Wheezy Child: Diagnostic and Therapeutic

Approach

Remziye Tanaç, M.D.Ege University Faculty of Medicine

Department of Pediatric Pulmonology and Allergy, Izmir, Turkiye.

Wheezing; Generally a pathological sound ( sometimes can be heard normally during forced expiratory maneuver) which shows pathological obstruction of lower respiratory tracts.

Wheezy Child; A child whose wheezing persists more than one month and/or has had 3 or more wheezing attacks.

Atypical WheezingGERHCystic fibrosisPrimary ciliary dyskinesiaImmune deficienciesBPDHeart diseasesFBATbcCongenital anomalies

Typical Wheezing Transient wheezingNonatopic (viral)Atopic (persistent)Severe intermittent(PRACTALL)

Tucson Children’s Respiratory Study

n= 1246Beginning in 1980, birth-cohort-11 years49 % wheezing in 0-6 years.

Martinez FD. et all. N. Eng. J. Med. 1995, 332: 133-138

Taussig LM et al JACITaussig LM et al JACI 2003;111:661-752003;111:661-75

Tucson Children’s Respiratory Study

Transient Early Wheezing• Exists in 0-3 years. • Disappears in third year.

Responsible for80 % in first year 60 % in second year 40 % in third year of all.

• Similar frequency history in family.• No asthma or atopy history in family.• No atopy, eosinophilia or

inflammation in infant. • Wheezing after viral infections.

Transient Early Wheezing (Lung Function Tests)

• Lung functions are decreased at birth.• Improves as the infant gets older.• Can’t exactly catch his/her coequals.• PEF variability in 11 years old and

response to metacholine are similar to normal children.

• Becomes COPD if smokes in adulthood.

Transient Early Wheezing Risc Factors

• Prematurity, low birth weight• Maternal smoking during pregnancy or in

postnatal period• Going to day-care center early• Siblings at home• Lower maternal age

Non-atopic Wheezing• 40 % of persistent wheezy

infants• They are non atopic.• Change in control of airway

tonus Congenital, infection relation?Congenital, infection relation?• Attacks are related with viral

infections (most commonly RSV)

• RSV increases the risk until 10th year, ineffective after 13rd year.

Tucson Children’s Respiratory StudyTucson Children’s Respiratory Study 472 LRTI;207 43.9 % RSV68 14.4 % Parainfluenza68 14.4 % Adenovirus, influenza, CMV, Chlamydia, rhinovirus, bacteria, mix infec.129 27.3 % non-infective pathogen

Non-Atopic Wheezing (Lung function tests)

• 0-3 years, RSV (+) Lung function test < RSV(-)

• Bronchodilatator responseRSV (+) Lung fxn test > RSV (-)

The difference persists during 11st year.

Atopic Wheezing (Asthma)• 60 % of persistent

wheezers.• 50 % : before 3rd year, 80

% : before 6th year• Family asthma history• Allergic rhinitis or atopic

dermatitis in patient• Eosinophilia, high serum

IgE level, BHR(+)• Early aeroallergen

sensitization

Early and Late Atopic WheezingEarly atopic wheezing

If atopic wheezing of children has been detected before 3 years old and if it persists during 6th yearHave worse lung function tests, more severe bronchial reactivity, higher serum IgE levels.

Late atopic wheezing If atopic wheezing of children has been detected after 3rd year and if it persists during 6th yearHave better lung function tests, milder bronchial reactivity, less high serum IgE levels.

Allergic sensitivity and asthmaAllergic sensitivity and asthmaFactors which alter asthma riscFactors which alter asthma risc

IncreasesIncreases• Early allergic

sensitization• Sensitization with

some aeoroallergens (perennial)

• Eosinophilia

DecreasesDecreasesIn young ages • Contact with other

children• Contact with cats• Contact with some

farm animals

Taussig LM et al JACITaussig LM et al JACI 2003;111:661-752003;111:661-75

AsthmaViral inf. wheezing

Transient wheezing

Tucson Children’s Respiratory Study

Major criteria Minor criteria

Parental asthma Allergic rhinitis

Eczema Wheezing without common cold

Eosinophilia > 4 %

Castro Rodriguez JA et al. AJRCCM 2000;162: 1403-6

CLINICAL INDEX FOR ASTHMA RISC

CLINICAL INDEX FOR ASTHMA RISC

Loose index Stringent index

Early wheezing Early frequent wheezing ≥ 3

+ +

1 major or two minor 1 major or two minor

Castro Rodriguez JA et al. AJRCCM 2000;162: 1403-6

Performance of Indexes

OR Sensitivity Specifity PPV NPV

Loose index 4 42 % 85 % 59 % 87-94 %

Stringent index

7 16 % 97 % 77 % 84-92 %

Cystic Fibrosis

• Recurrent RTI • Prolonged jaundice• Meconium ileus• Rectal prolapse• Extreme sweating• Steatorrhea• Growth retardness

• Sweat test• Cl > 60 mEq/l• Mutation analysis

Aspiration Syndromes

• H type TEF• Swallowing malfunction

Familial disautonomiaCleft palateCerebral palsyMusculary dystrophia

• GERH

• Scintigraphy• pH monitorization

Airway Compression

• Airway wall insufficiencyLaryngomalaciaTracheomalaciaSubglottic hemangioma

• Vasculary ring• Perihilar adenopathy

• Bronchoscopy• HRCT• MRI

Congenital Anomalies

• Congenital heart diseaseVSD, ASD, MS, hypoplastic

left heart• Tracheal bronchus• Diaphragmatic hernia

• ECG• ECHO• CT• Bronchoscopy

Immune Deficiencies

• IgG and subgroup deficiencies• Selective IgA deficiency• X linked infantile agammaglobulinemia -

Bruton• Common variable

hypogammaglobulinemia

IgAIgGIgG subgroup

Nonspecific Airway Irritation

• Child nursery centers• Tobacco smoke

ActivePassive

• Air pollutionSO2NONO2Particles

Infections

• RSV, Adenovirus....• Mycoplasma• Chlamydia• Tbc

Agents in Respiratory Tract Infections with Wheezing

0-12 months

1-5 years 6-15 years

RSV RSV Rhinovirus

P.Influenza P.Influenza Influenza

Adenovirus Influenza Mycoplasma

RSV Complications

• Acute ComplicationsApnea 0-6 ay 20 % SIDS

• Long-term complicationsAirway hyperreactivity

Wheezing-Asthma

Long term prognosis of bronchial hyperreactivity seen in these patients

Symptom %2 years 82 %

3.5 years 69 %

4-5 years 55 %

6-8 years 31 %

0,820,69

0,55

0,31

00,10,20,30,40,50,60,70,80,9

2years

3,5years

4-5years

6-8years

RESULT

RSV-LRTI Reactive airway 20-30 %

EUTF Department Of Pediatric Pulmonology & Allergy

1994 - 1998

Acute Bronchiolitis 161

More than 3 attacks 14.1 %

Family atopy history (+) 25 %

EUTF Department Of Pediatric Pulmonology & Allergy

Retrospective

314 patients 0-5 years oldGERH 18 % CF .006%Tracheal Br .006%Asthma 32 %FBA 1 %Bronchiolitis Ob. .025%Viral Inf.? 33 %

If the diagnosis of patient is asthma with a high probability according to all criteria

TREATMENT

CONTROLLED PARTLY CONTROLLED

UNCONTROLLED

Daytime symptoms None

(twice or less/ week)

More than twice /week

Three or more features of partly controlled asthma

present in any week

Nocturnal symtoms/ awakening

None Any

Limitation of activities None Any

Need for releiver/rescue treatment

None (twice or less/

week)

More than twice /week

PEF or FEV1 Normal < 80% predicted or personal best

Exacerbations None One or more /year One in any week

GINA 2006

Step 2 Step 3 Step 4 Step 5Step 1

Asthma EducationEnviromental Control

As needed rapid acting 2

agonists As needed rapid acting 2 agonists

Controller options

Select one Select one Add one or more

Add one or both

Low-dose ICS Low-dose ICS + LABA

Medium or high dose ICS+

LABA

Oral steroid

LTRA Medium or high dose ICS

LTRA Anti-IgE

Low-dose ICS+ LTRA

Theophylline

Low-dose ICS+ Theophylline

INCREASEREDUCE TREATMENT STEPS

GINA 2006

GINA 2006

• Antiinflammatory• LTRA effective?• Bronchodilatators

Efficacy of Bronchodilatator Usage

Bronchodilatators• Double-blind, randomized, placebo, cross overAtopic, n=48, 3 months - 1 year2 months 3x200 g SalbutamolClinical symptoms, Lung fxn tests

Result;Partial recovery.No statistical difference.

Chavasse R.:Arch.Dis.child. 2000, 2-5, 370-75

Bronchodilatators

2 agonists (short acting)Atopic n=43 < 2 years

Clinical Score +SD 3.75+1.25-2.80+1.65 p<0.0102 saturation 94.8 + 2.84 %– 95.2+ 2.54Effective (in acute period)

Bentur L.:Pediatrics 1992:89,133-37

ICS + Bronchodilatator effective

Teper A.M.: Am.J.Crit.Car.Med., 2005:171, 587

Bronchodilatators

Metaanalysis– <2 years agonist (short acting)• Randomized placebo controlled

8 study3 at home2 in hospital3 in Lung Function Test lab.

• Symptom scoresNo obvious benefit under 2 years

Bronchomotor tonus?Chavasse R.:Cochrane Database Sys.Rev. 2002: (3) CD 002873

Result: The studies are not sufficient to make a certain comment (bronchomotor tonus?). But it can be used according to guidelines in patients who are thought to be asthma with a high probability.

Efficacy of LTRA Usage

LTRA (Asthma)

• Double-blind, placebo controlled• n=689 n=228(placebo) n=461(LTRA)• 2-5 Years intermittent asthma• Duration 12 weeks• Symptom score• Drug usage

Knorr B.:Pediatrics 2001: 108:3, 1-3

Montelukast 4 mg*Montelukast 4 mg*(n=461)(n=461)

00 22WeeksWeeks

PhasePhase I I PreparationPreparation Mono-blindMono-blind

PhasePhase II IIAActive Treatmentctive Treatment (12 (12

wweekseeks))Double-blindDouble-blind

1414

PlaPlaccebo (n=228)ebo (n=228)

PlaPlacceboebo

Marked relief in symptoms.

0 2 4 6 8 10 12Weeks in study (postrandomization)

Placebo (n=227)Montelukast 4 mg* (n=458)

Knorr B et al. Pediatrics 2001;108:e48.

0.00

–0.10

–0.20

–0.30

–0.40

–0.50

–0.60

0.05

Chan

ge in

Sco

re (M

ean

± SE

)

LTRA (Asthma)• Placebo controlled study• n = 30 atopic asthma 2-5 years• Duration 4 weeks (montelukast 4 mg)• eNO, airway resistance (Rint)• Statistically significant difference in

antiinflammatory effect and resistanceStraub D.A.:Chest 2005 ; 127:509-14

Viral Infection – WheezingLTRA

RSV Inflammation

RSV

Cysteinyl Leukotrienes

(CysLTs)

TNF RANTES

IL-1IL-6

T-cell activation

IFNTh1

IL-4, IL-5Th2

MacrophagesNK cells

Neutrophils

van Schaik SM et al. Pediatr Pulmonol 2000;30:131-138

BasophilsMast cells

Eosinophils

Inflammatorymediators

Wheezing

48

cysLT concentration in secretion (log

pg/ml)

500

50Acute URI

(n=17)Bronchiolitis

(n=35)Recurrent wheeze (n=10)

p=0.009p=0.006

van Schaik SM et al. J Allergy Clin Immunol 1999;103:630-636

Montelukast - RSV Post-Bronchiolitis

• Randomized, double-blind, parallel• Hospitalized bronchiolitis• Proved RSV• 130 children • 3-36 months (mean 9 months)• Beginning of treatment: In 7 days• Duration of treatment: 28 days• Symptom score

Bisgaard H. Am J Respir Crit Care Med 2003;167:379-383

Symptom-free day and nights

(%)

Bisgaard H. Am J Respir Crit Care Med 2003;167:379-383

Days

30

20

10

00 7 14 21 28

Montelukast (n=61) mean number %22Placebo (n=55) mean number % 4

p=0.015

Weeks 48

Visits 7

8

Placeborun-in

Placebo

Montelukast 4 or 5 mg

36

1 2 3 4 5 6

241680-2-3

Bisgaard H et al. PREVIA Am J of Resp Crit Care Med 2005; 171, 315-22

Age: 2-5 years (mean 44 months)Mild asthma≥3 attacks in 12 months after URTIs

2.34

1.60

0

1

2

3

Montelukast 4 mg (n=265)

Placebo (n=257)

Exacerbations / years

32%

p0.001

Bisgaard H et al. Am J of Resp Crit Care Med 2005; 171, 315-22

As a result; in patients who has asthma with a high probability, LTRA can be used due to the guidelines.

But in patients whose asthma diagnosis is uncertain, good evaluation of the patient and more studies on this issue are needed for definite indication.

According to GINA 2006, LTRA is effective in postinfectious asthma exacerbations.

Usage and Efficacy of Inhaled Steroids

Antiinflammatory Treatment

Effectiveness ICS

School Child, Adolescent, Adult• Reduction in symptoms• Improvement in lung functions• Improvement in airway reactivity• Reduction in admissions to emergency room and

hospitalizationRytila P.:Allrgy 2004;59:839-41Merkus PJFM.:Eur.resp.J. 2004;23:861-68

Boehmer ALM.:Carr.Op.IPL Pulm.Med. 2006;12:34-41

ICS

Placebo controlled recurrent wheezingn = 30 age mean 16 (7-24) monthsTreatment: FP. 100-250 micrograms/day, duration 6 monthsSymptom score – 2 agonist usageSide effect (development, bone density)Result: effective, no side effects

Teper A.M.:Ped.Pulmonol.2004;37:111-15

ICSPlacebo controlled recurrent wheezingn = 26 age: (0-2)Treatment: FP 250 micrograms/day, duration 6 monthsVmax – FRCResult: Effective

Teper A.M.:Am.J.Crit.Care.Med. 2005;171: 584-89

ICSPlacebo controlled wheezy childn = 62 Age: 11.3 (7-20) monthsTreatment: FP 200 micrograms/day, duration 3 monthsSymptom score, VmaxFRCResult: Ineffective, duration is shortHofius W.:Am.J.Crit.Care.Med. 2005;171:328-33

ICS

Boehmer ALM: Cur.Op.Pulm.Med. 2006;12:34-41

ICS – Viral Wheezing

Placebo controlled studyn = 104 Age: 100 (84-119) monthsTreatment: BDP 400 g/gün

duration 6 monthsNumber of attacks, score , FEV1

No difference from placebo

Doul I.J.:BMJ. 1997;315:858-62

Beclomethasone 400 μg/gün

Placebo

Days with RTI sypmtoms %

16 ± 26 26 ± 29

Frequency (day/year)

5.6 ± 4.2 7.0 ± 6.1

Attack max score 3.2 ± 1.7 3.7 ± 1.8

Mean duration (day)

6.8 ± 6.0 6.3 ± 3.6

ICS – Viral Wheezing

FEV1 EffectiveDoul I.J.:BMJ 1997;315:858-62

ICS – Viral Wheezing

Placebo controlled studyn = 40 Age:1.9 (0.8-6.0)

yearsTreatment: 4 monthsScore, admission to E.R.

No difference from placebo.

Willson N.:Arch Dis.Child. 1995;72:317-20

Budesonide Placebo

Total duration

Daily score (med)

0.6 0.6

Symptom-free days (med)

73 78

Acute episode

Total score (mean)

30 31

Nocturnal / daytime cough

7.8/4.0 7.3/4.0

Nocturnal / daytime whe.

7.5/5.1 7.6/5.0

Number of episodeEpisode duration (d)

2.6

8.0

2.4

8.6

Result: Although ICSs are less effective in young ages when compared to school children and adults, it’s still more effective than the other medications in these ages.

Should be used in treatment.

Treatment in 0-2 Years (asthma)

• >3 exacerbations in last 6 months, responsive to bronchodilatators

•In acute attack (intermittent), first choice is β2 agonists.

•LTRA in viral wheezy child for controller effect

•In patients with persistent asthma, first choice is inhaled steroids (100-200 µgr /day)

•In frequently repetitive acute attacks, oral corticosteroids 3-5 days

PRACTA L.L.Allergy 2008; 63;5-34

Treatment in 3-5 Years (asthma)

• ICS first choiceBDS 100-200 µgrx2 days or Flutic 50-125 µgrx2 days

• Short acting β2 agonists, for every 4 hours 1-2 puff when needed• LTRA as a monotherapy in intermittent and mild persistent patients

instead of ICS • If not fully controlled with ICS, add LTRA • If not still well controlled, add LABA according to age. Increase ICS

dosage. Add theophylline.

PRACTALL.ALLERGY 2008:63;5-34

Well-controlled Asthma

• Daytime symptoms twice or less per week (not more than once on each day)

• No limitations of activities due to asthma• Night-time symptoms 0-1 per month • Reliever/rescue medications twice or less per week• Normal lung function (if able to measure)• 0-1 exacerbations in the last year

PRACTALL Allergy. 2008: 63;5-34

Result

• Inhale steroids are the main drugs in the treatment. Should be used.

• LTRA can be used as a monotherapy or with ICSs in post-infectious (viral) wheezings.

• Bronkodilatators can be used in acute period or if needed.PRACTALL 2008-GINA 2006

Treatment of Atypic Wheezing

• The underlying disease should be treated.

Thanks...