Background
Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, is a complex syndrome of varying intensity, clinical presentation, and natural history, rather than a single uniform disease.
First described in Iceland in 1874 and termed heykatarr, hypersensitivity pneumonitis is caused by sensitization to repeated inhalation of dusts containing organic antigens. These dusts can be derived from a variety of sources, such as dairy and grain products, animal dander and protein, wood bark, and water reservoir vaporizers. The most common antigens are thermophilic Actinomycetes species and avian proteins; the most common diseases are farmer's lung and bird fancier's lung.
Hypersensitivity pneumonitis is characterized by diffuse inflammation of lung parenchyma and airways in previously sensitized patients. Based on the length and intensity of exposure and subsequent duration of illness, clinical presentations of hypersensitivity pneumonitis are categorized as acute, subacute (intermittent), and chronic progressive.
Pathophysiology
Pathologically, acute hypersensitivity pneumonitis is characterized by poorly formed noncaseating interstitial granulomas and mononuclear cell infiltration in a peribronchial distribution with prominent giant cells.
The subacute, or intermittent, form produces more well-formed noncaseating granulomas, bronchiolitis with or without organizing pneumonia, and interstitial fibrosis.
Chronic forms reveal additional findings of chronic interstitial inflammation and alveolar destruction (honeycombing). Cholesterol clefts or asteroid bodies are present within or outside granulomas. Additionally, centrilobular fibrosis and bridging fibrosis are important hallmarks of chronic hypersensitivity pneumonitis.[1]
The pathologic features of chronic hypersensitivity pneumonitis, often associated with a poor prognosis, have the following 3 patterns of fibrosis:
- Predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci similar to usual interstitial pneumonia (UIP)
- Homogeneous linear fibrosis similar to fibrotic nonspecific interstitial pneumonia (NSIP)
- Irregular predominantly peribronchiolar fibrosis
Thus, chronic hypersensitivity pneumonitis may mimic usual interstitial pneumonia or fibrotic nonspecific interstitial pneumonia. To diagnose chronic hypersensitivity pneumonitis in a case with features resembling usual interstitial pneumonia, identifying areas of cellular interstitial pneumonia with giant cells or granulomas situated around bronchioles may lead to the correct diagnosis.[2] The finding of peribronchiolar fibrosis also may be helpful.[3]
Pathogenesis
Most patients have circulating immunoglobulin G antibodies that are specific for the offending antigen. The antibody (called precipitating antibody) reacts with a specific antigen to form a precipitation. However, approximately 50% of asymptomatic persons exposed to the sensitizing antigen also have these antibodies.
Although initially thought to be an immunocomplex-mediated process, subsequent studies showed that cell-mediated immunity is more important.[4]
Early response to the antigen is characterized by an increase in neutrophils in the alveoli and small airways followed by an influx of mononuclear cells. These cells release proteolytic enzymes, prostaglandins, and leukotrienes. The production and release of interleukins, cytokines, growth factors, and various other mediators from T lymphocytes and macrophages play important roles in hypersensitivity pneumonitis pathogenesis.
Epidemiology
Frequency
United States
Resistance or susceptibility to infection following exposure varies. Incidence also varies considerably. Studies document 8-540 cases per 100,000 persons per year for farmers and 6,000-21,000 cases per 100,000 persons per year for pigeon breeders. High attack rates are documented in sporadic outbreaks. Approximately 52% of office workers exposed to an infected humidifier were infected, and 27% of workers at a molding plant for polyurethane foam parts were infected.
Prevalence varies by region, climate, and farming practices. Hypersensitivity pneumonitis affects 0.4-7% of the farming population. Reported prevalence among bird fanciers is estimated to be 20-20,000 cases per 100,000 persons at risk.
International
The prevalence of farmer's lung in the United Kingdom is reported to be 420-3,000 cases per 100,000 persons at risk, in France is 4,370 cases per 100,000 persons at risk,[5, 6] and in Finland is 1,400-1,700 cases per 100,000 persons at risk.[7]
One epidemiologic study revealed that the estimated incidence of interstitial lung disease was 7.6 cases per 100,000 persons per year. Of all interstitial lung diseases, the most common was idiopathic pulmonary fibrosis (38.6%), followed by sarcoidosis (14.9%), cryptogenic organizing pneumonia (10.4%), interstitial lung disease associated with collagen-vascular diseases (9.9%), hypersensitivity pneumonitis (6.6%), and unclassified in 5.1% of cases.[8]
Mortality/Morbidity
Most patients recover completely after the inciting exposure ceases. Bird fancier's disease has a worse prognosis than farmer's lung. The outcomes of other varieties of hypersensitivity pneumonitis are more variable.
Sex
One epidemiological study revealed a male to female ratio of 1.2:1.
Age
Hypersensitivity pneumonitis is usually seen in the fourth to sixth decade of life. One study looking at 85 consecutive patients with hypersensitivity pneumonitis found a mean age of 53 +/- 14 years.[9]
Takemura T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y. Pathology of hypersensitivity pneumonitis. Curr Opin Pulm Med. Sep 2008;14(5):440-54. [Medline].
Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol. Sep 2008;39(9):1275-94. [Medline].
Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol. Feb 2006;30(2):201-8. [Medline].
Woda BA. Hypersensitivity pneumonitis: an immunopathology review. Arch Pathol Lab Med. Feb 2008;132(2):204-5. [Medline].
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. Oct 1993;50(10):941-4. [Medline].
Depierre A, Dalphin JC, Pernet D, Dubiez A, Faucompre C, Breton JL. Epidemiological study of farmer's lung in five districts of the French Doubs province. Thorax. Jun 1988;43(6):429-35. [Medline].
Terho EO. Work-related respiratory disorders among Finnish farmers. Am J Ind Med. 1990;18(3):269-72. [Medline].
Xaubet A, Ancochea J, Morell F, et al. Report on the incidence of interstitial lung diseases in Spain. Sarcoidosis Vasc Diffuse Lung Dis. Mar 2004;21(1):64-70. [Medline].
Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. Jul 2007;82(7):812-6. [Medline].
Ganier M, Lieberman P, Fink J, Lockwood DG. Humidifier lung. An outbreak in office workers. Chest. Feb 1980;77(2):183-7. [Medline].
Kane GC, Marx JJ, Prince DS. Hypersensitivity pneumonitis secondary to Klebsiella oxytoca. A new cause of humidifier lung. Chest. Aug 1993;104(2):627-9. [Medline].
Rose CS, Martyny JW, Newman LS, et al. "Lifeguard lung": endemic granulomatous pneumonitis in an indoor swimming pool. Am J Public Health. Dec 1998;88(12):1795-800. [Medline].
Gamboa PM, de las Marinas MD, Antepara I, Jauregui I, Sanz MM. Extrinsic allergic alveolitis caused by esparto (Stipa tenacissima). Allergol Immunopathol (Madr). Nov-Dec 1990;18(6):331-4. [Medline].
Zamarrón C, del Campo F, Paredes C. Extrinsic allergic alveolitis due to exposure to esparto dust. J Intern Med. Aug 1992;232(2):177-9. [Medline].
Rosenman KD. Asthma, hypersensitivity pneumonitis and other respiratory diseases caused by metalworking fluids. Curr Opin Allergy Clin Immunol. Apr 2009;9(2):97-102. [Medline].
Lee DK. Nicotine and hypersensitivity pneumonitis. Am J Respir Crit Care Med. Jul 15 2004;170(2):199-200; author reply 200. [Medline].
Terho EO, Husman K, Vohlonen I. Prevalence and incidence of chronic bronchitis and farmer's lung with respect to age, sex, atopy, and smoking. Eur J Respir Dis Suppl. 1987;152:19-28. [Medline].
Roussel S, Reboux G, Dalphin JC, Pernet D, Laplante JJ, Millon L. Farmer's lung disease and microbiological composition of hay: a case-control study. Mycopathologia. Nov 2005;160(4):273-9. [Medline].
Cappelluti E, Fraire AE, Schaefer OP. A case of "hot tub lung" due to Mycobacterium avium complex in an immunocompetent host. Arch Intern Med. Apr 14 2003;163(7):845-8. [Medline].
Embil J, Warren P, Yakrus M, et al. Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tub water. Hypersensitivity pneumonitis or infection?. Chest. Mar 1997;111(3):813-6. [Medline].
Jacobs RL, Thorner RE, Holcomb JR, Schwietz LA, Jacobs FO. Hypersensitivity pneumonitis caused by Cladosporium in an enclosed hot-tub area. Ann Intern Med. Aug 1986;105(2):204-6. [Medline].
Kahana LM, Kay JM, Yakrus MA, Waserman S. Mycobacterium avium complex infection in an immunocompetent young adult related to hot tub exposure. Chest. Jan 1997;111(1):242-5. [Medline].
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. May 2001;115(5):755-62. [Medline].
Travaline JM, Kelsen SG. Hypersensitivity pneumonitis associated with hot tub use. Arch Intern Med. Oct 13 2003;163(18):2250; author reply 2250-1. [Medline].
Marras TK, Wallace RJ Jr, Koth LL, Stulbarg MS, Cowl CT, Daley CL. Hypersensitivity pneumonitis reaction to Mycobacterium avium in household water. Chest. Feb 2005;127(2):664-71. [Medline].
Malmberg P. Health effects of organic dust exposure in dairy farmers. Am J Ind Med. 1990;17(1):7-15. [Medline].
Jacobsen G, Schlunssen V, Schaumburg I, Sigsgaard T. Increased incidence of respiratory symptoms among female woodworkers exposed to dry wood. Eur Respir J. Jun 2009;33(6):1268-76. [Medline].
Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. Oct 15 2003;168(8):952-8. [Medline].
Silva CI, Churg A, Müller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. Feb 2007;188(2):334-44. [Medline].
Lynch DA, Rose CS, Way D, King TE Jr. Hypersensitivity pneumonitis: sensitivity of high-resolution CT in a population-based study. AJR Am J Roentgenol. Sep 1992;159(3):469-72. [Medline].
Morell F, Roger A, Reyes L, Cruz MJ, Murio C, Munoz X. Bird fancier's lung: a series of 86 patients. Medicine (Baltimore). Mar 2008;87(2):110-30. [Medline].
D'Ippolito R, Chetta A, Foresi A, et al. Induced sputum and bronchoalveolar lavage from patients with hypersensitivity pneumonitis. Respir Med. Oct 2004;98(10):977-83. [Medline].
Lalancette M, Carrier G, Laviolette M, et al. Farmer's lung. Long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis. Jul 1993;148(1):216-21. [Medline].
Murayama J, Yoshizawa Y, Ohtsuka M, Hasegawa S. Lung fibrosis in hypersensitivity pneumonitis. Association with CD4+ but not CD8+ cell dominant alveolitis and insidious onset. Chest. Jul 1993;104(1):38-43. [Medline].
Trahan S, Hanak V, Ryu JH, Myers JL. Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biopsies from 15 patients. Chest. Jul 2008;134(1):126-32. [Medline].
Monkare S. Influence of corticosteroid treatment on the course of farmer's lung. Eur J Respir Dis. May 1983;64(4):283-93. [Medline].
[Guideline] Brown KK. Chronic cough due to chronic interstitial pulmonary diseases: ACCP evidence-based clinical practice guidelines. Chest. Jan 2006;129(1 Suppl):180S-185S. [Medline].
[Guideline] Tarlo SM. Cough: occupational and environmental considerations: ACCP evidence-based clinical practice guidelines. Chest. Jan 2006;129(1 Suppl):186S-196S. [Medline].
Wang P, Xu ZJ, Xu WB, et al. Clinical features and prognosis in 21 patients with extrinsic allergic alveolitis. Chin Med Sci J. Dec 2009;24(4):202-7. [Medline].
Sahin H, Brown KK, Curran-Everett D, et al. Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival. Radiology. Aug 2007;244(2):591-8. [Medline].
Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis. Chest. Jul 2008;134(1):133-8. [Medline].
Lima MS, Coletta EN, Ferreira RG, et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med. Apr 2009;103(4):508-15. [Medline].
Alegre J, Morell F, Cobo E. Respiratory symptoms and pulmonary function of workers exposed to cork dust, toluene diisocyanate and conidia. Scand J Work Environ Health. Jun 1990;16(3):175-81. [Medline].
Barbee RA, Callies Q, Dickie HA, Rankin J. The long-term prognosis in farmer's lung. Am Rev Respir Dis. Feb 1968;97(2):223-31. [Medline].
Bourke SJ, Banham SW, Carter R, Lynch P, Boyd G. Longitudinal course of extrinsic allergic alveolitis in pigeon breeders. Thorax. May 1989;44(5):415-8. [Medline].
Buschman DL, Gamsu G, Waldron JA Jr, Klein JS, King TE Jr. Chronic hypersensitivity pneumonitis: use of CT in diagnosis. AJR Am J Roentgenol. Nov 1992;159(5):957-60. [Medline].
Christensen LT, Schmidt CD, Robbins L. Pigeon breeders' disease--a prevalence study and review. Clin Allergy. Dec 1975;5(4):417-30. [Medline].
Cormier Y, Belanger J. Long-term physiologic outcome after acute farmer's lung. Chest. Jun 1985;87(6):796-800. [Medline].
Cormier Y, Belanger J, Tardif A, Leblanc P, Laviolette M. Relationships between radiographic change, pulmonary function, and bronchoalveolar lavage fluid lymphocytes in farmer's lung disease. Thorax. Jan 1986;41(1):28-33. [Medline].
Daman L, Lieberman P, Ganier M, Hashimoto K. Localized heat urticaria. J Allergy Clin Immunol. Apr 1978;61(4):273-8. [Medline].
Fink JN. Hypersensitivity pneumonitis. Clin Chest Med. Jun 1992;13(2):303-9. [Medline].
Fink JN, Ortega HG, Reynolds HY, Cormier YF, Fan LL, Franks TJ. Needs and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care Med. Apr 1 2005;171(7):792-8. [Medline].
Gruchow HW, Hoffmann RG, Marx JJ Jr, Emanuel DA, Rimm AA. Precipitating antibodies to farmer's lung antigens in a Wisconsin farming population. Am Rev Respir Dis. Oct 1981;124(4):411-5. [Medline].
Gurney JW. Hypersensitivity pneumonitis. Radiol Clin North Am. Nov 1992;30(6):1219-30. [Medline].
Hartman TE. The HRCT features of extrinsic allergic alveolitis. Semin Respir Crit Care Med. Aug 2003;24(4):419-26. [Medline].
Hendrick DJ, Faux JA, Marshall R. Budgerigar-fancier's lung: the commonest variety of allergic alveolitis in Britain. Br Med J. Jul 8 1978;2(6130):81-4. [Medline].
Klote M. Hypersensitivity pneumonitis. Allergy Asthma Proc. Nov-Dec 2005;26(6):493-5. [Medline].
Krasnick J, Meuwissen HJ, Nakao MA, Yeldandi A, Patterson R. Hypersensitivity pneumonitis: problems in diagnosis. J Allergy Clin Immunol. Apr 1996;97(4):1027-30. [Medline].
Madsen D, Klock LE, Wenzel FJ, Robbins JL, Schmidt CD. The prevalence of farmer's lung in an agricultural population. Am Rev Respir Dis. Feb 1976;113(2):171-74. [Medline].
Malmberg P, Rask-Andersen A, Hoglund S, Kolmodin-Hedman B, Read Guernsey J. Incidence of organic dust toxic syndrome and allergic alveolitis in Swedish farmers. Int Arch Allergy Appl Immunol. 1988;87(1):47-54. [Medline].
Moreno-Ancillol A, Dominguez-Noche C, Gil-Adrados AC, Cosmes PM. Hypersensitivity pneumonitis due to occupational inhalation of fungi-contaminated corn dust. J Investig Allergol Clin Immunol. 2004;14(2):165-7. [Medline].
Ohtani Y, Saiki S, Kitaichi M, et al. Chronic bird fancier's lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax. Aug 2005;60(8):665-71. [Medline].
[Guideline] Richerson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin Immunol. Nov 1989;84(5 Pt 2):839-44. [Medline].
Rose CS. Water-related lung diseases. Occup Med. Apr-Jun 1992;7(2):271-86. [Medline].
Salvaggio JE. Inhaled particles and respiratory disease. J Allergy Clin Immunol. Aug 1994;94(2 Pt 2):304-9. [Medline].
Salvaggio JE. The identification of hypersensitivity pneumonitis. Hosp Pract (Minneap). May 15 1995;30(5):57-62, 65-6. [Medline].
Salvaggio JE, Millhollon BW. Allergic alveolitis: new insights into old mysteries. Respir Med. Oct 1993;87(7):495-501. [Medline].
Schlueter DP. Response of the lung to inhaled antigens. Am J Med. Sep 1974;57(3):476-92. [Medline].
Selman M. Hypersensitivity pneumonitis: a multifaceted deceiving disorder. Clin Chest Med. Sep 2004;25(3):531-47, vi. [Medline].
Sharma OP, Fujimura N. Hypersensitivity pneumonitis: a noninfectious granulomatosis. Semin Respir Infect. Jun 1995;10(2):96-106. [Medline].
Vourlekis JS, Schwarz MI, Cherniack RM, et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med. May 15 2004;116(10):662-8. [Medline].
| Disease | Source of Exposure | Major Antigen |
| Farmer's lung | Moldy hay | Saccharopolyspora rectivirgula (Micropolyspora faeni) |
| Bagassosis | Moldy sugar cane fiber | Thermoactinomyces sacchari |
| Grain handler's lung | Moldy grain | S rectivirgula,Thermoactinomyces vulgaris |
| Humidifier/air-conditioner lung | Contaminated forced-air systems, heated water reservoirs | S rectivirgula, T vulgaris |
| Bird breeder's lung | Pigeons, parakeets, fowl, rodents | Avian or animal proteins |
| Cheese worker's lung | Cheese mold | Penicillium casei |
| Malt worker's lung | Moldy malt | Aspergillus clavatus |
| Paprika splitter's lung | Paprika dust | Mucor stolonifer |
| Wheat weevil | Infested wheat | Sitophilus granarius |
| Mollusk shell hypersensitivity | Shell dust | Sea snail shells |
| Chemical worker's lung | Manufacture of plastics, polyurethane foam, rubber | Trimellitic anhydride, diisocyanate, methylene diisocyanate |

