Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Abstract

Hypersensitivity pneumonitis (HP) is an inflammatory interstitial lung disease caused by a wide variety of organic particles and certain small-molecular weight chemical compounds that provoke an exaggerated immune response in susceptible individuals. The clinical manifestations are heterogeneous and have been classically described as acute, subacute and chronic. The chronic form has an insidious onset over a period of months or years, with progressive dyspnea and often evolves to fibrosis. The pathology is characterized by a bronchiolocentric interstitial mononuclear cell infiltration, nonnecrotizing poorly formed granulomas, cellular pneumonitis and variable degrees of fibrosis. However, morphological diagnosis of HP is complicated because the subacute/chronic forms may be difficult to distinguish from idiopathic pulmonary fibrosis/usual interstitial pneumonia and nonspecific interstitial pneumonia. In general, diagnosis of HP represents a challenge for clinicians that need to weigh a constellation of clinical, laboratory, radiographic and (when available) pathological evidence for each patient to assess the certainty of the diagnosis. The cornerstone of therapy is antigen avoidance. Although clinical trials are scanty, corticosteroids are usually indicated based upon expert opinion. In this review we summarize the current evidence regarding the diagnostic criteria and therapeutic strategies as well as the immunopathological mechanisms putatively implicated in the development of the disease.

Keywords

hypersensitivity pneumonitis - extrinsic allergic alveolitis - lung fibrosis

• References

• 1 Selman M. Hypersensitivity pneumonitis: a multifaceted deceiving disorder. Clin Chest Med 2004; 25 (3) 531-547 , vi
• 2 Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med 2006; 100 (4) 610-615
• 3 Tillie-Leblond I, Grenouillet F, Reboux G , et al. Hypersensitivity pneumonitis and metalworking fluids contaminated by mycobacteria. Eur Respir J 2011; 37 (3) 640-647
• 4 Nordness ME, Zacharisen MC, Schlueter DP, Fink JN. Occupational lung disease related to cytophaga endotoxin exposure in a nylon plant. J Occup Environ Med 2003; 45 (4) 385-392
• 5 Girard M, Lacasse Y, Cormier Y. Hypersensitivity pneumonitis. Allergy 2009; 64 (3) 322-334
• 6 Solaymani-Dodaran M, West J, Smith C, Hubbard R. Extrinsic allergic alveolitis: incidence and mortality in the general population. QJM 2007; 100 (4) 233-237
• 7 Buchvald F, Petersen BL, Damgaard K , et al. Frequency, treatment, and functional outcome in children with hypersensitivity pneumonitis. Pediatr Pulmonol 2011; 46 (11) 1098-1107
• 8 Dishop MK, Askin FB, Galambos C , et al. Children's Interstitial Lung Disease (chILD) Network: classification of diffuse lung disease in older children and adolescents: a multi-institutional study of the Children's Interstitial Lung Disease Network [abstract]. Mod Pathol 2007; 20: 287-288
• 9 Flaherty DK, Braun SR, Marx JJ, Blank JL, Emanuel DA, Rankin J. Serologically detectable HLA-A, B, and C loci antigens in farmer's lung disease. Am Rev Respir Dis 1980; 122 (3) 437-443
• 10 Rittner C, Sennekamp J, Mollenhauer E , et al. Pigeon breeder's lung: association with HLA-DR 3. Tissue Antigens 1983; 21 (5) 374-379
• 11 Selman M, Terán L, Mendoza A , et al. Increase of HLA-DR7 in pigeon breeder's lung in a Mexican population. Clin Immunol Immunopathol 1987; 44 (1) 63-70
• 12 Ando M, Hirayama K, Soda K, Okubo R, Araki S, Sasazuki T. HLA-DQw3 in Japanese summer-type hypersensitivity pneumonitis induced by Trichosporon cutaneum. Am Rev Respir Dis 1989; 140 (4) 948-950
• 13 Camarena A, Juárez A, Mejía M , et al. Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder's disease. Am J Respir Crit Care Med 2001; 163 (7) 1528-1533
• 14 Aquino-Galvez A, Camarena A, Montaño M , et al. Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis. Exp Mol Pathol 2008; 84 (2) 173-177
• 15 Bridgeman JS, Sewell AK, Miles JJ, Price DA, Cole DK. Structural and biophysical determinants of αβ T-cell antigen recognition. Immunology 2012; 135 (1) 9-18
• 16 Wucherpfennig KW, Sethi D. T cell receptor recognition of self and foreign antigens in the induction of autoimmunity. Semin Immunol 2011; 23 (2) 84-91
• 17 Hoppin JA, Umbach DM, Kullman GJ , et al. Pesticides and other agricultural factors associated with self-reported farmer's lung among farm residents in the Agricultural Health Study. Occup Environ Med 2007; 64 (5) 334-341
• 18 Dakhama A, Hegele RG, Laflamme G, Israël-Assayag E, Cormier Y. Common respiratory viruses in lower airways of patients with acute hypersensitivity pneumonitis. Am J Respir Crit Care Med 1999; 159 (4 Pt 1) 1316-1322
• 19 Israël-Assayag E, Dakhama A, Lavigne S, Laviolette M, Cormier Y. Expression of costimulatory molecules on alveolar macrophages in hypersensitivity pneumonitis. Am J Respir Crit Care Med 1999; 159 (6) 1830-1834
• 20 Depierre A, Dalphin JC, Pernet D, Dubiez A, Faucompré C, Breton JL. Epidemiological study of farmer's lung in five districts of the French Doubs province. Thorax 1988; 43 (6) 429-435
• 21 Warren CPW. Extrinsic allergic alveolitis: a disease commoner in non-smokers. Thorax 1977; 32 (5) 567-569
• 22 Baur X, Richter G, Pethran A, Czuppon AB, Schwaiblmair M. Increased prevalence of IgG-induced sensitization and hypersensitivity pneumonitis (humidifier lung) in nonsmokers exposed to aerosols of a contaminated air conditioner. Respiration 1992; 59 (4) 211-214
• 23 Arima K, Ando M, Ito K , et al. Effect of cigarette smoking on prevalence of summer-type hypersensitivity pneumonitis caused by Trichosporon cutaneum. Arch Environ Health 1992; 47 (4) 274-278
• 24 Dalphin JC, Debieuvre D, Pernet D , et al. Prevalence and risk factors for chronic bronchitis and farmer's lung in French dairy farmers. Br J Ind Med 1993; 50 (10) 941-944
• 25 Morell F, Roger A, Reyes L, Cruz MJ, Murio C, Muñoz X. Bird fancier's lung: a series of 86 patients. Medicine (Baltimore) 2008; 87 (2) 110-130
• 26 Blanchet MR, Israël-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 2004; 169 (8) 903-909
• 27 Sopori ML, Kozak W, Savage SM, Geng Y, Kluger MJ. Nicotine-induced modulation of T Cell function. Implications for inflammation and infection. Adv Exp Med Biol 1998; 437: 279-289
• 28 Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T. Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses. J Immunol 2009; 183 (10) 6681-6688
• 29 Ohtsuka Y, Munakata M, Tanimura K , et al. Smoking promotes insidious and chronic farmer's lung disease, and deteriorates the clinical outcome. Intern Med 1995; 34 (10) 966-971
• 30 Vogelmeier C, Krombach F, Münzing S , et al. Activation of blood neutrophils in acute episodes of farmer's lung. Am Rev Respir Dis 1993; 148 (2) 396-400
• 31 Laflamme C, Israël-Assayag E, Cormier Y. Apoptosis of bronchoalveolar lavage lymphocytes in hypersensitivity pneumonitis. Eur Respir J 2003; 21 (2) 225-231
• 32 Barrera L, Mendoza F, Zuñiga J , et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008; 177 (1) 44-55
• 33 Yamasaki H, Ando M, Brazer W, Center DM, Cruikshank WW. Polarized type 1 cytokine profile in bronchoalveolar lavage T cells of patients with hypersensitivity pneumonitis. J Immunol 1999; 163 (6) 3516-3523
• 34 Glimcher LH. Trawling for treasure: tales of T-bet. Nat Immunol 2007; 8 (5) 448-450
• 35 Simonian PL, Roark CL, Wehrmann F , et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol 2009; 182 (1) 657-665
• 36 Selman M, Pardo A, Barrera L , et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006; 173 (2) 188-198
• 37 Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol 2011; 12 (7) 597-606
• 38 Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity 2004; 21 (4) 467-476
• 39 Simonian PL, Roark CL, Born WK, O'Brien RL, Fontenot AP. Gammadelta T cells and Th17 cytokines in hypersensitivity pneumonitis and lung fibrosis. Transl Res 2009; 154 (5) 222-227
• 40 Dakhama A, Hegele RG, Laflamme G, Israël-Assayag E, Cormier Y. Common respiratory viruses in lower airways of patients with acute hypersensitivity pneumonitis. Am J Respir Crit Care Med 1999; 159 (4 Pt 1) 1316-1322
• 41 Udwadia ZF, Wright MJ, McIntosh LG, Leitch AG. Confusing serological abnormalities in bird fancier's lung. BMJ 1990; 300 (6738) 1519-1520
• 42 Seifert SA, Von Essen S, Jacobitz K, Crouch R, Lintner CP. Organic dust toxic syndrome: a review. J Toxicol Clin Toxicol 2003; 41 (2) 185-193
• 43 Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol 2006; 30 (2) 201-208
• 44 Lacasse Y, Selman M, Costabel U , et al; HP Study Group. Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol 2009; 149 (2) 161-166
• 45 Miyazaki Y, Tateishi T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y. Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest 2008; 134 (6) 1265-1270
• 46 Olson AL, Huie TJ, Groshong SD , et al. Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case series. Chest 2008; 134 (4) 844-850
• 47 Bourke SJ, Carter R, Anderson K , et al. Obstructive airways disease in non-smoking subjects with pigeon fanciers' lung. Clin Exp Allergy 1989; 19 (6) 629-632
• 48 Selman M, Vargas MH. Airway involvement in hypersensitivity pneumonitis. Curr Opin Pulm Med 1998; 4 (1) 9-15
• 49 Silva CI, Churg A, Müller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol 2007; 188 (2) 334-344
• 50 Hansell DM, Wells AU, Padley SPG, Müller NL. Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities. Radiology 1996; 199 (1) 123-128
• 51 Chung MH, Edinburgh KJ, Webb EM, McCowin M, Webb WR. Mixed infiltrative and obstructive disease on high-resolution CT: differential diagnosis and functional correlates in a consecutive series. J Thorac Imaging 2001; 16 (2) 69-75
• 52 Franquet T, Hansell DM, Senbanjo T, Remy-Jardin M, Müller NL. Lung cysts in subacute hypersensitivity pneumonitis. J Comput Assist Tomogr 2003; 27 (4) 475-478
• 53 Silva CI, Müller NL, Lynch DA , et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology 2008; 246 (1) 288-297
• 54 Nakata H, Kimoto T, Nakayama T, Kido M, Miyazaki N, Harada S. Diffuse peripheral lung disease: evaluation by high-resolution computed tomography. Radiology 1985; 157 (1) 181-185
• 55 Buschman DL, Gamsu G, Waldron Jr JA, Klein JS, King Jr TE. Chronic hypersensitivity pneumonitis: use of CT in diagnosis. AJR Am J Roentgenol 1992; 159 (5) 957-960
• 56 Sahin H, Brown KK, Curran-Everett D , et al. Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival. Radiology 2007; 244 (2) 591-598
• 57 Cormier Y, Brown M, Worthy S, Racine G, Müller NL. High-resolution computed tomographic characteristics in acute farmer's lung and in its follow-up. Eur Respir J 2000; 16 (1) 56-60
• 58 Malinen AP, Erkinjuntti-Pekkanen RA, Partanen PL, Rytkönen HT, Vanninen RL. Long-term sequelae of Farmer's lung disease in HRCT: a 14-year follow-up study of 88 patients and 83 matched control farmers. Eur Radiol 2003; 13 (9) 2212-2221
• 59 Bourke SJ, Banham SW, McKillop JH, Boyd G. Clearance of 99mTc-DTPA in pigeon fancier's hypersensitivity pneumonitis. Am Rev Respir Dis 1990; 142 (5) 1168-1171
• 60 McSharry C, Banham SW, Lynch PP, Boyd G. Antibody measurement in extrinsic allergic alveolitis. Eur J Respir Dis 1984; 65 (4) 259-265
• 61 Cormier Y, Bélanger J, Durand P. Factors influencing the development of serum precipitins to farmer's lung antigen in Quebec dairy farmers. Thorax 1985; 40 (2) 138-142
• 62 Mendoza F, Baltazares M, Ramírez A , et al. Detection of salivary and seric IgG and IgA antipooled pigeon sera activities in patients with pigeon breeder's disease. J Clin Lab Anal 1996; 10 (3) 149-154
• 63 McSharry C, MacLeod K, McGregor S , et al. Mucosal immunity in extrinsic allergic alveolitis: salivary immunoglobulins and antibody against inhaled avian antigens among pigeon breeders. Clin Exp Allergy 1999; 29 (7) 957-964
• 64 Cormier Y, Létourneau L, Racine G. Significance of precipitins and asymptomatic lymphocytic alveolitis: a 20-yr follow-up. Eur Respir J 2004; 23 (4) 523-525
• 65 Ando M, Konishi K, Yoneda R, Tamura M. Difference in the phenotypes of bronchoalveolar lavage lymphocytes in patients with summer-type hypersensitivity pneumonitis, farmer's lung, ventilation pneumonitis, and bird fancier's lung: report of a nationwide epidemiologic study in Japan. J Allergy Clin Immunol 1991; 87 (5) 1002-1009
• 66 Drent M, van Velzen-Blad H, Diamant M, Wagenaar SS, Donckerwolck-Bogaert M, van den Bosch JM. Differential diagnostic value of plasma cells in bronchoalveolar lavage fluid. Chest 1993; 103 (6) 1720-1724
• 67 Drent M, Wagenaar SS, van Velzen-Blad H, Mulder PG, Hoogsteden HC, van den Bosch JM. Relationship between plasma cell levels and profile of bronchoalveolar lavage fluid in patients with subacute extrinsic allergic alveolitis. Thorax 1993; 48 (8) 835-839
• 68 Haslam PL, Dewar A, Butchers P, Primett ZS, Newman-Taylor A, Turner-Warwick M. Mast cells, atypical lymphocytes, and neutrophils in bronchoalveolar lavage in extrinsic allergic alveolitis. Comparison with other interstitial lung diseases. Am Rev Respir Dis 1987; 135 (1) 35-47
• 69 Drent M, van Velzen-Blad H, Diamant M, Wagenaar SS, Hoogsteden HC, van den Bosch JM. Bronchoalveolar lavage in extrinsic allergic alveolitis: effect of time elapsed since antigen exposure. Eur Respir J 1993; 6 (9) 1276-1281
• 70 Schildge J, Klar B, Hardung-Backes M. Mast cells in bronchoalveolar lavage fluid of patients with interstitial lung diseases [in German]. Pneumologie 2003; 57 (4) 202-207
• 71 Drent M, Mulder PGH, Wagenaar SS, Hoogsteden HC, van Velzen-Blad H, van den Bosch JM. Differences in BAL fluid variables in interstitial lung diseases evaluated by discriminant analysis. Eur Respir J 1993; 6 (6) 803-810
• 72 Hariri LP, Mino-Kenudson M, Shea B , et al. Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum Pathol 2012; 43 (5) 660-668
• 73 Barrios RJ. Hypersensitivity pneumonitis: histopathology. Arch Pathol Lab Med 2008; 132 (2) 199-203
• 74 Gaxiola M, Buendía-Roldán I, Mejía M , et al. Morphologic diversity of chronic pigeon breeder's disease: clinical features and survival. Respir Med 2011; 105 (4) 608-614
• 75 Reyes CN, Wenzel FJ, Lawton BR, Emanuel DA. The pulmonary pathology of farmer's lung disease. Chest 1982; 81 (2) 142-146
• 76 Pérez-Padilla R, Gaxiola MN, Salas J, Mejía M, Ramos C, Selman M. Bronchiolitis in chronic pigeon breeder's disease: morphologic evidence of a spectrum of small airway lesions in hypersensitivity pneumonitis induced by avian antigens. Chest 1996; 110 (2) 371-377
• 77 Fukuoka J, Franks TJ, Colby TV , et al. Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases. Am J Surg Pathol 2005; 29 (7) 948-954
• 78 Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol 2008; 39 (9) 1275-1294
• 79 Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol 2006; 30 (2) 201-208
• 80 Vourlekis JS, Schwarz MI, Cool CD, Tuder RM, King TE, Brown KK. Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 2002; 112 (6) 490-493
• 81 Reghellin D, Poletti V, Tomassett S , et al. Cathepsin-K is a sensitive immunohistochemical marker for detection of micro-granulomas in hypersensitivity pneumonitis. Sarcoidosis Vasc Diffuse Lung Dis 2010; 27 (1) 57-63
• 82 Verma H, Nicholson AG, Kerr KM , et al. Alveolar proteinosis with hypersensitivity pneumonitis: a new clinical phenotype. Respirology 2010; 15 (8) 1197-1202
• 83 Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer's lung. Am Rev Respir Dis 1992; 145 (1) 3-5
• 84 Ramírez A, Sansores R, Chapela R , et al. Inhaled beclomethasone versus oral prednisone. A clinical trial in patients with hypersensitivity pneumonitis [abstract]. Am J Respir Crit Care Med 1995; 151: A605
• 85 Carlsen KH, Leegaard J, Lund OD, Skjaervik H. Allergic alveolitis in a 12-year-old boy: treatment with budesonide nebulizing solution. Pediatr Pulmonol 1992; 12 (4) 257-259
• 86 Tanaka H, Tsunematsu K, Nakamura N , et al. Successful treatment of hypersensitivity pneumonitis caused by Grifola frondosa (Maitake) mushroom using a HFA-BDP extra-fine aerosol. Intern Med 2004; 43 (8) 737-740
• 87 Khoor A, Leslie KO, Tazelaar HD, Helmers RA, Colby TV. Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001; 115 (5) 755-762
• 88 Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med 2006; 100 (4) 610-615
• 89 Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE. Thalidomide for chronic sarcoidosis. Chest 2002; 122 (1) 227-232
• 90 Ye Q, Chen B, Tong Z , et al. Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease. Eur Respir J 2006; 28 (4) 824-831
• 91 Pérez-Padilla R, Salas J, Chapela R , et al. Mortality in Mexican patients with chronic pigeon breeder's lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis 1993; 148 (1) 49-53
• 92 Vourlekis JS, Schwarz MI, Cherniack RM , et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med 2004; 116 (10) 662-668
• 93 Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis. Chest 2008; 134 (1) 133-138
• 94 Lima MS, Coletta EN, Ferreira RG , et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med 2009; 103 (4) 508-515
• 95 Bang KM, Weissman DN, Pinheiro GA, Antao VC, Wood JM, Syamlal G. Twenty-three years of hypersensitivity pneumonitis mortality surveillance in the United States. Am J Ind Med 2006; 49 (12) 997-1004