bubble_chart Overview

Extrinsic allergic alveolitis is an allergic alveolitis caused by repeated inhalation of certain antigenic organic dusts, often involving the terminal bronchioles as well. In American literature, the term hypersensitivity pneumonitis is more commonly used. Domestically reported cases mainly include farmer's lung, bagassosis, mushroom worker's lung, bird breeder's lung, and dampness transformation device lung. Although the disease has many causes, the pathological, clinical symptoms, signs, and X-ray manifestations are extremely similar.

bubble_chart Etiology

Exogenous allergic alveolitis has numerous causes, commonly including organic dusts containing actinomycetes and fungal spores, animal and plant proteins, bacteria and their byproducts, insect antigens, and certain chemicals. The antigenic properties of some dusts remain unclear to this day. It is generally believed that the primary cause of farmer's lung is *Thermoactinomyces vulgaris*. In recent years, domestic researchers have reported another thermophilic actinomycete related to farmer's lung—*Streptomyces thermohygroscopicus*. Among various antigens, thermophilic actinomycetes are the most common and significant, particularly *Micropolyspora faeni*, followed by *Thermoactinomyces vulgaris*. These organisms exhibit fungal morphology but are classified as bacteria. They thrive in damp, warm, and decaying organic matter, with large quantities found in compost, soil, food, and contaminated water. Farmers often develop the disease after inhaling moldy hay, grain, or bagasse. Mushroom cultivation environments contain abundant thermophilic actinomycetes, predominantly *Thermoactinomyces vulgaris*, and inhalation by workers can lead to mushroom worker's lung. Bird breeder's lung (e.g., pigeon breeder's lung, parrot breeder's lung) is caused by avian serum, droppings, feather dust, or eggs. Some suggest that the dust on pigeon feathers, composed of keratin particles approximately 1 μm in size, is a more significant antigen than pigeon serum or excreta. Domestic reports also describe silk textile workers developing allergic alveolitis from inhaling silk dust (possibly sericin) in factory air. The cause of humidifier or air conditioner lung is *Thermoactinomyces candidus*. In the chemical industry, widely used substances like toluene diisocyanate and phthalic anhydride may act as haptens and induce allergic alveolitis. The antigenic properties of conditions affecting tobacco growers and tea leaf workers remain incompletely understood.

bubble_chart Pathogenesis

In recent years, it has been considered that extrinsic allergic alveolitis is an immune complex disease, with type III hypersensitivity being its primary mechanism, while type IV hypersensitivity is also involved. The activation of the complement system plays a significant role, and activated alveolar macrophages may be the central link in the {|###|}mechanism of disease{|###|}.

(1) Complement-mediated type III hypersensitivity: In sensitized individuals, symptoms appear 4–8 hours after re-exposure to the antigen. Intradermal injection of the antigen can induce an Arthus reaction within 4–6 hours, and IgG and complement deposits can be found in skin biopsy samples from the reaction site. Precipitating antibodies (IgG class) against the corresponding antigen can be detected in the serum of most patients. Bronchial provocation tests using the antigen can induce pulmonary function changes identical to those seen in clinical extrinsic allergic alveolitis. Therefore, this disease is associated with complement-mediated type III hypersensitivity, and immune complexes play a crucial role.

(2) T lymphocyte-mediated type IV hypersensitivity: In recent years, the role of type IV hypersensitivity in the pathogenesis of this disease has been recognized. Pathological examination of lung tissue from patients reveals caseous granuloma formation, and lymphocytes exposed to the corresponding antigen in vitro can produce macrophage migration inhibitory factor (MIF). Animal experiments have shown that transferring sensitized T lymphocytes into experimental animals, followed by antigen inhalation challenge, induces lung {|###|}injury{|###|} very similar to human extrinsic allergic alveolitis. Elevated levels of lymphokines have also been found in the bronchoalveolar lavage fluid of patients with extrinsic allergic alveolitis. These findings support the involvement of type IV hypersensitivity in the pathogenesis of this disease.

(3) Role of local macrophages: Moldy hay and Micropolyspora faeni can directly stimulate alveolar macrophages, leading to the release of proteolytic enzymes that cleave C₃ and release C_3b. The latter binds to complement receptors on the macrophage surface, further activating macrophages and subsequently inducing lung tissue lesions, including granuloma formation.

Currently, it is believed that extrinsic allergic alveolitis is initially mediated by type III hypersensitivity, followed by a shift to predominantly type IV hypersensitivity. Additionally, macrophage activation and the resulting inflammatory response can contribute to lung {|###|}injury{|###|} through non-immune pathways. However, many details remain unclear.

bubble_chart Pathological Changes

The lesions primarily involve the alveoli, alveolar septa, blood vessels, and terminal bronchioles, with pathological changes related to the disease stage.

Acute phase: The alveolar walls and bronchiolar walls exhibit edema, with significant infiltration of lymphocytes and a marked increase in plasma cells, along with monocytes and histiocytes, while eosinophil infiltration is relatively minimal. After approximately 2 weeks, the edema subsides, and numerous tumor-like epithelial granulomas and Langhans giant cells form, many of which are encapsulated by collagen fibers. Pulmonary granulomas are typical lesions of the acute phase, usually appearing within 3 weeks of onset and slowly resolving within a year. At this stage, glucocorticoids can promote their absorption.

Chronic phase: The predominant features are interstitial fibrosis, lymphocyte infiltration of the alveolar walls, and collagen fiber proliferation, particularly around the bronchioles and associated small stirred pulse. Sometimes, thickening occurs due to the proliferation of muscle fibers and endothelial cells. By this stage, granulomatous lesions have largely disappeared. Due to the traction and contraction caused by fibrosis, the condition may eventually progress to lung qi emphysema or even honeycomb lung, accompanied by pulmonary stirred pulse hypertension and right ventricular hypertrophy.

bubble_chart Clinical Manifestations

(1) Acute Type Caused by short-term inhalation of high concentrations of antigens. The onset is abrupt, typically occurring 4–12 hours after antigen exposure. Initial symptoms include dry cough and chest tightness, followed by fever, shivering, shortness of breath, and cyanosis. Sinus tachycardia is often present, with fine moist rales audible in both lungs. Approximately 10–20% of patients may exhibit asthma-like wheezing. The total white blood cell count increases, predominantly neutrophils. Symptoms usually resolve within a few days to a week after cessation of exposure.

(2) Chronic Type Caused by repeated or continuous inhalation of small amounts of antigens. The onset is insidious, but dyspnea progresses gradually and may become severe enough to occur at rest. In the advanced stage, irreversible histological changes due to diffuse pulmonary interstitial fibrosis lead to exertional dyspnea and weight loss. Diffuse fine moist rales are heard in both lungs, accompanied by respiratory failure or cor pulmonale.

bubble_chart Auxiliary Examination

(1) X-ray Findings vary depending on the stage and severity of the disease. Early-stage or mild cases may show no abnormalities, and sometimes clinical manifestations are inconsistent with X-ray changes. In typical acute cases, diffuse thickening of lung markings or small, ill-defined scattered nodular shadows are observed in the middle and lower lung fields. These lesions are reversible, and shadows may resolve within weeks after cessation of exposure. In chronic advanced stages, the lungs exhibit widespread reticulonodular shadows accompanied by reduced lung volume. Multiple small cystic lucencies often appear, presenting as honeycomb lung.

(2) Pulmonary Function The typical change is restrictive ventilatory dysfunction, with reduced forced vital capacity (FVC) and total lung capacity (TLC), while the forced expiratory volume in 1 second (FEV1/FVC ratio) increases. Both diffusing capacity for carbon monoxide (DLCO) and lung compliance decrease. In severe and advanced cases, arterial oxygen saturation decreases during exercise. Pulmonary function impairment in chronic-stage patients is often irreversible.

(3) Serological Tests A positive precipitin antibody reaction indicates prior exposure to the corresponding antigen. If there is a relevant exposure history, symptoms and signs, and X-ray findings, a positive reaction greatly aids diagnosis.

(4) Bronchoalveolar Lavage In bronchoalveolar lavage (BAL) fluid from patients with extrinsic allergic alveolitis, the proportion of lymphocytes increases, as do the levels of IgG and IgM. In recent years, many authors have suggested that BAL fluid has significant diagnostic value for extrinsic allergic alveolitis, potentially obviating the need for lung biopsy and facilitating early treatment to halt disease progression.

(5) Provocation Test If clinical suspicion of the disease exists but serological tests are negative, a provocation test may be performed. Some authors have used aerosolized extracts of moldy hay in farmers with suspected farmer’s lung, observing reactions such as fever, leukocytosis, and increased minute ventilation in most patients, while controls showed no response. Since provocation tests for extrinsic allergic alveolitis are not standardized, they should not be performed for antigens already confirmed to cause pulmonary symptoms, particularly in patients with significant pulmonary function impairment. {|104|}

bubble_chart Diagnosis

The pulmonary symptoms of extrinsic allergic alveolitis are nonspecific. The diagnosis of this disease should be based on a comprehensive analysis of exposure history, typical clinical symptoms, pulmonary signs, chest X-ray findings, serum precipitating antibody tests, bronchoalveolar lavage, and pulmonary function tests to make an accurate diagnosis.

bubble_chart Treatment Measures

The most fundamental preventive measure is to completely avoid exposure to disease-causing organic dust. Improve the production environment, pay attention to dust prevention and ventilation, and strictly adhere to operational procedures. For example, harvested hay and grains should be dried before storage; poultry farming areas should be cleaned regularly, and bird droppings should be properly handled; dampness transformation devices and water in air conditioning systems should be kept clean to avoid contamination; workers in environments polluted by organic dust should undergo regular medical monitoring. Individuals with obvious chronic respiratory diseases, such as chronic asthmatic bronchitis, bronchial asthma, chronic obstructive lung disease, or allergic constitutions, should not engage in jobs that involve close contact with organic dust.

Once the disease occurs, the affected person should immediately leave the contaminated environment and rest in bed. Those with significant dyspnea and cyanosis should receive oxygen therapy. For acute cases, symptomatic treatment and short-term high-dose hormone therapy are recommended. Prednisone at 60mg/d, taken orally for 4 weeks, followed by a gradual reduction until discontinuation, has shown good efficacy. Additionally, re-exposure to known pathogenic antigens should be avoided. Hormone therapy may also be attempted during the chronic phase, but the results are often unsatisfactory.

bubble_chart Differentiation

The conditions that need to be differentiated from extrinsic allergic alveolitis include viral pneumonia, foxtail millet granulomatous lung subcutaneous nodules, sarcoidosis, idiopathic pulmonary fibrosis, and bronchial asthma. The differentiation between extrinsic allergic alveolitis and bronchial asthma is shown in Table 1 below.

Table 1　Differentiation between Extrinsic Allergic Alveolitis and Bronchial Asthma

	Extrinsic Allergic Alveolitis	Extrinsic Bronchial Asthma
Atopy	Mostly absent	Mostly present
Histological Changes	Lymphocytic infiltration of alveoli and interstitial spaces	Bronchial wall edema and eosinophilic infiltration
Site of Lesion	Alveoli and interstitial spaces	Bronchi
Onset	Occurs 4–6 hours after antigen exposure	Occurs rapidly after antigen exposure
Systemic Symptoms	Fever, chills, fatigue, etc.	Almost none
Signs	Fine crackles	Wheezing
X-ray Findings	Fine nodular shadows or normal in acute phase	Hyperinflation or normal
Pulmonary Function Changes	Restrictive ventilatory impairment, decreased diffusion capacity	Obstructive ventilatory impairment
Serological Tests	Positive precipitating antibodies, normal IgE	Elevated IgE, negative precipitating antibodies
Main Type of Hypersensitivity	Type III/IV	Type I