Hypersensitivity Pneumonitis

Hypersensitivity Pneumonitis

Extrinsic Allergic Alveolitis

Martha Burk MD, MS

Definition“…a group of immunologically mediated lung

diseases in which the repeated inhalation of certain finely dispersed antigens of a wide variety, mainly including organic particles or low molecular weight chemicals, provokes a hypersensitivity reaction with granulomatous inflammation in the distal bronchioles and alveoli of susceptible subjects”

Bourke et al Eur Respir J 2001

Epidemiology First recognized in grain workers in 1713 Prevalence difficult to assess

Not caused by a single etiologic agent A complex syndrome varying in

Intensity Clinical presentation

Lack of agreement on diagnostic criteria

Causative Antigens The Simple List

Bacteria Fungi Animal proteins Insect proteins Amoebae Chemicals Medications Soybean hulls

Causative Agent Source DiseaseThermophilic actinomycetes Moldy hay, plant

materials, compostFarmer’s Lung

Aspergillus Animal bedding

Ubiquitous

Dog house disease

Aureobasidium sp Contaminated water Sauna-taker’s disease

Alternaria sp Wood, wood pulp Wood worker’s lung

Candida albicans Saxophone mouthpiece Sax lung

Mixed ameba, fungi, bacteria Cold mist and other humidifiers, air conditioners

Nylon plant Office worker’s Air conditioner’s lung

Ventilation pneumonitis

Bacteria, fungi Metal working fluids Machine operator’s lung

Isocyanates Paints, plastics Paint refinisher’s lung

Anhydrides Plastics Chemical worker’s lung

Plastic worker’s lung

Epoxy worker’s lung

Cobalt Hard metal lung disease

Berylliosis Berylliosis

Patel et al J Allergy Clin Immunol 2001

Worksite-related Agents Organic Antigens Antigen

Farmer’s lung Micropolyspora faeni Aspergillus species Streptomyces albus

Sacharopolyspora rectivirgula

Malt worker’s lung Aspergillus species

Wood worker’s lung Penicillium chrysogenum Alternaria species Merulius lacrymans Saccharomonospora viridis Cryptostroma corticale Aureobasidium pullulans Wood dust

Cheese worker’s lung Penicillium casei

Sugar cane worker’s lung (Bagassosis) Thermoactinomyces vulgaris

Detergent worker’s lung Bacillus subtilis

Cork worker’s lung Penicillium frequentens

Coffee worker’s lung Coffee bean dust

Cotton worker’s lung (Bysinnosis) Bract of cotton flower

Wheat worker’s lung Wheat weevil

Metal worker’s lung Rapid growing mycobacteria

www.lungcancerfrontiers.com

Inorganic Antigens Associated with HP Non-microbial

Paints, resins, plastics Diisocyanates

Insulation, polyurethane Trimellitic anhydride

Vineyard sprayer’s lung (fungicide) Copper sulfate

Pesticide/insecticide Pyrethrum

Home or Work-related Agents Organic Antigens Microbial

Humidifier lung Acanthamoebae castellani Acanthamoebae polyphagaNaegleria gruberi Thermoactinomyces candidus

Bird breeder’s lung (budgies, pigeons) Bird droppings

Rodent handler’s lung Urinary antigens, serum, pelts

Hot tub/spa lung Mycobacterium avium complex

Inorganic Antigens Associated with HP Non-microbial

Polyurethane foam insulation Diisocyanates

www.lungcancerfrontiers.com

How much antigen are we talking about?

Airborne Fungi In Industrial Environments

Study of six industrial facilities Poultry house Swinery Feed preparing and storing house at

swinery Grain Mill Wooden panel factory Organic waste recycling facility

Samples collected by multiple methods

Lugauskas et al Ann Agric Environ Med 2004

Grain Mill 49 species of 20 fungal genera isolated

Penicillium, Aspergillus, Mucor, Alternaria, Cladosporium, Rhizopus and others

Poultry House 31 species of 13 fungal genera

Aspergillus, Penicillium, Rhizopus, Trichophyton Swinery

33 species from 15 fungal genera Aspergillus, Penicillium, Cladosporium, Zygomycetes

Food processing and storing house 35 fungal species from 18 genera

Aspergillus, Zygomycetes, Staphylotrichum Wood panel factory

21 fungal species from 10 genera Paecilomyces, Rhizopus*

Organic waste recycling facility 40 fungal species from 21 genera

Penicillium, Aspergillus, Cladosporium, GeotrichumRhizopus cause of ODTS among wood trimmers

Inciting antigens are ubiquitous!

So why doesn’t everyone exposed to these environments develop hypersensitivity pneumonitis?

Antigen Qualities Size

1-5 microns, usually <3 microns Inhaled into distal bronchial tree and alveoli

Induce an IgG response IgE sometimes formed as well

Many are capable of stimulating the complementary cascade Delayed cellular response

Environmental Factors Antigen concentration Duration of exposure Frequency/intermittency of exposure Particle size Antigen solubility Use of airway protection Variability in work practice

Hypersensitivity pneumonitis: current concepts Eur Respir J 2001 18:81s-92s

Genetic Susceptibility Approximately 5-15% of exposed individuals develop

disease ~4% budgerigar’s fanciers ~8% pigeon breeders ~4% farmers

Males affected > females Familial forms of HP documented

No confirmed genetic factors May represent undetected common exposures

Ethnicity may matter Pigeon fancier’s disease worse in Mexican Americans

compared with Caucasian Americans Higher prevalence of HLA-DR7 in Mexican Americans

HLA-DPB1 associated with more severe disease in beryllium exposure

Hypersensitivity pneumonitis: current concepts Eur Respir J 2001 18:81s-92s

Additional Factors Occurs more frequently in nonsmokers Onset may be triggered by

Non-specific lung inflammation Infections

Mycoplasma– Case studies of HP development after Mycoplasma

infection

Influenza A common in lower airways of patients presenting with acute HP

Inhibitory Effect of Nicotine Fewer inflammatory diseases in smokers

Sarcoidosis Ulcerative colitis Radiation pneumonitis

In vivo and in vitro experimental HP in rats Nicotine associated with dose-dependent decreases in

Macrophage, lymphocytes and neutrophils IFN gamma, TNF

Smokers develop fewer antibodies when exposed to antigens Yet, if they do develop HP

More insidious More chronic Worse prognosis

Blanchet et al Am J Resp Crit Care Med 2004

Occupational Respiratory Disease Surveillance

Table 8-1. Hypersensitivity pneumonitis: Number of deaths by sex, race, and age, and median age at death, U.S. residents age 15 and over, 1990-1999

YrNo. of Deaths

Under-lying Cause (%)

Sex Race Age Group (yrs)Median

Age   (yrs)M F W B O

15-24

25-34

35-44

45-54

55-64

65-74

75-84

85+

1990 41 63.4 31 10 38 1 2 - 1 1 3 8 11 15 2 73.0

1991 36 72.2 28 8 34 - 2 2 - 1 2 4 11 11 5 73.5

1992 18 77.8 14 4 17 1 - - 1 2 2 2 3 7 1 72.5

1993 46 52.2 31 15 44 1 1 - 1 1 4 7 14 14 5 71.5

1994 36 75.0 28 8 36 - - - - - 2 5 8 12 9 76.5

1995 37 62.2 24 13 32 5 - - 1 - 6 4 7 14 5 75.0

1996 51 76.5 35 16 49 2 - - 3 3 5 7 11 16 6 73.0

1997 38 71.1 25 13 38 - - - - 1 2 6 8 14 7 76.0

1998 38 63.2 31 7 37 1 - - - - 2 3 10 17 6 78.5

1999 57 64.9 36 21 56 1 - - 3 2 9 5 11 19 8 74.0

TOTAL 398 67.1 283 115 381 12 5 2 10 11 37 51 94 139 54 74.0

CDC National Instititute for Occupational Safety and Health

Hypersensitivity pneumonitis:

Number of deaths, crude and age-adjusted mortality rates, U.S. residents age 15 and over, 1979-1999

                                                            CDC National Instititute for Occupational Safety and Health

Immunopathogenesis Acute phase

Inhaled Ag binds IgG Ab Macrophage activated and release IL-8, IL-6

Chemotactic for monocytes/macrophage Differentiation of CD4+ TH0 cells to TH1 cells Differentiation of B cells to plasma cells (IL-6) Maturation of CD8+ cells into cytotoxic cells

TH1 cells secrete TNF alpha -> fever Subacute phase

Macrophage develop into epithelioid cells and multinucleated giant cells

Lymphoid follicles with plasma cells develop in lesions Chronic phase

Macrophage express TGF beta Fibrosis Angiogenesis

Patel et al J Allergy Clin Immunol 2001

Ag Stimulates

Activates

Stimulates

Memory cells

Helper cells

Cytotoxic cells

Lymphokines

Ab formation

Lymphocyte

T cell

Chemokines

Opal and DePalo Chest 2000Gudmundsson et al J Immunology 1998Patel et J Allergy Clin Immunol 2001

Over-expressed In rat models of HP

IFN gamma key to granuloma formation in mouse models

Key Players In Fibrosis

Lymphocyte

MacrophageNeutrophils

Fibroblast

AlveolarEpithelial Cell

TGF-TNF-TGF-

Angiotensin II

Angiotensin II

IFN-

Fibroblast ProliferationExtracellular Matrix Formation

IL-1

TGF-

TNF

Clinical Features

Classification Systems

Classical Boyd Cormier Selman

Acute Acute progressive Active ActiveNonprogressive and intermittent

Subacute Acute intermittent nonprogressive

ActiveProgressive and intermittent

Chronic Nonacute Residual Chronic Progressive

Nonprogressive

J Allergy Clin Immunol

1989;89:839

Clin Allergy

1982;12(suppl):53

Clin Pulm Med

1996;3:72

Interstitial Lung DiseaseSchwarz, MI, King, TE Jr, (Eds) 4th Ed, Hamilton, BC Decker 2003

UpToDate

Acute Abrupt onset

Cough Dyspnea Chest tightness Fevers Chills Malaise Myalgias Anorexia Nausea/vomiting

Sx 4-8 hrs after high level exposure

Sx subside over hours -days complete recovery in 7-10

days Prognosis good

Clinical Diffuse rales Tachypnea Central cyanosis

Labs Leukocytosis Restrictive pattern on

PFTs Positive serum

precipitins

Radiographs 1-5mm bilateral

pulmonary nodules Bilateral consolidation Ground glass infiltrates

Kupeli, et al Postgrad Med 2003Non-neoplastic Disorders of the Lower Respiratory Tract 2002 American Registry of Pathology and the Armed Forces Institute of Pathology

Acute HP

www.emedicine.com

London Southbank University@myweb.lsbu.ac.uk

Differential DiagnosisAcute stage

Acute tracheobronchitis, bronchiolitis, pneumonia Acute endotoxin exposure Organic dust toxic syndrome Allergic bronchopulmonary aspergillosis Reactive airways dysfunction syndrome Acute Respiratory Distress Syndrome Aspiration pneumonitis Bronchiolitis obliterans organizing pneumonia Diffuse alveolar damage

Patel et al J Allergy Clin Immunol 2001

Subacute

More insidious onset Dyspnea Cough

Occurs after weeks to months of exposure

Prognosis good

Exam Diffuse rales Hypoxia

Labs Restrictive defect Hypoxemia

Radiographs Air trapping Micronodules

Kupeli, et al Postgrad Med 2003Non-neoplastic Disorders of the Lower Respiratory Tract 2002 American Registry of Pathology and the Armed Forces Institute of Pathology

Differential DiagnosisSubacute stage

Recurrent pneumonia ABPA Granulomatous lung diseases Infection – mycobacteria, fungi Pneumoconiosis Langerhans’ cell histiocytosis Churg-Strauss syndrome Wegener’s granulomatosis Sarcoidosis

Patel et al J Allergy Clin Immunol 2001

Chronic Sx occur over 4-12

months Dyspnea Fatigue Cough

Prognosis is poor Inciting antigen

unlikely to be isolated

Labs Same as for prior stages

Pathology Fibrosis Patchy alveolar infiltrate

Mononuclear cells Bronchocentric pattern

Non-necrotizing granulomas

Bronchiolitis obliterans Organizing pneumonia

Radiographs Honeycombing

Kupeli, et al Postgrad Med 2003Non-neoplastic Disorders of the Lower Respiratory Tract 2002 American Registry of Pathology and the Armed Forces Institute of PathologyHayakawa et al Respirology 2002

Chronic HP

www.emedicine.comHayakawa et al Respirology 2002

Differential Diagnosis

Chronic stage Idiopathic pulmonary fibrosis Chronic obstructive pulmonary disease with

pulmonary fibrosis Bronchiectasis/bronchiolectasis Mycobacterium avium complex

Patel et al J Allergy Clin Immunol 2001

Clinical Course Acute illness resolves in weeks if

recognized early and patient exposure to antigen is eliminated

Subacute or chronic illness More insidious symptoms Increased risk of emphysema, fibrosis,

asthma Avian sensitivity associated with poor

prognosis similar to interstitial lung disease 5 year mortality 50% Clubbing on exam portends a worse prognosis

Major History of symptoms compatible with HP

Appear or worsen within hours after antigen exposure Evidence of exposure to antigen

History, Environmental investigation, Serum Ab or BAL Ab

BAL lymphocytosis Histologic findings compatible with HP Compatible radiographic findings

Minor Basilar crackles Decreased diffusion capacity Decreased O2 saturation with rest or activity

Synopsis of Diseases of the Chest 3rd ed

Diagnostic Criteria

1. Known exposure to offending antigenA.History of appropriate exposureB. Environmental tests confirm Ag presenceC. Positive serum IgG to Ag

2. Compatible clinical, radiologic, physiologic findingsA. Respiratory (+/- constitutional) Si/SxB. Compatible CXR/CT findingsC. Altered PFTs, gas exchange

3. BAL with lymphocytosisA.Low CD4/CD8 B. Positive specific imm response to Ag

4. Positive inhalation challenge testA. Reexposure to environmentB. Lab exposure to suspected Ag

5. Compatible histopathologyA. Poorly formed, noncaseating granulomasB. Mononuclear infiltrate Atlas of Nontumor Pathology Travis, et al 2002

American Registry of Pathology and the

Armed Forces Institute of Pathology

Definite 1,2,31,2,4A1,2A,3,5

Probable 1,2A,3Subclinical 1,3ASensitization 1

Diagnostic Value to History/Exam Multicenter trial studying consecutive patients

presenting with a pulmonary syndrome for which HP was considered in the differential diagnosis

Objective: Identify diagnostic criteria and develop clinical prediction rule History of exposure to Ag Presence of precipitating Ab Recurrent episodes of Sx Inspiratory crackles on exam Sx occurring 4-8 hrs after exposure Weight loss

400 patients in derivation cohort 261 patients in validation cohort HRCT and BAL defined presence or absence of HP

Lacasse et al Am J Respir Crit Care Med 2003

Significant Predictors of HP

Variables OR CIExposure 38.8 11.6-129.6

Precipitating Abs present 5.3 2.7-10.4

Recurrent episodes 3.3 1.5-7.5

Inspiratory rales 4.5 1.8-11.7

Sx 4-8 hrs after exposure 7.2 1.8-28.6

Weight loss 2.0 1.0-3.9

Sensitivity 86% Specificity 86%Rules do not apply to subacute or chronic forms HP

Lacasse et al Am J Respir Crit Care Med 2003

Pulmonary Function Classically, a restrictive pattern

Decreased FEV1 and FVC Decreased total lung capacity Decreased diffusion capacity

Concomitant bronchiolitis may result in obstructive defect

Hypoxemia Bronchial hyperreactivity

Chest RadiographyCXR Acute

Fine micronodular pattern Diffuse ground-glass

opacity Normal

Chronic Interstitial fibrosis

CT Acute

Profuse centrilobular micronodules

Ground-glass opacities Evidence of air trapping

Chronic Honeycombing Poorly defined nodules Fibrosis Lobar volume loss

Imaging of Diseases of the Chest 3rd ed Armstrong et al Mosby London 2000

Ground Glass Opacities

www.emedicine.com

Bronchoalveolar Lavage Immediate (within 48 hours)

Neutrophils Days later

T lymphocyte predominant alveolitis CD8+ predominant CD4/CD8 usually < 1.0

20-70% lymphocytes Few disease processes > 50%

Increased mast cells, usually > 1% Problem

Lymphocytic response seen in asymptomatic patients with antigen exposure, and patients with organic dust toxic syndrome

Atlas of Nontumor Pathology Non-Neoplastic Disorders of the Lower Respiratory TractHypersensitivity pneumonitis: current concepts Eur Respir J 2001 18:81s-92s

Histopathology Cellular bronchiolitis Interstitial lymphocytic

infiltrate Usually bronchocentric

Scattered, small, poorly formed non-necrotizing granulomas

Large histiocytes with foamy cytoplasm

Fibrosis Indistinguishable from

other causes in advanced disease

Approximately 80% of subacute and chronic cases have this triad

Differential DiagnosisTable Modified from Atlas of Nontumor Pathology

Histologic feature

Hypersensitivity Pneumonitis

Sarcoidosis LIP

Granulomas

Frequency 2/3 open biopsies 100% of cases 5-10% cases;

Well formed or poorly formed

Morphology

Distribution

Poorly formed

Mostly random, some peribronchiolar

Well formed

Lymphangitic, peribronchiolar, perivascular

Random

Intraluminal fibrosis

2/3 open biopsies Very rare Unusual

Lymphocyte infiltrates

Mild-moderate

Peribronchiolar

Absent or minimal Extensive, diffuse

Dense fibrosis Advanced cases Advanced cases Unusual

BAL lymphocytosis

CD8>CD4(CD4/CD8 < 1.0)

CD4>CD8(> 3.5 has a PPV 75%)

Usually B cells

Non-neoplastic Disorders of the Lower Respiratory Tract

Predictive Value of BAL Cell Differentials in the Diagnosis of Interstitial Lung Disease (ILD)

Retrospective evaluation 3,975 BALF samples from 3,118 pts Collected January 1997 – November 2003 Determine pre-test and post-test probabilities Relative frequencies of diagnoses based on

available information (prior to BAL) were used as pre-test probabilities

Post-test probabilities determined using Bayes’ rule based on cell differentials and the CD4/CD8 ratio

Eur Respir J 2004; 24: 1000-1006

Probability of ILD as a function of CD4/CD8 in suspected ILD

CD4/CD8

n Pre-test

<0.5 0.5-3.5 >3.5

Sarcoidosis 239 33.7 9.1

*

40.3 69.1

***

UIP 112 15.8 13.6 12.2 5.2

*

EAA 66 9.3 27.3

*

17.2

*

12.5

Post-test

Eur Respir J 2004; 24: 1000-1006

Likelihood of EAA rose 3x with a CD4/CD8 <0.5

p<0.05; *** p<0.001Versus the respective a priori value

Probability of ILD as a function of lymphocytes and CD4/CD8 in suspected ILD when the percentage of granulocytes was low (eosinophils <2% and neutrophils <4%)

Lymph % and CD4/CD8

n

Pre-test

Low High Low High Low High

Sarcoidosis 182 45.2 28.6

***

86.1

***

56.1 86.5

***

33.3 55.6

UIP 25 6.2 9.4 5.6 3.5 0.0 3.0 0.0

EAA 35 8.7 1.4

***

0.0 17.5

*

2.7 39.4

***

29.6

***

Post-test

<30 30-50 >50

•p<0.05; *** p<0.001•Low CD4/CD8 <3.5

Eur Respir J 2004; 24: 1000-1006

Likelihood of EAA rose nearly 4x independently of CD4/CD8 when lymphocytes were very high and granulocytes were low

Probability of ILD as a function of lymphocytes and CD4/CD8 in suspected ILD when the percentage of granulocytes was high (eosinophils >1% and neutrophils >3%)

Lymph % and CD4/CD8

n

Pre-test

Low High Low High Low High

Sarcoidosis 57 18.6 13.9 44.4*

23.1 50.0

*

21.4 0.0

UIP 87 28.3 34.2 22.2 11.5 6.3 0.0* 0.0

EAA 31 10.1 3.0* 5.6 34.6

***

37.5

***

50.0

***

50.0

Post-test

<30 30-50 >50

p<0.05; *** p<0.001Low CD4/CD8 <3.5

Eur Respir J 2004; 24: 1000-1006

Likelihood of EAA rose nearly 5x independently of CD4/CD8 when lymphocytes were very high and granulocytes were high

Who Gets HP?

Farmers

Farmers moving hay into a barn, [between 1895 and 1910]

Bartle BrothersGlass plate negative Reference Code: C 2-10232-1729 Archives of Ontario, I0002526

Thermophilic actinomycetes Hay, grain, compost, manure

Avian proteins Pigeon, duck, turkey, quail

Amoebae (Naegleria, Acanthamoeba) Contaminated air conditioning systems

Thermophilic actinomycetes Contaminated air conditioning systems

Bird Fanciers

www.ryancordell.com

Bird Fanciers Avian proteins Case study

67 yo 150+ pack-yr smoker Raised budgerigars 1980-88 Diagnosed as IPF 1988

1994 diagnosed with Bird Fancier’s Lung Lymphocytic alveolitis and organizing pneumonia by

TBBx Serum precipitins positive for bird antigens

Disease stable until 2000 Developed low grade fever and increased dyspnea Bronchocentric alveolitis on CT/chest Patient acquired feather duvet

Inase et al Internal Medicine 2004

www.ladygouldianfinch.com

Nursing Home Aviary

Factory Workers Metalworking fluid aerosols

Pseudomonas fluorescans Mycobacterium avium complex

Cheese mold Penicillium

Plastics and resins Anhydrides

Paint catalysts, adhesives, and foam Diisocyanates

Contaminated ventilation systems Naegleria, Acanthamoebae

www.groupnch.com

www.defra.gov.uk

Patients With H/O Medication Use

Amiodarone Gold Procarbazine Minocycline Chlorambucil Sulfasalazine Beta blockers HMG co-A Reductase inhibitors

Others Wood workers

Alternaria species Malt workers

Aspergillus Bathtub refinishers

and Paint refinishers Diisocyanates

Lab workers Rat urinary proteins

Domestic engineers Ventilation systems,

compost, chemicals, greenhouses

Office employees Ventilation systems

Anybody! Household mold Air conditioning Saunas, Hot tubs Birds Goose down

Diagnostic Approach Detailed history and physical exam

Patient may not associate symptoms with antigen exposure Symptoms may be delayed for hours Temporal relationship weaker with chronic forms

Positive precipitating antibodies Once thought to be hallmark Demonstrates immune response Lack sensitivity and specificity for HP Serve as markers for antigen exposure Poorly standardized antigens Improper quality controls

Enzyme-linked immunosorbent assay More sensitive, but less specific

Bronchoscopy Lung biopsy No single clinical or laboratory feature is diagnostic

Occupational History Current and previous occupations Description of job processes Chemical exposure Symptom improvement away from work? Similar symptoms in coworkers? Use of respiratory protection at work

Environmental History Pets (especially birds) Hobbies and recreational activities Presence of humidifiers, swamp coolers, indoor

vented dryers Use of hot tubs, saunas Visible fungal growth in household/workplace History of flooding or water damage to walls and

carpets History of recent renovation/remodeling Similar symptoms in home occupants Feather pillows, comforters, bedding, jackets Use of air fresheners, spray cleaners

www.brickleyenv.com

www.indoorairpro.com

Treatment Antigen avoidance

Responsible antigen may be difficult to isolate Multiple antigens may be involved Half-lives of animal dander, proteins measured in years Exposure may be unavoidable Disease may progress in spite of antigen avoidance

Corticosteroids 0.5 mg/kg/d for severe, acute episodes Subacute episodes may benefit from 1 mg/kg/day 2-4 weeks Improved short term effect No difference in long term effects (5 years)

Role of inhaled steroids and beta agonists unclear May provide symptomatic relief

UpToDateMonkare Eur J Respir Dis 1983Kokkarinen et al Am Rev Respir Dis 1992Patel et al J Allergy Clin Immunol 2001

Value of steroidsMonkare Eur J Respir Dis 1983

93 pts with Farmer’s lung studied prospectively No impact on lung function or work capacity Minor improvements in radiographic changes

Kokkarinen et al Am Rev Respir Dis 1992 36 pts in double blind, placebo control 20 received prednisolone x 8 wks 16 received placebo 1 month follow up

Steroids improved DLCO 5 year follow up

No statistical significance between groups Symptoms recurred

– 6 pts receiving steroids– 1 pt in placebo group

Summary of HP Antigen exposure is necessary but insufficient Important exposures occur at home

Pet birds, feathers, humidifiers, indoor molds and bacteria Challenging to diagnose

Nonspecific symptoms Variable clinical presentation Variable radiographic findings Lack of a “gold standard” diagnostic test

Immunopathogenesis remains unclear Can be improved with antigen avoidance, and

steroids in severe, acute cases Unrecognized/untreated it may lead to

development of asthma, emphysema or interstitial fibrosis