1. Interesting case January 26, 2011

2. A Thai 71 years-old female pt., married, Ex-govern teacher, Buddhism, Bangkok CC: Acute dyspnea 1d PI: 3 week PTA develop progressive dyspnea with low grade fever and dry cough within 2 d , then go to clinic and found abnormal CXR=>go to private hospital for admission Dx:atypical pneumonia and Receive iv Levofloxacin for 1 day  clinical worsening CXR progress=>on BiPAP, add tazocin and tamiflu Information data

3. Day 3 : start dexa 5 mg iv q 6 hrs.=>clinical improved within 12 hrs. Day 4: CXR improved switch to oral pred and levofloxacin about 3d then D/C with HM 1 wk 1 week PTA develop fever with chill then return to same hospital Dx: sepsis Rx: cefazolin+maxipime *3d=>no fever (H/C:NG) HM : invanz IV OD 1d develop fever and dyspnea then go to KCMH At KCMH SpO2 room air 89-90% Information data

4. U/D : HT and DLP for 2 yr No Hx of atopy, autoimmune or drug allergy No FH of autoimmune or CA No smoking She has many types of bird at home and farming quail for 6 months Information data

5. Physical examination Vital signs : BT 38.5 C, RR 24/min, PR 108 bpm, BP 100/60 mmHg GA : An old Thai female, normal consciousness, sick HEENT : not pale, no jaundice Neck : LN cannot be palpated, no neck vein engorged Heart : Tachycardia without significant murmur Lungs : bilateral basilar crackles Abdomen : no hepatosplenomegaly Extremities : no lesion, no edema Neuro : grossly intact Information data

6. Lab : Hct 35% wbc 9840 N90 L6 E0 Plt 256,000 BUN 14 Cr 0.6 TB 1.6 DB1.3 ALP 366 AST 574 ALT 373 ABG pH 7.4 pO2 84 pCO2 33 (canula 5LPM) Information data

7. Chest X rayday1

8. HRCT Diffuse heterogeneous ground glass opacities with interlobular septal thickening scattering in both lungs More pronounce in both upper lobes and RML

9. HRCT Minimal amount of Rt. Pleural effusion

10. BAL Wbc 410 PMN 71% Mono 29% Small amount of cell composed ciliated cell, alveolar macrophage mixed with some mixed inflammatory cell predominate mononuclear cells TransbronchialBx Alveolar septa are mildly thickening and increase fibroblastic stroma and mild lymphocyte inf.,mildpneumocyteproliferate,focal accumulation of alveolar macrophage, no neoplasm,nogranuloma, or identified organism Bronchoscope

11. After steroid Rx 12 Jan 2011 19 Jan 2011

12. Hypersensitivity pneumonitis Boonthorn 26 January 2011

13. Introdution Definition Epidemiology Diagnotic criteria Classification Investigation Pathology and pathophysiology Treatment Outline

14. extrinsic allergic alveolitis occurs upon exposure to organic dust associated with farming (moldy grain or hay handling) term “farmers lung” other most common settings contacts with birds (pigeons, parakeets) humidifiers, moldy wood chemical compounds (e.g. isocyanates, zinc) Introduction Allergy 2009: 64: 322–334

15. Pulmonary disease with symptoms of dyspnea and cough resulting from inhalation of Ag to which patient has been previously sensitized ( HP study group ) An inappropriate immune response to inhaled Ag that causes shortness of breath, restrictive lung defect, interstitial infiltrates seen on lung imaging caused by accumulation of large numbers of activated T lymphocytes in the lungs, characterized by episodic bouts of fever a few hours after exposure ( Cormier and Schuyler ) Definition Allergy 2009: 64: 322–334 Asthma and the workplace. New York: Marcel Dekker, 2006 Am J RespirCrit Care Med 2003;168: 952–958.

16. Population-based study (in New Mexico), estimated annual incidence of ILD = 30 per 100,000 ( HP<2% ) prevalence of farmers lung in exposed farmers from 0.5% to 3% ( complicated by geographical variables, climatic conditions and, farming practices ) Epidemiology Allergy 2009: 64: 322–334

17. RadioGraphics 2009; 29:1921–1938

18. Diagnostic criteria Allergy 2009: 64: 322–334

19. Diagnostic criteria Allergy 2009: 64: 322–334 J Allergy ClinImmunol1989;84:839–844 Most widely used are those from Richerson et al. History and physical findings and pulmonary function tests indicate an interstitial lung disease X-ray film is consistent There is exposure to a recognized cause There is antibody to that antigen

20. Diagnostic criteria HP study Allergy 2009: 64: 322–334 Am J RespirCrit Care Med 2003;168: 952–958

21. Diagnostic criteria Allergy 2009: 64: 322–334 Am J RespirCrit Care Med 2003;168: 952–958

22. Classification of HP Richerson’s classification of HP Allergy 2009: 64: 322–334 J Allergy ClinImmunol1989;84:839–844

23. Chest X-ray to rule out other diseases In acute HP ground-glass infiltrates, nodular and/or striated patchy opacities Up to 20% have normal chest X-rays In subacute HP Distribution is usually diffuse but often sparing the bases. None of these findings is specific of HP Investigation Allergy 2009: 64: 322–334

24. patchy airspace disease and multiple ill-defined lung nodules with minimal upper lung volume loss RadioGraphics 2009; 29:1921–1938

25. Investigation High-resolution CT patterns are not specific but suggest that HP be considered in the differential diagnosis when present Allergy 2009: 64: 322–334

26. Insidious hypersensitivity pneumonitis in a 39-year-old woman with history of exposure to parakeets and cockatiels. (a) HRCT demonstrates extensive ground-glass opacity with a centrilobularconcentration. (b) Axial CT image obtained after therapy and removal from exposure shows complete resolution RadioGraphics 2009; 29:1921–1938

27. Insidious hypersensitivity pneumonitis. Axial high-resolution CTimages depict ill-defined centrilobular ground-glass opacities RadioGraphics 2009; 29:1921–1938

28. Pulmonary function tests No discriminative properties in differentiating HP from other interstitial lung diseases Acute HP restrictive pattern with low DLCO Chronic HP most frequent profile is obstructive defect resulting from emphysema In HP study 39 of 177 patients (22%) DLCO could be normal results at the time of diagnosis Investigation Allergy 2009: 64: 322–334

29. Specific antibodies only 1–15% of people exposed to HP antigen develop disease while in some cases the majority of exposed individuals have high titre of serum precipitating Ab but they remain asymptomatic 10% of people exposed to Saccharopolysporarectivirgula, main agent for Farmer’s lung,developAb while only 0.3% => disease can be useful as supportive evidence Investigation Allergy 2009: 64: 322–334

30. Specific antibodies Antigens available for testing in most centres pigeon and parakeet sera, dove feather antigen, Aspergillus sp., Penicillium, S. rectivirgula and Thermoactinomycesviridans ( pigeon breeder’s disease, bird fancier’s lung, farmer’s lung and humidifier lung ) Trichosporoncutaneum (summer-type HP) determination of precipitins or total IgGAb ( ELISA technique lacks standardization ) Investigation Allergy 2009: 64: 322–334

31. Serum precipitin Negative predictive value 81-88% and positive predictive value 71-75% for prevalence of HP 20-35% EurRespir J 2007; 29: 706–712

32. Sera were collected in Sweden and South Africa and levels of IgG antibodies specific to pigeon, budgerigar and parrot antigens were quantified using the UniCAP system Comparison of the two methods resulted in a good concordance with a level of agreement of 94.1% (kappa statistic = 0.83) Int Arch Allergy Immunol 2004;134:173–178

33. Inhalation challenge lack standardization both in inhalation protocols and criteria defining positive response Bronchoalveolarlavage normal number of lymphocytes rules out all but residual disease alveolar lymphocytosis HP, sarcoidosis, interstitial pneumonia associated with collagen vascular disease, silicosis, BOOP , HIV-associated pneumonitis and drug-induced pneumonitis Investigation Allergy 2009: 64: 322–334

34. Bronchoalveolarlavage CD4+/CD8+ ratio depends on Stage of disease type and dose of inhaled antigen duration of antigenic exposure CD4+/CD8+ ratio < 1 => HP (chronic) high CD4+/CD8+ ratio related to sarcoidosis Transbronchial biopsy limited usefulness for diagnosis of farmer’slung Investigation Allergy 2009: 64: 322–334

35. Lung biopsy In acute stages interstitial lymphocytes infiltrates and fibrosis, edema, noncaseatinggranulomas, and bronchiolitisobliterans Macrophages with foamy cytoplasm in alveolar space In chronic stages widespread fibrotic reaction (prominent feature) often without predominant involvement of upper lobes with contraction Emphysema Investigation Allergy 2009: 64: 322–334

36. 2 most common and most characteristic histopathologic featuresof HP: lymphocytic infiltrates within the interstitium, sometimes referred to as cellular interstitial pneumonitis (arrowheads), and a poorly formed granuloma (arrow). RadioGraphics 2009; 29:1921–1938

37. Current Opinion in Pulmonary Medicine 2008, 14:440–454

38. Current Opinion in Pulmonary Medicine 2008, 14:440–454

39. Current Opinion in Pulmonary Medicine 2008, 14:440–454

40. Current Opinion in Pulmonary Medicine 2008, 14:440–454

41. Type III and IV hypersensitivity High titres of antigen-specific precipitating serum IgG that can fix complement Ab specific to offending agent are increased in both serum and BAL resulting C5 induces macrophages activation cells infiltration, particularly lymphocytes, and formation of granuloma in lung Pathology and pathophysiology Allergy 2009: 64: 322–334

42. Important actors in HP: inflammatory cells Lymphocytes main cells involved in pathophysiology of HP 60–90% of BAL-recovered cells CD8+ lymphocytes, CD45 RO T lymphocytes, B lymphocytes Neutrophils Elastase break down of elastic fibres promote emphysema production of oxygen-free radicals and trigger development of fibrosis Pathology and pathophysiology Allergy 2009: 64: 322–334

44. Promoting and protective factors Aetiological agents Small slowly degradable particles adjuvant effect causes release of ROS,PGs,LTs and proteolytic compounds Viral infection could enhance HP by increasing expression of CD86 co-stimulatory molecule on APC Genetic predispositions polymorphism in TNF-α-308 promoter associated with high production of TNF in patients with bird-fancier’s lung Pathology and pathophysiology Allergy 2009: 64: 322–334

45. Promoting and protective factors Nicotine HP and specific antibodies are more frequent in nonsmokers smoking habits affect alveolar macrophages phagocytosis and decrease capacity to produce IL-1 and TNF decrease total BAL cells like lymphocytes ,B7 co-stimulatory molecules on macrophages In smokers, viral infection not increase CD86 molecules expression on macrophages Suppressive cells tolerogenic DC able to drive differentiation of Treg cells Pathology and pathophysiology Allergy 2009: 64: 322–334

46. ideal treatment for any form of HP is contact avoidance with offending Ag only drugs currently used for HP are oral corticosteroids Dose is unclear Recommend 50 mg of oral prednisolone daily others suggest 20 mg would be sufficient Low-dose steroids seem as effective as contact avoidance Treatment Allergy 2009: 64: 322–334