Eosinophilic bronchitisEosinophilic bronchitis

Exercise, cold air

Eosinophilic bronchitis

Airway hyperresponsiveness

Late asthmatic reaction

Early asthmatic reaction

Allergen

Th2

IL-5IL-4Mast cell

Th2

Mast cell

Inflammation

Variable airflow

limitation

Chronic airflow

limitation

Symptoms

Airway hyperresponsiveness

Symptoms are nonspecificSymptoms are nonspecific

Other respiratory and non-respiratory conditions

Hargreave F, AAAAI 2006

Induced sputum in OA: usefulnessInduced sputum in OA: usefulness

• To identify occupational eosinophilic bronchitis (due to an allergen or chemical sensitizer) with or without asthma.

• This is done by serial measurements of induced sputum following periods at work and away from work.

• Eosinophils that increase at work and fall away from work indicate eosinophilic bronchitis.

• To support the diagnosis when the workplace sensitizer is unknown.

• To monitor airway inflammation before/after specific inhalation challenge (SIC).

Compatible clinical history

Asthma diagnosis• Reversible airflow

obstruction

• AHR

Work-relatednessSensitization • Skin prick tests

• Sepecific IgE

Methacholine test

+ –Still at work

No Asthma

No longer at work

SIC

+

Occupacional asthma

–

Return to work

SIC PEF monitoring

+–

Non-occupationalasthma

Chan-Yeung M, Malo JL. N Eng J Med 1995

Induced sputum

Changes in induced sputum after Changes in induced sputum after specific inhalation challengesspecific inhalation challenges

Lemière C et al. J Allergy Clin Immunol 2001;107:1063-8

Clinically significant increase: 0.26 x106 eosinophils/mL

bas 10 20 30 min 1h 2h 4h 6h 8h 10h 24h0

20

40

60

80

100

120

0

20

40

60

80

% Fall in FEV1 % eosinophils in sputum

PC20 methacholine > 16 mg/mlPC20 > 16 mg/ml

Latex-induced eosinophilic bronchitis

Allergen challenge

After budesonide 800 mcg/day one month

Latex 99 ng/m3 60 minutes

Quirce et al. JACI 2001

Normal Peak Expiratory Flow variability

200220240260280300320340360380400

1 2 3 4 5 6 7 8 9 10 11 12 13 14

MaximumMinimum

PEF L/min

Days at work

Eosinophilic bronchitisEosinophilic bronchitis• Isolated chronic cough, productive of sputum • Normal lung function without variable airflow limitation• Airway hyperresponsiveness absent • Eosinophilia in sputum and BAL • Cough reflex to capsaicin increased • Normal daily variability in peak expiratory flow (<20%)

• Upper airway symptoms are common • Middle age patients • Smoking is unusual• Prevalence of atopy similar to general population • Cough, sputum eosinophilia and cough reflex to capsaicin

improve with inhaled corticosteroids Gibson et al. Lancet 1989

Causes of isolated chronic coughCauses of isolated chronic cough

Primary Cause of Cough No. of patients (%)

Rhinitis 24Asthma 17.6Postviral 13.2

Eosinophilic bronchitis 13.2

Gastroesophageal reflux 7.7

Unexplained 6.6COPD 6.6Bronchiectasis 5.5

ACE inhibitor-induced cough 4.4

Lung cancer 2.2

Cryptogenic fibrosing alveolitis 1.1

Brightling CE et al. AJRCCM 1999

Asthma Eosinophilic bronchitis

Pathogenic mechanisms IgE-dependent

IgE-independent

Unknown

Allergic sensitization?

Clinical symptoms Dyspnea, cough, wheeze Isolated cough

Atopy Common Same as general population

Variable airflow obstruction Present Absent

Airway hyperresponsiveness Present Absent

Sputum eosinophilia Usually Always at diagnosis

Cough reflex

hypersensitivity

Normal or increased Increased

Bronchial biopsy

eosinophilic infiltration

Yes Yes

Bronchoalveolar lavage

eosinophilia

Yes Yes

Mast cell infiltration of

airway smooth muscle

Yes Absent

Brightling CE et al. N Eng J Med 2002

Microlocalization of mast cells in the Microlocalization of mast cells in the airway smooth muscle airway smooth muscle

A

D

C

B

0

2

4

6

8

10

12

Act

ivat

ed b

asop

hils

(%

)

Healthy controls

Eosinophilic bronchitis

Asthma

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

2E

osin

ophi

lic

prec

urso

rs (

%)

Healthy controls

Eosinophilic bronchitis

Asthma

0

2

4

6

8

10

12

Act

ivat

ed e

osin

ophi

ls C

D69

+ (

%)

Healthy controls

Eosinophilic bronchitis

Asthma

*

*

0

0,5

1

1,5

2

2,5

3

3,5

4

Act

ivat

ed e

osin

ophi

ls C

D25

+ (

%)

Healthy controls

Eosinophilic bronchitis

Asthma

*

*

Sastre B et al (submitted).

0

300

600

900

1200

1500

1800

PG

E2

in s

putu

m s

uper

nata

nt (

pg/m

l)

Healthy controls

Eosinophilic bronchitis

Asthma

*

†

0

50

100

150

200

250

300

350

LT

C4

in s

putu

m s

uper

nata

nt (

ng/m

l)

Healthy controls

Eosinophilic bronchitis

Asthma

†A B

PGEPGE22 LTCLTC44

Sastre B et al (submitted).

Diagnostic criteria for occupational Diagnostic criteria for occupational eosinophilic bronchitiseosinophilic bronchitis

• Isolated chronic cough (lasting more than 3 weeks) that worsens at work

• Sputum eosinophilia 3% in sputum

• Increases in sputum eosinophils are related to exposure to the offending agent (either at work or after SIC)

• Spirometric parameters are normal and are not significantly affected by exposure to the offending agent

• Absence of bronchial hyperresponsiveness to methacholine both at work and away from work

• Other causes of chronic cough are rule out.

Quirce S. Curr Opin Allergy Clin Immunol 2004;4:87-91

Causative agentCausative agent No. of No. of workers workers

ConfirmedConfirmed Author, yearAuthor, year

Tetrahydrophtalic anhydride

1 ? Kobayashi, 1994

Cyanoacrylate

Methacrylate

1 At/off work

SIC in the lab

Lemière, 1997

Latex 1 At/off work/SIC lab Quirce, 2001

Mushroom spores 3 (7.1%) At work Tanaka, 2002

Lysozyme 1 (4.7%) SIC in the lab Quirce, 2004

Welding fumes 1 At/off work/SIC lab Yacoub, 2005

Formaldehyde 1 SIC in the lab Yacoub, 2005

Chloramine T 1 SIC in the lab Krakowiak, 2005

Isocyanate (MDI) 1 At/off work/SIC lab Di Stefano, 2005

Cereal flour 1 Di Stefano, 2005

RemarksRemarks

• The examination of induced sputum should be part of the diagnostic algorithm for workers who complain of asthma-like symptoms in the workplace.

• Induced sputum is a diagnostic tool complementary to objective monitoring of lung function during periods at work and away from work, and before/after specific inhalation challenge

• Eosinophilic bronchitis (without asthma) should be regarded as an occupationally-induced condition when work related changes in sputum samples are significant and reproducible.

RecommendationsRecommendations• In patients with chronic cough due to nonasthmatic

eosinophilic bronchitis, – the possibility of an occupation-related cause needs to be considered.

(Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A)

– when a causal allergen or occupational sensitizer is identified, avoidance is the best treatment. (Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A)

– first line treatment is inhaled corticosteroids (except when a causal allergen or sensitizer is identified). Level of evidence low; benefit, substantial; grade of recommendation, B.

– If symptoms are persistently troublesome and/or the natural history of eosinophilic airway inflammation progresses despite treatment with high dose inhaled corticosteroids, oral corticosteroids should be given. (Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A)

Brightling CE. Chest 2006;129:116S-21S

Park SW et al. Chest 2004

Follow-up of patients with EB after Follow-up of patients with EB after treatment with ICStreatment with ICS

Observational study of the natural Observational study of the natural history of eosinophilic bronchitishistory of eosinophilic bronchitis

• 52 patients with EB, 32 with follow-up 1 year• Mean duration of follow-up: 3.1 years (1-6 years)

– 3 patients developed asthma (9%)

– 5 patients FEV1/FVC (post-bd) <70% (16%)

– 1 complete resolution of cough and eosinophilia (3%)

– 13 persistent cough and eosinophilia >3% on one or more occasions (41%)

– 7 persistent cough and eosinophilia < 3% (22%)

– 3 symptom free and eosinophilia >3% occasionally (9%)

Berry MA et al. Clin Exp Allergy 2005

Not all cases of occupational Not all cases of occupational asthma are associated with asthma are associated with airway eosinophilia, and airway eosinophilia, and airway inflammation with airway inflammation with eosinophils may occur in the eosinophils may occur in the absence of asthmaabsence of asthma

Wardlaw AJ et al. Multidimensional phenotyping: towards a new taxonomy for airway disease. Clin Exp Allergy 2005;35:1254-62.

Wardlaw AJ et al. Multidimensional phenotyping: towards a new taxonomy for airway disease. Clin Exp Allergy 2005;35:1254-62.