Raghu G, Remy-Jardin M, Myers JL, et al; American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68. doi: 10.1164/rccm.201807-1255ST. PubMed PMID: 30168753.
Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respir Med. 2018 Feb;6(2):138-153. doi: 10.1016/S2213-2600(17)30433-2. Epub 2017 Nov 15. Review. PubMed PMID: 29154106.
Travis WD, Costabel U, Hansell DM, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013 Sep 15;188(6):733-48. doi: 10.1164/rccm.201308-1483ST. PubMed PMID: 24032382.Morisset J, Johannson KA, Jones KD, et al; HP Delphi Collaborators. Identification of Diagnostic Criteria for Chronic Hypersensitivity Pneumonitis: An International Modified Delphi Survey. Am J Respir Crit Care Med. 2018 Apr 15;197(8):1036-1044. doi: 10.1164/rccm.201710-1986OC. Epub 2017 Nov 27. PubMed PMID: 29172641.
Definition, Etiology, PathogenesisTop
Hypersensitivity pneumonitis (HP) is a complex syndrome resulting from repeated inhalational exposure to a wide variety of organic particles or chemical agents small enough to reach the alveoli (<5 microm). In susceptible individuals exposure to these antigens triggers an exaggerated immune response of the small airways and lung parenchyma (mediated by immune complexes, complement activation, and cellular immunity). More than 200 causative factors have been identified, including animal, insect, fungal, and bacterial proteins, and low-molecular-weight chemical compounds. The disease is typically characterized by a lymphocytic (CD8+-dominant) and granulomatous inflammation with a bronchiocentric distribution, although advanced fibrosis can be observed in chronic disease.
Clinical Features and Natural HistoryTop
1. Acute/subacute HP is characterized by a flu-like syndrome and generally manifests a few hours after exposure. Symptoms include cough, dyspnea, fever, chills, arthralgia, and malaise. Signs include an accelerated respiratory rate, tachycardia, and bilateral crackles at the lung bases. Untreated disease resolves within a day to a few weeks. In the case of repeated exposure to the antigen (even at low levels), patients develop dyspnea on exertion, cough, and sometimes also a low-grade fever. In general, acute HP is nonprogressive and intermittent, with spontaneous improvement in the setting of antigen avoidance. Subacute HP may result from repeated low-level exposures and is characterized by slowly progressive dyspnea, fatigue, and cough that develops over weeks to months.
2. Chronic (irreversible) HP develops over months to years and can lead to pulmonary fibrosis. Many patients with chronic HP have no recognizable acute deterioration and present as slowly progressive pulmonary fibrosis. In the field of interstitial lung disease (ILD), this is one of the most difficult diagnoses to make. The classification of HP into distinct acute, subacute, and chronic forms can be misleading, as clinical manifestations frequently overlap. Nevertheless, symptoms of chronic HP typically include productive cough, weight loss, loss of appetite, and malaise, whereas signs include tachypnea, bilateral crackles at the lung bases, rarely clubbing, and signs of chronic respiratory insufficiency.
Obtaining a thorough medical history is the cornerstone of establishing a diagnosis of HP. History should include environmental exposures (occupational, pets/animals, birds, feather pillows/duvets, hobbies including woodworking and gardening, the use of humidifiers and saunas, basement flooding, and visible mold in the home), similar symptoms in household members/coworkers, and the course of the disease.
1. Laboratory tests: Patients with acute HP may have elevated white blood cell counts with neutrophilia, elevated serum C-reactive protein levels and erythrocyte sedimentation rate, and positive serum precipitating antibodies against the offending antigen. The finding of a specific IgG-precipitating antibody in the serum of a patient with suspected HP indicates exposure but does not indicate that the precipitating antibody is pathogenic. Hence, precipitating antibodies are neither sensitive nor specific. In patients with chronic HP precipitating antibodies are variably present, and mild elevations of immunoglobulin levels or acute phase markers may be apparent.
2. Imaging studies:
1) Chest radiographs: In patients with acute HP the findings may be normal. A fine micronodular pattern or diffuse ground-glass opacities can be observed. In chronic HP diffuse, irregular reticular patterns are typically observed in the middle and upper lung zones.
2) High-resolution computed tomography (HRCT): In acute HP typical findings include diffuse, fine, poorly demarcated centrilobular nodules, focal air trapping, and a mosaic pattern caused by highly heterogeneous parenchymal density (a combination of ground-glass opacities and hypodense areas reflecting the air trapping). Distinctive HRCT findings in chronic HP include a combination of reticular, ground-glass, and centrilobular nodular opacities with associated signs of fibrosis, including traction bronchiectasis and occasionally honeycomb changes (see Idiopathic Pulmonary Fibrosis). It can often be difficult to differentiate chronic HP from idiopathic pulmonary fibrosis (IPF) on the basis of imaging studies alone, although the presence of air trapping and absence of a lower zone predominance are suggestive of chronic HP. Expiratory computed tomography (CT) images are very useful and should be part of the HRCT protocol.
3. Pulmonary function testing reveals a restrictive pattern (this may be minor in patients with early disease) with decreased carbon monoxide diffusing capacity of the lungs (DLCO). The 6-minute walk test reveals a shortened walk distance and frequently resting or exertional hypoxemia (or both).
4. Bronchoscopy often reveals high cellularity of bronchoalveolar lavage (BAL) fluid and an increased proportion of lymphocytes with predominant CD8+ cells. An elevated neutrophil count can also be observed in chronic fibrotic disease and is associated with poor prognosis.
5. Lung biopsy: Patients with acute HP do not require tissue confirmation, given the self-limited nature of their disease. Transbronchial biopsy can occasionally be diagnostic in the presence of bronchiocentric granulomatous inflammation. Surgical lung biopsy is indicated in patients who do not meet a sufficient number of clinical criteria for a definitive diagnosis and to exclude other disease entities that require different management, especially IPF.
Three complementary findings support a diagnosis of HP:
1) Clinical and functional features of an underlying ILD.
2) Relevant history of exposure based on thorough clinical assessment, circulating specific antibodies, or both.
3) HRCT with typical findings suggestive of HP.
If the diagnosis is doubtful, perform BAL. The presence of BAL lymphocytosis and “typical” HRCT makes the diagnosis of HP confident even in the absence of a definitive antigen exposure. Lung biopsy is indicated in patients in whom a diagnosis has not been established and other diseases must be excluded; this decision is usually made in a specialized center.
An accelerated decline in lung function has been demonstrated for most forms of HP with continued antigen exposure. Thus, early diagnosis and antigen avoidance are the mainstays of treatment. Pharmacologic therapy acts as an adjunct for patients with severe or progressive disease. It should be noted, however, that the use of glucocorticoids and other immunosuppressive agents in HP is primarily supported by anecdotal reports with little in the way of controlled trials.
1. Acute HP resolves without treatment in the majority of patients. In patients with severe symptoms use oral prednisone 0.5 mg/kg/d (40-60 mg/d) for 1 to 2 weeks, then taper the dose over 4 to 6 weeks. Treatment of respiratory insufficiency: see Acute Respiratory Failure.
2. Chronic HP: In patients with severe subacute progressive or chronic disease, oral prednisone 0.5 mg/kg/d for 4 weeks followed by a taper to a maintenance dose over 2 months is suggested. After 6 months assess for clinical response and continue therapy only in patients with objective improvement (assessed by spirometry, DLCO, plethysmography, and gas exchange at rest and during exercise). Cytotoxic agents such as azathioprine, mycophenolate mofetil, and cyclophosphamide have been used in patients with progressive refractory disease, but their efficacy is largely unproven and based on expert opinion. In patients with airflow obstruction or persistent cough, consider treatment with an inhaled corticosteroid or a beta2-agonist. Lung transplantation is reserved for patients with end-stage fibrosis.