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 Thermophilic actinomycetes Aspergillus Aureobasidium sp Alternaria sp Candida albicans Mixed ameba, fungi, bacteria Moldy hay, plant materials, compost Animal bedding Ubiquitous Contaminated water Wood, wood pulp Saxophone mouthpiece Cold mist and other humidifiers, air conditioners Metal working fluids Paints, plastics Plastics Disease Farmer’s Lung Dog house disease Sauna-taker’s disease Wood worker’s lung Sax lung Nylon plant Office worker’s Air conditioner’s lung Ventilation pneumonitis Machine operator’s lung Paint refinisher’s lung Chemical worker’s lung Plastic worker’s lung Epoxy worker’s lung Hard metal lung disease Berylliosis Patel et al J Allergy Clin Immunol 2001 Bacteria, fungi Isocyanates Anhydrides Cobalt Berylliosis Worksite-related Agents Organic Antigens Farmer’s lung Antigen Micropolyspora faeni Aspergillus species Streptomyces albus Sacharopolyspora rectivirgula Malt worker’s lung Wood worker’s lung Aspergillus species Penicillium chrysogenum Alternaria species Merulius lacrymans Saccharomonospora viridis Cryptostroma corticale Aureobasidium pullulans Wood dust Cheese worker’s lung Sugar cane worker’s lung (Bagassosis) Detergent worker’s lung Cork worker’s lung Coffee worker’s lung Cotton worker’s lung (Bysinnosis) Wheat worker’s lung Metal worker’s lung Penicillium casei Thermoactinomyces vulgaris Bacillus subtilis Penicillium frequentens Coffee bean dust Bract of cotton flower Wheat weevil Rapid growing mycobacteria www.lungcancerfrontiers.com Inorganic Antigens Associated with HP Paints, resins, plastics Insulation, polyurethane Vineyard sprayer’s lung (fungicide) Pesticide/insecticide Non-microbial Diisocyanates Trimellitic anhydride Copper sulfate Pyrethrum Home or Work-related Agents Humidifier lung Organic Antigens Microbial Acanthamoebae castellani Acanthamoebae polyphaga Naegleria gruberi Thermoactinomyces candidus Bird breeder’s lung (budgies, pigeons) Rodent handler’s lung Hot tub/spa lung Bird droppings Urinary antigens, serum, pelts Mycobacterium avium complex Inorganic Antigens Associated with HP Polyurethane foam insulation Non-microbial Diisocyanates 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, Geotrichum Rhizopus 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 Infections lung inflammation 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 Sex Yr No. of Deaths Under-lying Cause (%) M 31 28 14 31 28 24 35 25 31 36 283 F 10 8 4 15 8 13 16 13 7 21 115 W 38 34 17 44 36 32 49 38 37 56 381 Race B 1 1 1 5 2 1 1 12 O 2 2 1 5 1524 2 2 2534 1 1 1 1 3 3 10 3544 1 1 2 1 3 1 2 11 Age Group (yrs) 4554 3 2 2 4 2 6 5 2 2 9 37 5564 8 4 2 7 5 4 7 6 3 5 51 6574 11 11 3 14 8 7 11 8 10 11 94 7584 15 11 7 14 12 14 16 14 17 19 139 85 + 2 5 1 5 9 5 6 7 6 8 54 Median Age (yrs) 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 TOTAL 41 36 18 46 36 37 51 38 38 57 398 63.4 72.2 77.8 52.2 75.0 62.2 76.5 71.1 63.2 64.9 67.1 73.0 73.5 72.5 71.5 76.5 75.0 73.0 76.0 78.5 74.0 74.0 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 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 Memory cells Stimulates T cell Activates Cytotoxic cells Lymphocyte Stimulates Helper cells Chemokines Lymphokines Ab formation Over-expressed In rat models of HP IFN gamma key to granuloma formation in mouse models Opal and DePalo Chest 2000 Gudmundsson et al J Immunology 1998 Patel et J Allergy Clin Immunol 2001 Key Players In Fibrosis Angiotensin II TGF-β Macrophage TNF-α IL-1 Neutrophils TGF-β TNF−α Alveolar Epithelial Cell Fibroblast IFN-γ Angiotensin II TGF-β Lymphocyte Fibroblast Proliferation Extracellular Matrix Formation Clinical Features Classification Systems Classical Acute Boyd Acute progressive Cormier Active Selman Active Nonprogressive and intermittent Subacute Acute intermittent nonprogressive Nonacute Residual Active Progressive and intermittent Chronic Chronic Progressive Nonprogressive J Allergy Clin Immunol 1989;89:839 Clin Allergy 1982;12(suppl):53 Clin Pulm Med 1996;3:72 Interstitial Lung Disease Schwarz, MI, King, TE Jr, (Eds) 4th Ed, Hamilton, BC Decker 2003 UpToDate Acute Abrupt onset Clinical Diffuse rales Tachypnea Central cyanosis Cough Dyspnea Chest tightness Fevers Chills Malaise Myalgias Anorexia Nausea/vomiting Labs Leukocytosis Restrictive pattern on PFTs Positive serum precipitins Sx 4-8 hrs after high level Radiographs exposure Sx subside over hours -days Prognosis good complete recovery in 7-10 days Kupeli, et al Postgrad Med 2003 1-5mm bilateral pulmonary nodules Bilateral consolidation Ground glass infiltrates Non-neoplastic Disorders of the Lower Respiratory Tract 2002 American Registry of Pathology and the Armed Forces Institute of Pathology Acute HP London Southbank University@myweb.lsbu.ac.uk www.emedicine.com Differential Diagnosis Acute 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 Exam Diffuse rales Hypoxia Labs Restrictive defect Hypoxemia months of exposure Prognosis good Radiographs Air trapping Micronodules Kupeli, et al Postgrad Med 2003 Non-neoplastic Disorders of the Lower Respiratory Tract 2002 American Registry of Pathology and the Armed Forces Institute of Differential Diagnosis Subacute 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 Chronic Sx occur over 4-12 Labs months Dyspnea Fatigue Cough Same as for prior stages Pathology Fibrosis Patchy alveolar infiltrate Prognosis is poor Inciting antigen Mononuclear cells Bronchocentric pattern unlikely to be isolated Non-necrotizing granulomas Bronchiolitis obliterans Organizing pneumonia Radiographs Honeycombing Kupeli, et al Postgrad Med 2003 Non-neoplastic Disorders of the Lower Respiratory Tract 2002 American Registry of Pathology and the Armed Forces Institute of Pathology Chronic HP www.emedicine.com Hayakawa 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 Diagnostic Criteria Major History of symptoms compatible with HP Appear or worsen within hours after antigen exposure History, Environmental investigation, Serum Ab or BAL Ab Evidence of exposure to antigen BAL lymphocytosis Histologic findings compatible with HP Compatible radiographic findings Basilar crackles Decreased diffusion capacity Decreased O2 saturation with rest or activity Synopsis of Diseases of the Chest 3rd ed Minor 1. Known exposure to offending antigen A.History of appropriate exposure B. Environmental tests confirm Ag presence C. Positive serum IgG to Ag 2. Compatible clinical, radiologic, physiologic findings Definite A. Respiratory (+/- constitutional) Si/Sx B. Compatible CXR/CT findings C. Altered PFTs, gas exchange 3. BAL with lymphocytosis A.Low CD4/CD8 B. Positive specific imm response to Ag A. Reexposure to environment B. Lab exposure to suspected Ag Probable Subclinical Sensitization 1,2,3 1,2,4A 1,2A,3,5 1,2A,3 1,3A 1 4. Positive inhalation challenge test 5. Compatible histopathology A. Poorly formed, noncaseating granulomas B. Mononuclear infiltrate Atlas of Nontumor Pathology Travis, et al 2002 American Registry of Pathology and the Armed Forces Institute of Pathology 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 Exposure Precipitating Abs present Recurrent episodes Inspiratory rales Sx 4-8 hrs after exposure Weight loss Sensitivity 86% OR 38.8 5.3 3.3 4.5 7.2 2.0 Specificity 86% CI 11.6-129.6 2.7-10.4 1.5-7.5 1.8-11.7 1.8-28.6 1.0-3.9 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 Radiography CXR Acute Fine micronodular pattern Diffuse ground-glass opacity Normal CT Acute Profuse centrilobular micronodules Ground-glass opacities Evidence of air trapping Chronic Chronic Honeycombing Poorly defined nodules Fibrosis Lobar volume loss Interstitial fibrosis 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 Few disease processes > 50% 20-70% lymphocytes 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 Tract Hypersensitivity 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 Diagnosis Table Modified from Atlas of Nontumor Pathology Histologic Hypersensitivity Sarcoidosis feature Pneumonitis Granulomas Frequency Morphology Distribution Intraluminal fibrosis Lymphocyte infiltrates Dense fibrosis BAL lymphocytosis 2/3 open biopsies 100% of cases LIP 5-10% cases; Well formed or poorly formed Random Poorly formed Mostly random, some peribronchiolar 2/3 open biopsies Mild-moderate Peribronchiolar Advanced cases CD8>CD4 (CD4/CD8 < 1.0) Well formed Lymphangitic, peribronchiolar, perivascular Very rare Absent or minimal Advanced cases CD4>CD8 (> 3.5 has a PPV 75%) Unusual Extensive, diffuse Unusual 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 n CD4/CD8 Sarcoidosis UIP EAA 239 112 66 33.7 15.8 9.3 Pre-test 9.1 * 13.6 27.3 * Post-test <0.5 0.5-3.5 40.3 12.2 17.2 * >3.5 69.1 *** 5.2 * 12.5 p<0.05; *** p<0.001 Versus the respective a priori value Likelihood of EAA rose 3x with a CD4/CD8 <0.5 Eur Respir J 2004; 24: 1000-1006 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%) Post-test Lymph % and CD4/CD8 Sarcoidosis UIP EAA n 182 25 35 Pretest 45.2 6.2 8.7 <30 Low High 30-50 Low High Low >50 High 28.6 86.1 56.1 *** *** 9.4 1.4 *** 5.6 0.0 3.5 17.5 * 86.5 *** 0.0 2.7 33.3 3.0 39.4 *** 55.6 0.0 29.6 *** Likelihood of EAA rose nearly 4x independently of CD4/CD8 when lymphocytes were very high and granulocytes were low •p<0.05; *** p<0.001 •Low CD4/CD8 <3.5 Eur Respir J 2004; 24: 1000-1006 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 Sarcoidosis UIP Pretest 18.6 28.3 Post-test <30 Low High 30-50 Low High >50 Low High n 57 87 13.9 44.4 23.1 * 34.2 22.2 11.5 50.0 * 6.3 21.4 0.0* 0.0 0.0 EAA 31 10.1 3.0* 5.6 34.6 *** 37.5 *** 50.0 *** 50.0 Likelihood of EAA rose nearly 5x independently of CD4/CD8 when lymphocytes were very high and granulocytes were high p<0.05; *** p<0.001 Low CD4/CD8 <3.5 Eur Respir J 2004; 24: 1000-1006 Who Gets HP? Farmers Farmers moving hay into a barn, [between 1895 and 1910] Bartle Brothers Glass plate negative Reference Code: C 2-10232-1729 Thermophilic actinomycetes Hay, grain, compost, manure Pigeon, duck, turkey, quail Contaminated air conditioning systems Contaminated air conditioning systems Avian proteins Amoebae (Naegleria, Acanthamoeba) Thermophilic actinomycetes Bird Fanciers www.ryancordell.com Bird Fanciers Avian proteins Case study 67 yo 150+ pack-yr smoker www.ladygouldianfinch.com 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 Developed low grade fever and increased dyspnea Bronchocentric alveolitis on CT/chest Patient acquired feather duvet Inase et al Internal Medicine 2004 Disease stable until 2000 Nursing Home Aviary Factory Workers Metalworking fluid aerosols Pseudomonas fluorescans Mycobacterium avium complex Cheese mold www.groupnch.com www.defra.gov.uk Penicillium Plastics and resins Anhydrides Paint catalysts, adhesives, and foam Diisocyanates Contaminated ventilation systems Naegleria, Acanthamoebae 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 Domestic engineers Ventilation systems, compost, chemicals, greenhouses Office employees and Paint refinishers Diisocyanates Ventilation systems Lab workers Rat urinary proteins 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 More sensitive, but less specific Enzyme-linked immunosorbent assay 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 UpToDate Monkare Eur J Respir Dis 1983 Kokkarinen et al Am Rev Respir Dis 1992 Patel et al J Allergy Clin Immunol 2001 Value of steroids Monkare 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 No statistical significance between groups Symptoms recurred – 6 pts receiving steroids – 1 pt in placebo group 5 year follow up 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
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