Extrinsic allergic alveolitis

Introduction to exogenous allergic alveolitis Exogenous allergic alveolitis (EAA), also known as hypersensitivity pneumonitis (HP), is an immune-mediated lung disease caused by repeated inhalation of organic dust or chemically active substances. For fever, cough, dyspnea, hypoxemia, and generalized muscle and joint pain, the basic histopathological changes are diffuse mononuclear infiltration of the early pulmonary stroma, alveolar and terminal bronchioles, often followed by Granuloma, which can progress to interstitial fibrosis in the late stage, was first reported by Campbell in 1932. basic knowledge The proportion of illness: 0.003% Susceptible people: no special people Mode of infection: respiratory transmission Complications: respiratory failure, pulmonary heart disease

The cause of exogenous allergic alveolitis

Host factor (30%):

Although people who have not found any genetic background have been susceptible to EAA so far, it is certain that the occurrence of EAA is closely related to the host. The study found that under certain working conditions, there will always be a small number of workers with EAA symptoms, which occur. Although the rate is related to exposure to dust, it is often between 5% and 20%. A recent survey found that 8% of pigeon breeders experienced EAA symptoms, 7% of farm workers and 15% of them were contaminated. EAA will occur in office staff working in an air-conditioned environment, suggesting that EAA has a certain genetic background. EAA occurs mostly in adults. Children only happen by chance. Allergies are not the most important determinant, although some studies suggest some HLA-II. Types of antigens such as HLA-DR3, DR7 and DQW3 are closely related to certain pathogens in certain populations, but have not been confirmed so far.

Organic dust (25%):

When organic substances enter the body, they can produce many biological effects, which can cause toxic effects on alveolar epithelial cells through direct or indirect pathways. Direct toxic substances include compounds with enzymatic activity, endotoxin, substances that cause non-specific precipitin and histamine, Certain organisms can also directly activate the complement pathway after entering the body, leading to an increase in vascular permeability and release of chemotactic factors, allowing white blood cells to accumulate in the lungs.

Organic substances can activate alveolar macrophages, leading to the release of cytokines (such as IL-1, TNF-, PDGF, etc.), lipoxygenase metabolites, peroxides and proteases, which have now been shown to be involved in the development of EAA. Denis et al found that high levels of IL-1 and TNF- were expressed in both the experimental animal model and the patient's bronchoalveolar lavage fluid (BALF), and alveolar macrophages stimulated with actinomycete antigens were The amount of IL-1 and TNF produced in vitro can also significantly inhibit the EAA response in test animals.

Immunopathological mechanism (25%):

Mast cells play a role in the pathogenesis of EAA. Some scholars have reported that the number of mast cells increased significantly in BALF of peasant lungs, and the activity of the disease was related to the number of mast cells in lung tissue sections. Histopathological studies found these Mast cells were degranulated. In the experimental EAA animal model, the degree of EAA lesions in mast cell-deficient mice was significantly less than that in normal mice. The number of mast cells in lung tissue of human symptomatic peasant lung patients was less asymptomatic. The number of people who are also exposed to organic matter has increased significantly. The reason for the increase in the number of mast cells in EAA and its exact role in the pathogenesis of EAA is still not fully understood. Some scholars believe that the increase of mast cells may be related to the stimulation of IL-3. Relatedly, its possible role is to regulate the inflammatory response.

Type I allergy: Although the number of mast cells in the lungs of farmers has increased, there is no direct evidence that the occurrence of EAA is associated with IgE-mediated type I allergy, because most of these patients have normal IgE levels, and eosinophils are not. Increased, and in patients with allergic constitution, the incidence of EAA is not elevated, as for some patients with lungs, when using the pigeon's antigen for skin allergy test, immediate skin reactions may occur, and about 10% of patients may develop asthma-like symptoms when inhaled, and Muers et al believe that this type I allergy may be mediated by IgG4 subtype antibodies rather than IgE.

Type II allergy: Although Wenzel et al found that there is Ig and complement deposition on mononuclear cells and bronchial walls in lung biopsies of peasant lung patients, so far there is not enough evidence to suggest that EAA is associated with type II allergy. .

Type III allergy: Type III allergy is thought to play an important role in the pathogenesis of EAA. Immune complexes can not only cause the release of inflammatory cytokines such as IL-1, TNF-, but also activate alveolar macrophages. But there are some phenomena that do not support this assumption:

1 Precipitating antibodies are related to environmental exposure, and are not related to disease, because most patients with precipitating antibodies do not develop after continuous exposure to antigen.

2 After the patient is stimulated by antigen inhalation, the serum complement level does not decrease.

3 Lung histopathology is not a typical antigen-antibody complex mediated vasculitis manifestation.

Type IV allergy: Although histopathological findings may be related to the different time of the disease at the time of biopsy, there is evidence that type IV allergy plays a very important role in the pathogenesis of EAA. From this point, this is why Some drugs that inhibit cell-mediated hypersensitivity, such as cortisone acetate, anti-macrophage serum, antibodies against certain pro-inflammatory cytokines, and cyclosporine can significantly reduce or inhibit experimental pulmonary granuloma In addition to histological findings of macrophages in the alveolar and interstitial lungs, lymphocyte infiltration, patients also showed many immune responses related to cellular immunity (T cell dependence) and humoral immunity (B cell dependence). For example, antigen-induced lymphocyte proliferation, lymphokine release, specific antibodies and immunoglobulin production, etc., Keller et al reported that the percentage of T cells in BALF in asymptomatic chronic EAA patients is increased, when these patients are exposed to antigen, The percentage is higher, and they also found that T-repressor cell activity was reduced in BALF in patients with lung disease in pigeons, a recent study showed that In BALF of summer pneumonia, T lymphocytes respond less to stimuli than peripheral blood T cells. This reduction is not due to the presence of inhibitory T cells or inhibitors, but due to the production of IL by T lymphocytes in BALF. The ability to reduce 2, which indicates that there is an abnormality in immune regulation.

4. Pathology Most of the different EAA have similar pathological changes, which mainly depend on the intensity of antigen inhalation and the stage of the disease at the time of biopsy. In the early stage of the disease (generally within 2 weeks of the onset), the lesion mainly affects Respiratory bronchioles and adjacent blood vessels and alveoli, alveolar and interstitial cells with distinct lymphocytes, plasma cells and activated alveolar macrophages infiltrate, macrophage cytoplasm usually has characteristic vacuolar-like changes, fusion giant Cells can also be seen sometimes, some bronchioles can be blocked, the wall is destroyed, 25% to 50% of cases can develop bronchiolitis (BO), 15% to 25% of cases can be accompanied Obliterative bronchiolitis with organizing pneumonia (BOOP), alveolar capillaries can present vasculitis, with cellulose deposition, small thrombosis and infiltration of neutrophils, eosinophils and mononuclear cells.

The above pathological manifestations can completely disappear with the detachment from allergens without leaving traces. In the subacute phase (usually a few months later), pathologically non-caseous necrotic granuloma can occur, very similar to sarcoidosis, but EAA The granuloma often exists in the vicinity of the bronchioles, and the sarcoidosis granuloma is often in the bronchial and subpleural areas. In chronic cases, the main pathological changes are interstitial fibrosis, and granulomatous lesions can exist or disappear. Interstitial fibrosis varies greatly between cases, but most of them occur in the upper lobe of the lung. Fibrosis can be localized or diffuse. Immunofluorescence can detect plasma cells and lymphocytes in the bronchial wall of the lesion. There were IgG, IgA and IgM on the surface, and C3 staining on the surface of the tissue cells was positive.

The disease can be caused by a variety of different antigenic substances, but its pathology and clinical have the same or similar performance. It has been confirmed that a variety of allergens can cause the disease, and their sources are different, most of which are occupational exposure to antigens. Depending on the conditions of exposure to antigens, they can be called peasant lungs, cane pneumoconiosis, mushroom workers' lungs, pigeons' lungs, chemical workers' lungs, etc. In recent years, some EAAs related to the family environment have emerged, such as humidifier lungs. Air-conditioning lungs, summer pneumonia, etc., lead to EAA antigens mostly derived from microorganisms (such as actinomycetes, bacteria, fungi, etc.), animals, plants, small molecule chemicals and certain drugs.

Exogenous allergic alveolitis prevention

Avoiding the inhalation of antigens is the best preventive measure. Farmers need to wait until they are dried and put them into the warehouse to prevent mold, raise poultry, and keep birds in the shelter to prevent mold or other pollution.

Complications of exogenous allergic alveolitis Complications, respiratory failure, pulmonary heart disease

In advanced cases, there are usually respiratory failure and pulmonary heart disease.

Exogenous allergic alveolitis symptoms Common symptoms Hypoxemia Inhalation burst sounds of both lungs Breathing difficulties Respiratory failure Chronic cough fatigue Pulmonary fibrosis Fatigue Interstitial fibrosis

The clinical performance of EAA depends on the following:

1 immunity to inhaled antigen;

2 patterns of exposure to dust, such as time, number of times, dosage, etc.;

3 The susceptibility of the body, the intensity and frequency of exposure to dust in the above three points is the most important determinant. Although the clinical manifestations of EAA are complex and the pathogenic antigens are diverse, they can be divided into acute, sub- 3 kinds of acute and chronic.

Acute type

Acute cases usually have a clear history of antigen exposure. Typical symptoms are fever (sometimes up to 40 ° C), cough, chills, fatigue and difficulty breathing. Symptoms often appear 4 to 6 hours after exposure to the antigen, lasting about 18 to 24 hours. Physical examination revealed that the patient had fever, difficulty breathing, and even cyanosis. The lungs sometimes smelled wet, but wheezing was rare. In some cases, only fever occurred, so it was often misdiagnosed as viral or bacterial pneumonia. The histological response to acute symptoms is inflammation of the alveolar and interstitial lung cells. The inflammatory cells are mainly lymphocytes, most of which are CD8 T lymphocytes with cytotoxic activity, which is associated with CD4 T lymphocytes seen in sarcoidosis. On the contrary, in addition to lymphocytes, the number of plasma cells and activated alveolar macrophages also increased significantly, and inflammatory exudation was sometimes seen in the alveolar cavity. Immunofluorescence staining showed antigenic deposition in the pulmonary interstitial and alveolar spaces. However, immunoglobulin or complement is rarely seen, and bronchiolitis obliterans (OB) has also been reported. With the relief of acute symptoms, histological changes can gradually return to normal.

2. Subacute type

Clinical symptoms are more insidious, can have cough, cough, fatigue and difficulty in breathing, loss of appetite, easy fatigue and weight loss can also be seen, the double lung bottom burst sound is usually the main physical examination found, generally no fever.

3. Chronic type

It can be changed from acute type or no acute type. In other words, pulmonary fibrosis can be caused by repeated inhalation of large doses of antigen, or by long-term low-dose inhalation of antigen. The latter is more common in the lungs of pigeons, air-conditioning. Pneumonia and other inhaled indoor environment and antigen-related diseases, clinical manifestations are usually progressive dyspnea, fatigue, loss of appetite and weight loss, these symptoms often appear in the late stages of the disease, usually in irreversible pulmonary interstitial fibrosis Later, in chronic cases with no acute form, in addition to possible chronic cough, there are generally no early symptoms and signs, and a diffuse pop sound can be found on physical examination. In advanced cases, there are usually signs of respiratory failure and pulmonary heart disease.

For patients with acute phase, because there is often a clear history of antigen exposure, further examination is unnecessary. As long as the patient is out of contact with the antigen, the symptoms are gradually relieved, and the diagnosis can be established, but if the patient lives, the working environment There is no clear allergic factor, and the inhalation challenge test can be used to determine the relationship between allergens and clinical symptoms. Although the inhalation challenge test is helpful in clarifying the relationship between allergens and clinical symptoms, it is harmful to patients. Because clinical application can lead to EAA symptoms in patients, clinical use is limited.

For patients with respiratory symptoms and restricted ventilatory dysfunction, the possibility of EAA should be suspected. For the prevention of pulmonary fibrosis, it is important to diagnose early. It is very important to carefully ask about the medical history, which is not only important for diagnosis, but also important. It is helpful to find the cause of EAA. When there is no clear clue from the medical history, and clinically suspected to be EAA, laboratory tests will help the diagnosis.

Examination of exogenous allergic alveolitis

1.BALF check

It is very important to clarify the pathogenesis of EAA. Although BALF analysis has certain significance for the whole patient, it is of little significance for individual patients. The normal human BALF is mainly composed of alveolar macrophages (> 90%), followed by lymphocytes (6% to 8%). In EAA, sarcoidosis and other respiratory diseases, the number of lymphocytes in BALF increased significantly, but the lymphocytes of EAA were mainly CD8 lymphocytes. The disease of sarcoidosis is mainly CD4. The number of CD8 lymphocytes is highly correlated with the symptoms of acute phase. Marayama et al found that the number of CD8 decreased gradually with the prolongation of EAA, and the time of BALF examination was also closely related to the course of disease. In early BALF, the number of neutrophils, complement and mast cells increased significantly. Yoshizawa et al reported that the number of CD8 in BALF in non-fibrotic EAA patients was higher than that in BALF in patients with EAA who had fibrosis.

In general, BALF cell composition analysis is very helpful in distinguishing between normal people, those who are not exposed to allergens, and patients, but it is not diagnostic for distinguishing between symptomatic and asymptomatic antigen contacts.

2. Serum immunoglobulin G

Although EAA patients have high levels of IgG antibodies against specific antigens in the systemic circulation, most people who are exposed to the antigen but are asymptomatic have high levels of specific IgG, so the increase in specific IgG only indicates that the patient has a history of chronic antigen exposure. It does not make much sense for diagnosis.

3. Skin antigen test

Since the skin test response can take many forms, such as immediate, delayed, and biphasic, the skin antigen test does little to diagnose EAA.

4. Chest X-ray examination

In the acute phase, the typical manifestations are patchy infiltrates in the bilateral lungs, and the shadows are interstitial or alveolar nodular changes. These shadows are usually bilateral and symmetric, and some may appear as hilar blur, often easy Confused with acute pulmonary edema, some cases of early onset chest X-ray findings can be completely normal, subacute stage is characterized by linear and small nodular shadows, reticular nodular changes, no mediastinum or hilar lymphadenopathy, generally Without pleural effusion or pleural thickening, the chronic phase mainly manifests as diffuse pulmonary interstitial fibrosis, and can develop into "honeycomb lung" in the late stage.

5. Pulmonary function test

Most of the cases showed restrictive ventilatory dysfunction, which was manifested in a decrease in VC and other lung volume, decreased lung function and lung compliance, but airway resistance was usually normal.

Blood gas analysis showed decreased arterial oxygen saturation, post-exercise aggravation and mild arterial carbon dioxide reduction. In some cases, the lung function returned to normal with the relief of acute symptoms. A few cases may show obstructiveness in the early stage of exposure to antigen. Ventilation dysfunction.

6. Inhalation challenge test

This challenge test is performed in a special laboratory. Before the start of the test, the patient's basic lung function is measured, and then the patient is inhaled with a suspected allergen extract through a mechanical nebulizer inhaler, and then the patient's symptoms, signs, lung function and White blood cell count, until 24h, the most common positive reaction occurred 4 to 6 hours after inhalation of antigen, patients may have chills, fever, cough, difficulty breathing, physical examination of the lungs can be heard and fine wet voice, lung function is restricted Ventilation dysfunction, manifested as decreased FVC and decreased DLCO, bronchospasm can occur in a few cases, this stimulation test can not only be used to identify allergens, but also a way to directly prove the relationship between allergens and disease, but in Care must be taken when interpreting the results of the challenge test, as some patients, endotoxin and other components in the inhaled antigen extract may cause a fever, another potential risk factor may be severe pneumonia symptoms and may lead to permanent Impaired lung function.

The samples extracted for the challenge test are usually collected in the working environment and in the home. The challenge test should be carried out under close supervision. The patient needs to be monitored for at least several hours. The typical method is to receive continuous monitoring for 12 to 24 hours after inhalation of the antigen. .

Diagnosis and differentiation of exogenous allergic alveolitis

Diagnostic criteria

Clinical main diagnostic criteria:

1 has a history of antigen exposure or the presence of specific antibodies in serum;

2 clinical symptoms of EAA;

3 chest radiographs or high-resolution CT meet EAA performance.

Clinical secondary diagnostic criteria:

1 has a double lung sound;

2 lung diffusion function is reduced;

3 blood gas analysis showed arterial hypoxemia;

4 lung histology has a performance consistent with EAA;

5 positive inhalation challenge test;

Lymphocyte elevation in 6BAL, at least 4 minor criteria plus 3 major standard diagnoses can be established.

Differential diagnosis

EAA needs to be differentiated from inhaled heat, other granulomatous diseases, immune system diseases, infectious diseases, and other fibrotic lung diseases.

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