinophil infiltrationSmooth muscle

Hypertrophy and contraction

Oedema

Hyperplasia ofMucos glands

Barnes PJ

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AsthmaNormal

Getting to asthmatic inflammation

– what does it take ???

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Inflammation in asthma

Barnes PJ

Chronic inflammation

Structural changes

Acuteinflammation

Steroidresponse

Time

12

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Environment Genetic susceptibility

Chronic allergic inflammation(Mast cells, T-Cells, Eosinophils)

AIRWAY WALL THICKENING

Pathogenesis

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Classification of asthma

• Severity of attacks

(Acute)

�Mild

�Moderate

�Severe

�Respiratory arrest

imminent

• Class of disease

(Chronic)

�Infrequent episodic

asthma

�Frequent episodic

asthma

�Persistent asthma

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Asthma : chronic respiratory disease, that can

have acute exacerbation

AsthmaAcute Asthma

Chronic Asthma

2 aspect of asthma

Asthma management

Chronic asthma

•Long term

management

•Algorithm diagnosis

& treatment

Acute asthmaAcute asthmaAcute asthmaAcute asthmaAcute asthmaAcute asthmaAcute asthmaAcute asthma

•• Attack Attack

managementmanagement

•• Algorithm attack Algorithm attack

management management

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Asthma medication, function category

Reliever

• To relieve / reduce

symptoms and/

attack

• As needed use

• Bronchodilators

• β2-agonist,

xanthenes, systemic

steroid

• Oral, inhalation,

injection

Controller

• To control / prevent symptoms and/ attack

• Long term use

• Anti-inflammations

• Inhaled steroid, ALTR

• Oral, inhalation,

• For FEA & PA, not for IEA

Acute asthma management

Asthma attack / symptoms present:

– First line therapy

• ββββ2 agonist

• Ipratropium bromide

Chronic asthma (long term management):

– First line therapy

• Inhaled steroid

• Long-acting ββββ2 agonist (LABA)

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Asthma Attack

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Why happened ??

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Asthma

Triggers

Attack

• House dust mite

(HDM)

• Smoke (polution)

• Food

• Infection

Longterm

management

failure

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PathophysiologyTrigger

Airway obstruction

Nonuniform Hyperinflation

ventilation

Atelectasis Mismatching of Decreasedventilation and perfution compliance

Decreased

surfaktant Alveolar hypoventilation Increased work

Acidosis of breathing

Pulmonary

vasoconstriction

Bronchocontriction, Mucosal edema, Excessive secretionBronchocontriction, Mucosal edema, Excessive secretionBronchocontriction, Mucosal edema, Excessive secretionBronchocontriction, Mucosal edema, Excessive secretion

↑↑↑↑ PaCOPaCOPaCOPaCO2222

↓↓↓↓ PaOPaOPaOPaO2222

84.4%84.4%84.4%84.4%

3.9%3.9%3.9%3.9%11.7%11.7%11.7%11.7%

MildMildMildMild

ModerateModerateModerateModerate

SevereSevereSevereSevere

Severity of asthma attack

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Estimation of severity of asthma attack

Sign/

Symptom

Mild Moderate Severe Imminent

respiratory

arrest Activities (infant)

Walking (loudly cried)

Talking (weak cried)

Rest (stop eating)

Talking Complete sentences

Phrasesor or partial sentences

Single words or short phrases

Position Can lie down

Prefer to seat Tripod-like sitting positions

Alertness Maybe agitated Usually agitated

Usually agitated

Confused

Cyanotic Absent Absent Present

Wheezing Moderate, end of eksp.

Loud, eksp. + insp.

Audible Difficult/ can’t be heard

Breathing difficulties

Minimal Moderate Severe

Acessory Muscle of respiration

Usually not Usually yes Yes Paradoxical movement

Retraction No intercostal to mild retraction

Moderate +, tracheosternal retraction

Deep +, +, nassal flaring

Decrease/ none

Respiratory rate

Tachypnea Tachypnea Tachypnea Decreasing

Pulse rate Normal Tachycardia Tachycardia Bradicardia

Pulsus paradoxus

Absent (<10 mmHg)

Present 10-20 mmHg

Present >20 mmHg

absent (Fatique resp. muscle)

PEF / FEV1 - pre-b.dilat. - post-b.dilat

(% predictive- >60% >80%

value/ % good 40-60% 60-80%

-value) <40% <60%

SaO2 >95% 91-95% <90%

PaO2 Normal >60 mmHg <60 mmHg

PaCO2 <45 mmHg <45 mmHg >45 mmHg

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Algorithms asthma attack

Clinic/ ERClinic/ ERClinic/ ERClinic/ ERRate attack severityRate attack severityRate attack severityRate attack severity

First managementFirst managementFirst managementFirst management

• ββββ2222----agonist nebulization (neb) 3x, 20’ intervalagonist nebulization (neb) 3x, 20’ intervalagonist nebulization (neb) 3x, 20’ intervalagonist nebulization (neb) 3x, 20’ interval• 3333rdrdrdrd neb + anticholinergicneb + anticholinergicneb + anticholinergicneb + anticholinergic

Moderate attackModerate attackModerate attackModerate attack

((((neb 2-3x, partially response)• Give O2

• Reevaluate → moderate→ One day care (ODC)(ODC)(ODC)(ODC)

• IV line

Mild attackMild attackMild attackMild attack

(neb 1x, good response

• Hold out 1-2 hours, , , ,

may go homemay go homemay go homemay go home

• Attack reappear→→→→moderate attackmoderate attackmoderate attackmoderate attack

Severe attackSevere attackSevere attackSevere attack(neb 3x,

bad/ no response)• O2 since beginning

• IV line

• Chest X ray

• Reevaluate→severe

→hospitalized

One Day Care (ODC)One Day Care (ODC)One Day Care (ODC)One Day Care (ODC)

• O2 continued• gGve oral steroid

• Neb every 2 hrs

• Improve in 8-12 hrs,

stable→ may go home

• No improve within 12 hrs,hospitalized

Hospital RoomHospital RoomHospital RoomHospital Room

• O2 continued

• Overcome dehidration

and acidosis

• IV steroid every

6-8 hrs

• Neb every 1-2 hrs

• IV aminophylline, initial-

maintenance

• Improve neb every 4-6hrs

• Stable within 24 hrs,

may go home

• No improvement,

impending resp failure -

PICUPICUPICUPICU

May go homeMay go homeMay go homeMay go home

• GGGGive β2-agonist(inhalation / oral)

• Patient with

controller, continued

• Viral ARI as trigger

steroid oral may given

• Visit outpatient clinic

in 24 hours

NoteNoteNoteNote::::

• severe attack from beginning, directly neb with

ipratropium• neb can be replaced by adrenalin sc 0.01 ml/kgBw/x,

max 0.3ml/x

• O2 2-4L/mnt from the start, including during neb

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Goals of management for asthma attack

• Relieve the symptoms quickly and precisely

• Reduce hypocxemic

• Lung function, back to normal

• After attack: reevaluation

Asthma attack

Nebulization 1-2 x

Good responses

Discharge

Bronchodilator

Poor responses

ODC

Oxygen

Nebulization

Oral Steroid

IVFD

Good Response Poor Response

Discharge

Wards

Oxygen

Nebulization

IVFD

IV/oral Steroid

Rehydration

Amynophylline

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Why no response ???

• Dehidration

• Metabolic acidosis

• Atelectasis

Severe Attack• No/ bad response after nebulization• Oxygen• Parenteral, rehidration, acidosis correction

• Steroid IV• lnitial Aminophylline IV, then the maintenance

• Nebulization• Chest X-ray• Good: May Go Home• No/ bad response: Intensive Care

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Oxygen

• Must be given in severe attack

• In severe attack, hypocxemic

Nebulization (severe attack)

• β2 agonist and ipratropium bromide vs

β2 agonist alone � better result:

– Decreased of hospitalization rate

– Decreased of symptom scoring

– Improve lung functions

– Drugs duration of action, longer

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Combination of salbutamol and ipratropium bromide

• The use of ipratropium alone, more inferior then ββββ2 agonist ����slow onset of action

• Combination use with ββββ2 agonist:

– Onset of action, faster

– Prolong effect bronchodilatation

���� masih kontroversi

���� Watson, 1988 : if large airway is involved

���� Rubin, 1996 : not routine in the beginning

of attack

ß2 agonist + ipratropium bromide

• Not acceptable yet for

-Mild asthma attack

-Moderate asthma attack

• Already acceptable

- Severe asthma attack

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IVFD

• Redehidration

– Drink less due to breathing difficulties

– vomiting

• Acid-base and electrolyte correction

• Give parenteral medication

Steroid

• Intravenous or oral

• Antiinflamation

• Controversy: the use of nebulizer

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Aminophylline

• Initial, 6-8 mg/kgBW/IV for 10-20 minutes

• Maintenance, 0,5-1 mg/kgBW/hours

• Need aminophylline plasma level

monitoring

• Be careful, narrow margin of safety

Use of other medication• Adrenaline, there is maximal dose, effect on α and β

• Salbutamol SC, have to be careful

• MgSO4, no signiffican

• Steroid inhaler, very high dose

(1600-2000 µg)

• Antibiotic, not use

• Mucolitic, not suggest for severe attack

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Longterm Management

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Classification of disease

Clinical parameter ,

And lung function

Infrequent episodic

asthmaPersistent asthma

Frequent episodic

asthma

Freq of attacks < 1x /month Daily> 1x /month

Duration of attacks < 1 week Daily>1 week

Between episodes No symptomsFrequent nocturnal

symptoms Symptoms (+)

Sleep and activity Normal AffectMay affect

Physical exam Normal AbnormalMay affect

Controller No need Steroid/combinationSteroid/combination

Lung function (No attacks)

PEF/FEV1 >80%PEF/FEV1 <60%

Variability 20-30%PEF/FEV1 60-80%

Variability (attacks) >15% > 50%> 30%

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Evolving treatment options

1975

1980

1985

1990 19952000

Large use of

short-acting

ß2-agonists

“Fear” of

short-acting

ß2-agonists

Single

inhaler therapy

(Symbicort®)

ICS treatment

introduced

1972

Adding

LAßA to ICS therapyKips et al, AJRCCM 2000

Pauwels et al, NEJM 1997

Greening et al, Lancet 1992

Bronchospasm Inflammation Remodelling43

Goal of asthma management

• Minimal (ideally no) chronic symptoms

• Minimal (infrequent) exacerbations

• No emergency visits

• Minimal (ideally no) use of as needed ß2-

agonist

• No limitations on activities (exercise)

• (Near) Normal lung function

• Minimal (or no) adverse effects from medicine44

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Allergen

avoidance

Immuno-

therapy

Pharmaco-

therapy

Education

Asthma management

COSTS

GINA, 200245

Cost ?

Availability ?

46

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Avoidance

• Avoidance of triggers : House dust mite

• Pre and during pharmacotherapy

GINA, 200247

Family Education

• Aim to:– Increase understanding

– Increse skill

– Increse satisfaction

– Increse confidence

– Increse compliance and self management

– Patient-family-doctor relationshipsGINA,2002

48

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Immunotherapy

• Desensitisation

• Controversial

• Multifactorial triggers

• Not populair

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Pharmacotherapy

Reliever:• ββββ2 agonist : inhaler, nebulized, oral

• Epinephrine : subcutan

• Theophylline : oral, I.V.

• Anticholinergic (ipratropium br) : inhaler

• Steroid : oral, I.M.

Controller:

• Steroid : inhaler

• LABA : inhaler, oral

• Leukotrien : oral

PNAA, 200250

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When??

Classifications Controller Reliever

Infrequent

episodic asthma

No Yes

Frequent

episodic asthma

Yes Yes

Persistent

asthma

Yes Yes

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Medications

• Bronchodilators

• Antiinflammations

• Anti-remodelling

• Anti IgE

• Immunizations: ??

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TREATING ASTHMATREATING ASTHMATREATING ASTHMATREATING ASTHMA

with with with with BronchodilatorsBronchodilatorsBronchodilatorsBronchodilators alonealonealonealone

is likeis likeis likeis like

PaintingPaintingPaintingPainting over rust over rust over rust over rust !!!!!!!!!!!!53

Infrequent episodic asthma

• No daily medication

• Treatment of exacerbations depend on

severity of attacks

• β-2 agonist as needed

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Frequent episodic and persistent

asthma

• Controller medications: every day

• Corticosteroid with or without any drugs

• Combination with LABA, TSR, ALT

• Gradual reduction if stable in 6-8 weeks

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Anti-inflammations

• Antihistamine

• Disodium Cromoglycate (DSCG)

• Corticosteroids

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Long-term placebo-controlled trial of ketotifen in the

management of preschool children with asthma

Loftus BG, Price JF

J Allergy Clin Immunol 1987; 79:350-5

The results suggest that:

“Ketotifen has no place in the management of young children with frequent asthma”

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Inhaled disodium cromoglycate (DSCG) as

maintenance therapy in children with asthma:

a systematic review.

Tasche MJA, Uijen JHJ, Bernsen RMD, de Jongste JC, van der Wouden JC.

Thorax 2000; 55:913-20

“Insufficient evidence that DSCG has a beneficial effect as maintenance treatment

in children with asthma”

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Low dose steroid

Medium dose steroid

Low dose steroid + LABA

Low dose steroid + ALTR

Low dose steroid +TSR

High dose steroid

Medium dose steroid + LABA

Medium dose steroid + ALTR

Medium dose steroid + TSR

ORAL

STEROID

Longterm management

59

Corticosteroids

• The most effective anti-inflammatory medications

• Improving lung function

• Airway hiperresponsiveness:�

• Reducing symptoms

• Frequency and severity of exacerbations:�

• Improving quality of life

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Epithelial Repair Following Steroid Treatment

Before After

P Howarth, 1999P Howarth, 199961

Steroid efficacy in asthma

Benefit

Steroiddose

Side-effects

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Type of inhalation therapy

• Metered dose inhaler (MDI)

– With spacer

– Without spacer

• Dry powder inhaler (DPI)

– Turbuhaler, cyclohaler

• Nebulizer

– Jet

– Ultrasonic

63

Benefit of steroid inhalation

• Low dose

• Directly to respiratory tract

• Fast onset

• Minimal systemic side effects

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LABA’s and ICS - complementary modes of action

Smooth muscledysfunction

Airwayinflammation

• Bronchoconstriction• Bronchial hyperreactivity• Hyperplasia• Inflammatory mediator release

• Inflammatory cell infiltration / activation

• Mucosa oedem• Cellular proliferation• Epithelial damage• Basement membrane thickening

�

� �

�

�

�

� �

�

�

�

Symptoms / exacerbations

LABA CS

65

CS + LABA Vs CS double dose

• Increases in PEF and FEV1

• Similar improvements in asthma

symptoms

• Similar in use of rescue medications

• Similar adverse event

• Similar in sputum markers of airway

inflammationAm J Respir Crit Care Med 2000; 161:996-1001

Eur Respir J 2001; 18:262-8

Pediatr Pulmonol 2002; 34:342-50 66

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Adding LABA to steroid improves FEV1

Pauwels et al, NEJM 1997

Pulmicort®

100 µg bid Pulmicort®

400 µg bid Pulmicort® 100 µg bid+ Oxis® 9 µg bid

Pulmicort® 400 µg bid+ Oxis® 9 µg bid

%

pre

dic

ted

70

75

80

85

90

-1 0 1 2 3 6 9 12Months

67

Corticosteroids and LABA improves quality of life of school-age children with asthma

*p<0.01 vs baseline†p<0.05 vs placeboIncreased

functional status

Decreasedfunctional status

Mean

FS

IIR

sco

re

Mahajan et al. Pediatr Asthma Allergy Immunol 1998

0

Chronicallyill children

Well children

80

90

100

0 12Time (weeks)

84

PlaceboSalmeterol 50 µg bid

**

*

*

*

207 children, 57% receiving inhaled corticosteroids

FSIIR, functional status IIR

† †

68

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Adverse event

• Hoarseness

• Throat irritations

• Candidiasis

• Headaches

• Growth??

Longterm steroid……

69

Positive impact of inhalation therapy

• Quality of life

• Quality of therapy

• Quality of life

• Quality of therapy

INHALATION

ORAL

Patient

Fam

ily F

inan

cia

l

• To another doctor• Go abroad

(Low performance of Indonesian pediatricians ����)

Stable asthma

Patient Get Patient

-

70

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71