Hypersensitivity Pneumonitis


Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is an immune-mediated inflammatory form of diffuse interstitial pulmonary disease caused by inhalation of various antigens that affect susceptible patients. Occasionally, an HP reaction pattern may be seen in association with drug toxicity. Bacterial, mycobacterial, fungal, animal protein, and chemical compound causative antigens have been identified, with common examples listed in Table 32.1 .

TABLE 32.1


Disease Agent Common Source
Farmer’s lung Saccharopolyspora rectivirgula, Thermoactinomyces vulgaris, Absidia corymbifera Moldy hay, grain, silage
Humidifier lung T. vulgaris Contaminated forced-air systems; water reservoirs
Mushroom worker’s lung Thermoactinomyces sacchari Moldy mushroom compost
Woodworker’s lung, wood pulp worker’s lung Alternaria tenuis , wood dust Oak, cedar, and mahogany dust; pine and spruce pulp
Japanese summer-type pneumonitis Trichosporum cutaneum (T. asahii) Contaminated old houses (tatami mats)
Hot tub lung Mycobacterium avium complex Hot tub water
Metal-working fluid–associated hypersensitivity pneumonitis Mycobacterium immunogenum Metal-working fluids
Bird fancier’s lung, pigeon breeder’s disease Avian proteins Avian droppings, feathers (parakeets, budgerigars, pigeons, chickens, turkeys)
Laboratory worker’s lung Proteins of rats, gerbils Urine, serum, pelt proteins
Chemical worker’s lung Isocyanates; trimellitic anhydride Polyurethane foams, spray paints, finishes, sealants, special glues

HP occurs most commonly in middle-aged adults and is more common in nonsmokers when compared to demographically matched smokers, which is suspected to be due to the immunosuppressive effects of cigarette smoke on the intrapulmonary immune mediator cells that are implicated in HP. Smokers who do develop HP are more likely to develop chronic disease, however, and have a worse prognosis than nonsmokers. Certain occupations and hobbies that involve materials harboring the causative antigens have been described in the literature and should be queried during the collection of a detailed exposure history.

The development of HP is influenced by the size, immunogenicity, duration of exposure, and number of inhaled organic particles and the immune response of the affected individual. Not all equal exposures lead to the development of HP. Farmer’s lung (one of the most common types of HP), for instance, is estimated to occur in 9% to 12% of exposed farmers, and bird fancier’s lung is estimated to occur in 15% of bird keepers. It is not yet clear which variables determine the initial presentation and clinical course of the disease. Regardless of the type of causative antigen or its environmental setting, only a small percentage of individuals with any given antigenic exposure develop HP.

The pathogenesis of HP is incompletely understood, but it is accepted that HP results from a non–immunoglobulin (Ig)E-mediated hypersensitivity reaction. The antigens associated with the development of HP usually occur in aerosolized particles of less than 3 µm in diameter, which enables their deposition in the distal airspaces, resulting in type 3 (antigen-antibody complex) and type 4 (delayed cell-mediated) hypersensitivity reactions. There is also evidence that alterations in neutrophil chemotaxis are involved in the pathophysiology of HP.

Prevalence and Epidemiology

The prevalence and incidence of HP in the general population are difficult to evaluate, as disease manifestation is influenced by climatic, seasonal, and geographic conditions; differing diagnoses of the disease; methods to establish the diagnosis; intensity of exposure; smoking habits; and genetic risk factors.

Clinical Presentation

Traditionally, HP has been described in terms of acute, subacute, and chronic manifestations. Although this classification has merits, there is significant clinical overlap of these stages, and many patients present with findings not purely conforming to one category.

An alternative classification scheme described in a 2011 publication by Lacasse and coworkers sorted patients into clusters on the basis of clinical presentation, physical examination, laboratory results, chest radiograph findings, computed tomography (CT) findings, and bronchoalveolar lavage (BAL) results. This cluster system found that HP patients were most effectively grouped into two clusters. Cluster 1 patients had more recurrent systemic symptoms and fewer abnormal chest radiographs than those in cluster 2. Cluster 2 patients also had more severe restrictive lung disease patterns on pulmonary function testing and more pronounced fibrotic changes on CT. Although this classification scheme may best fit the HP patient population, the acute, subacute, and chronic subgroups persist in the literature and will be maintained throughout this chapter.

Acute HP manifests with abrupt onset of symptoms within 2 to 9 hours of antigenic exposure in a previously sensitized patient. Influenza-like symptoms often predominate, including chills, fever, myalgia, headache, and nausea. Respiratory symptoms range from mild cough to severe dyspnea and occasionally may progress to respiratory failure. Symptoms gradually decrease within hours or days of exposure cessation but may recur after reexposure.

Subacute HP can be triggered by continuous exposure to antigen or repeated acute exposure. Symptoms may appear gradually over a period of several days to weeks. Patients usually present with milder symptoms compared with acute HP, often experiencing exertional dyspnea and cough with or without fever. Numerous exacerbations and remissions of subacute HP over an extended time may be seen in patients with subacute HP.

Chronic HP can develop as a progression from acute or subacute HP or may occur without any preceding HP history. Cough and exertional dyspnea are common initial manifestations, and fatigue and weight loss may be quite severe. Bilateral crackles are commonly present on auscultation, and digital clubbing may occur. Chronic HP may progress either to emphysematous or fibrotic end-stage forms, which confer a worse prognosis ( Figs. 32.1 and 32.2 ). Pneumothorax, pneumomediastinum, and subcutaneous air are rare manifestations of HP.

Fig. 32.1

Emphysema in hypersensitivity pneumonitis. High-resolution CT scan shows centrilobular emphysema. No other abnormalities are present. The patient was a lifelong nonsmoker.

(Courtesy Dr. Yvon Cormier, Hospital and University Laval, Ste. Foy, Quebec, Canada.)

Fig. 32.2

Progression of fibrosis in a patient exposed to red cedar. (A) High-resolution CT scan through the lung bases shows patchy ground-glass opacities with minimal superimposed reticulation and lobular areas of decreased attenuation and vascularity. (B) CT scan 11 years later shows progression of reticulation and architectural distortion with development of traction bronchiectasis and bronchiolectasis and honeycombing resulting from fibrosis. Minimal ground-glass opacities and focal areas of decreased attenuation are present.


Nonspecific clinical presentation and variable occurrence in exposed individuals require that physicians maintain a high index of suspicion and collect a meticulous history in making the diagnosis of HP. In up to 40% of histologically proven cases of HP, the offending agent is not identified. In most cases, however, the diagnosis of HP can be made based on a combination of history of exposure to a possible allergen, clinical features, lung function tests, and consistent radiologic findings. The 2003 HP Study, a prospective multicenter study, identified factors that had significant predictive power in identifying active HP. These included known exposure to an offending antigen, onset of symptoms within 8 hours after exposure, the presence of precipitating antibodies, and the presence of inspiratory phase crackles on physical examination.

Laboratory Findings

Laboratory testing in HP may include hematologic assessment, pulmonary function testing, testing for serum precipitins (precipitating antigens) to common causative antigens, specific inhalation challenge, BAL, and lung biopsy.

Hematologic evaluation in HP may reveal slight to moderate neutrophilic leukocytosis with lymphopenia, particularly during acute and subacute episodes. Nonspecific markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate, may be elevated. Serum precipitating antibodies against the offending antigens may be present, and although these IgG antibodies are excellent markers of exposure to specific antigens in the environment, they are considered confirmatory evidence rather than pathognomonic for HP, and their absence does not exclude the diagnosis of HP. Numerous studies have documented the presence of serum precipitins in asymptomatic individuals with exposure to certain antigens, and conversely, the absence of serum precipitins in patients with HP has also been documented.

BAL in active HP may show heightened overall cellularity, as well as an elevated proportion of lymphocytes. Notably, during an acute exacerbation, the proportion of neutrophils may be higher than that of lymphocytes. Specific inhalation challenge (SIC) tests involve nebulized antigenic exposure in a controlled clinical setting under medical supervision, with pulmonary function testing performed at multiple time points during the examination. SIC examinations are of questionable clinical utility in confirmation of HP diagnosis and may at best provide confirmatory evidence.

Lung Function

Functional abnormalities in HP include a reduction in the carbon monoxide diffusing capacity, predominantly restrictive lung function with a reduction of total lung capacity and forced vital capacity, and resting hypoxemia that usually worsens during exercise. Although restrictive lung function is the most commonly described long-term outcome in patients who have chronic HP, obstructive pattern findings are identified in some patients.

Pathologic Findings

Classic histologic findings of HP have been described, regardless of the type of inciting antigen. The histologic patterns of HP vary with the stage of disease and may mimic the patterns of other interstitial lung diseases.

Information about the lung biopsy findings of acute HP is limited, as biopsy is rarely performed. Histologic abnormalities described in these patients are nonspecific and include neutrophilic infiltration of the airspace and respiratory bronchioles combined with interstitial pneumonia, acute vasculitis, organizing pneumonia, and a pattern of diffuse alveolar damage.

Subacute HP is characterized by a triad of cellular bronchiolitis; chronic bronchiolocentric cellular interstitial pneumonia composed predominantly of lymphocytes; and scattered, small, poorly formed noncaseating granulomas ( Fig. 32.3 ). Only approximately 60% of patients have all three findings at biopsy, however. In patients with only cellular interstitial pneumonia, the histologic features can be identical to the features of nonspecific interstitial pneumonia (NSIP). Other abnormalities that may be seen include areas of organizing pneumonia and constrictive bronchiolitis (or obliterative bronchiolitis) characterized by smooth muscle hypertrophy, peribronchiolar fibrosis, and partial airway obstruction.

Fig. 32.3

Histologic findings of subacute hypersensitivity pneumonitis. (A) Photomicrograph of surgical lung biopsy specimen shows a moderate chronic lymphocytic inflammatory interstitial infiltrate in a predominantly peribronchiolar distribution (arrowheads). (B) Higher-power view shows chronic lymphocytic inflammatory interstitial infiltrate in a peribronchiolar distribution, cellular bronchiolitis (arrow), and a poorly formed granuloma (arrowhead). These findings are characteristic of hypersensitivity pneumonitis and correlate with the poorly defined centrilobular nodules seen on high-resolution CT .

(Courtesy Dr. John English, Department of Pathology, Vancouver General Hospital, Vancouver, Canada.)

Histologically, the chronic stage of HP often shows fibrosis superimposed upon findings of subacute HP. NSIP pattern and usual interstitial pneumonia pattern are histologic features of chronic HP and may be the predominant or the only histologic finding.

Manifestations of the Disease


HP may yield a radiograph with no significant abnormalities, and its only utility may be in excluding other differential considerations. For instance, in a study of patients with bird breeder’s lung and abnormal high-resolution CT, 7 (33%) of 21 patients with subacute HP and 1 (4%) of 24 patients with chronic HP had normal chest radiographs. If abnormalities are present, acute HP most commonly manifests with middle or upper lung zone–predominant nodular or reticulonodular opacities ( Fig. 32.4 ).

Fig. 32.4

Acute hypersensitivity pneumonitis on chest radiography. Anteroposterior chest radiograph shows extensive bilateral hazy areas of increased opacity (ground-glass opacities) and patchy areas of consolidation. The diagnosis of acute hypersensitivity pneumonitis (bird fancier’s lung) was based on the clinical findings and history of exposure.

The radiographic features of subacute HP include hazy areas of increased opacity (ground-glass opacities) ( Fig. 32.5 ) and poorly defined nodular opacities ( Fig. 32.6 ). Although an upper lung zone predominance is commonly seen in other forms of HP, subacute HP has a more variable geographic pattern, and a diffuse or even lower lung zone predominance may be seen. Diffuse consolidation is rare in patients with subacute HP, and when present, superimposed infection should be considered ( Fig. 32.7 ). Pneumomediastinum, pneumothorax, and subcutaneous air may be seen in some patients, presumably resulting from overdistention or disruption of alveoli with obliteration of the respiratory bronchioles ( Fig. 32.8 ).

Fig. 32.5

Subacute hypersensitivity pneumonitis on chest radiography. Posteroanterior chest radiograph shows bilateral hazy areas of increased opacity (ground-glass opacities) involving mainly the lower lung zones. Incidental note is made of an accessory azygos fissure. The patient was a bird fancier with biopsy-proven hypersensitivity pneumonitis who presented with clinical findings of asthma.

Fig. 32.6

Subacute hypersensitivity pneumonitis on chest radiography. Magnified view of left lung from a chest radiograph shows poorly defined small nodular opacities in a patient with pigeon breeder’s lung. This appearance correlates with the poorly defined centrilobular nodules seen on high-resolution CT.

Fig. 32.7

Subacute hypersensitivity pneumonitis from isocyanate exposure. (A) Posteroanterior chest radiograph shows bilateral hazy areas of increased opacity (ground-glass opacities) and poorly defined nodular opacities in the middle and lower lung zones with relative peripheral sparing. (B) High-resolution CT at the level of the inferior pulmonary veins shows diffuse ground-glass opacities in a peribronchovascular distribution and minimal consolidation posteriorly secondary to organizing pneumonia.

Fig. 32.8

Subacute hypersensitivity pneumonitis. (A) Posteroanterior chest radiograph shows bilateral hazy areas of increased opacity (ground-glass opacities) and pneumomediastinum (arrowheads). (B) High-resolution CT at the level of the aortic arch shows diffuse ground-glass opacities and a few ill-defined centrilobular nodules (arrowheads) typical of hypersensitivity pneumonitis. Note small right pneumothorax (arrow) and pneumomediastinum. The patient had biopsy-proven hypersensitivity pneumonitis resulting from exposure to feathers in a bedcover (feather duvet), who presented with pneumomediastinum and right pneumothorax.

The radiographic manifestations of chronic HP may include reticular opacities, honeycombing, and volume loss ( Fig. 32.9 ). The fibrosis may be diffuse and severe in all lung zones or have an upper or middle lung zone predominance. Hilar and mediastinal lymph node enlargement may be seen and is a nonspecific finding ( Fig. 32.10 ).

Fig. 32.9

Chronic hypersensitivity pneumonitis: radiographic findings. (A) Posteroanterior chest radiograph shows mild bilateral reticular pattern in the lower lung zones in a patient with symptoms of dyspnea over 2 years. (B) Posteroanterior chest radiograph obtained 18 months after (A) when the patient became more symptomatic shows bilateral hazy areas of increased opacity (ground-glass opacities) and irregular lines. (C) Posteroanterior chest radiograph obtained 3 months after (B) shows increase of ground-glass opacities and lower lung volumes. The patient was a bird fancier with subacute and chronic hypersensitivity pneumonitis.

Fig. 32.10

Chronic hypersensitivity pneumonitis associated with lymph node enlargement in a patient exposed to feathers. (A) Posteroanterior chest radiograph shows extensive bilateral reticular pattern and mediastinal and bilateral hilar lymphadenopathy. (B) High-resolution CT scan at the level of the bronchus intermedius shows patchy ground-glass opacities and superimposed fine reticulation. A few ill-defined centrilobular nodules (arrowheads) and centrilobular emphysema are also present. Note subcarinal and bilateral hilar lymph node enlargement.

Computed Tomography

A multicenter study by Lacasse and coworkers showed that the diagnosis of HP often can be made or rejected with confidence based on clinical history and high-resolution CT findings without the need for bronchoscopy or biopsy. Transbronchial biopsy and surgical biopsy are generally considered for patients in whom bronchoalveolar lavage and high-resolution CT fail to yield a confident diagnosis. High-resolution CT frequently shows characteristic findings in patients with normal or nonspecific chest radiographs ( Fig. 32.11 ).

Fig. 32.11

Subacute hypersensitivity pneumonitis in patient with progressive dyspnea while working in a bird hospital. (A) Posteroanterior chest radiograph shows no definite abnormalities. (B) Coronal reformatted CT image obtained at the same day of the chest radiograph shows poorly defined centrilobular nodules and diffuse ground-glass opacities mainly in the upper and middle lung zones.

Acute Phase

Because of the milder clinical manifestations and often rapid resolution of the symptoms, high-resolution CT is uncommonly performed in the assessment of patients with acute HP. CT in acute HP may be completely unremarkable. When abnormalities are present, the most common high-resolution CT findings consist of diffuse ground-glass opacities and consolidation. Centrilobular nodules also may be seen. The diffuse airspace opacification seen in acute HP may be due to diffuse alveolar damage or acute organizing pneumonia.

Subacute Phase

High-resolution CT in subacute HP may show poorly defined small centrilobular nodules ( Fig. 32.12 ), symmetric patchy or diffuse bilateral ground-glass opacities, and lobular areas of decreased attenuation and vascularity on inspiratory images (mosaic attenuation) and air-trapping on expiratory images ( Figs. 32.13 and 32.14 ). a

a References .

Imaging abnormalities in subacute HP may show a diffuse distribution, an upper lung zone predominance, or may even show a middle and lower lung zone predominance with sparing of the bases.

Fig. 32.12

Subacute hypersensitivity pneumonitis: schematic representation and CT appearance of centrilobular nodules. (A) Schematic representation shows typical distribution and appearance of nodular pattern of subacute hypersensitivity pneumonitis on high-resolution CT. The nodules are poorly defined and have ground-glass attenuation. The nodules usually measure 3–5 mm in diameter and typically appear as clusters. They are centered a few millimeters away from the pleural surfaces, interlobar fissures, and interlobular septa (centrilobular distribution). (B) High-resolution CT scan targeted to the right lung shows characteristic centrilobular nodules in a patient with bird breeder’s lung.

Jul 21, 2019 | Posted by in GENERAL RADIOLOGY | Comments Off on Hypersensitivity Pneumonitis
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