Exogenous allergic alveolitis

　　Exogenous allergic alveolitis can be caused by various different antigenic substances, but its pathology and clinical manifestations are similar or identical. It has been confirmed that there are many allergens that can cause this disease, with different sources, most of which are occupational exposure to antigens leading to the disease. Depending on the conditions of exposure to antigens, it can be called farmer's lung, sugarcane dust lung, mushroom worker's lung, pigeon keeper's lung, chemical worker's lung, and so on. In recent years, some EAA related to the home environment ((Exogenous Allergic Alveolitis). Also, diseases such as humidifier lung, air conditioner lung, and summer-type pneumonia have陆续 appeared. The antigens causing EAA mostly come from microorganisms (such as actinomycetes, bacteria, fungi, etc.), animals, plants, small molecular chemical substances, and certain drugs. Common antigens and their sources.

　　Whether the inhaled antigenic substances lead to the occurrence of EAA depends on the nature of the host and the organic matter. To date, no immune mechanism can explain all the pathogenic and clinical manifestations.

　　1. Host factors Although it has not been found yet which genetic background population is prone to EAA, it can be肯定 that the occurrence of EAA is closely related to the host. Research has found that under certain working conditions, a small number of workers will develop EAA symptoms, and the incidence rate is usually between 5% and 20%. A recent survey found that 8% of pigeon breeders will develop EAA symptoms, 7% of farmers and 15% of office workers working in polluted air conditioning environments will develop EAA, indicating that the occurrence of EAA has a certain genetic background. EAA mostly occurs in adults, and children only occur occasionally. Allergic体质 is not the most important determining factor. Although some studies suggest that certain HLA-Ⅱ type antigens such as HLA-DR3, DR7, and DQW3 are closely related to certain pathogens in certain populations, this has not been confirmed yet.

　　2. Organic dust After organic matter enters the body, it can produce many biological effects, exerting toxic effects on alveolar epithelial cells through direct or indirect pathways. Direct toxic substances include compounds with enzyme activity, endotoxins, substances that can cause non-specific precipitins, histamine, and some organic matter can directly activate the complement pathway after entering the body, leading to increased vascular permeability and the release of chemotactic factors, causing leukocytes to aggregate in the lungs.

　　Organic matter can activate alveolar macrophages, leading to the release of cytokines (such as IL-1, TNF-α, PDGF, etc.), metabolites of lipoxygenase, peroxides, and proteases, which have now been confirmed to be involved in the occurrence of EAA. Denis et al. found that both in the experimental animal model and in the bronchoalveolar lavage fluid (BALF) of patients, there is a high level of expression of IL-1 and TNF-α, and alveolar macrophages stimulated by actinomycete antigens can also produce IL-1 and TNF-α in vitro.

　　3. Mast cells play a certain role in the pathogenesis of EAA. Some scholars have reported that the number of mast cells in the BALF of farmers' lung is significantly increased, and the activity of the disease is related to the number of mast cells in the lung tissue sections. Histopathological studies have found that these mast cells are in a degranulation state. In the experimental EAA animal model, the EAA lesions in mast cell-deficient mice were significantly less than those in normal mice. The number of mast cells in the lung tissue of symptomatic farmers' lung patients is significantly higher than that of asymptomatic individuals who are also exposed to organic matter. As for the reason why the number of mast cells increases in EAA and their exact role in the pathogenesis of EAA, it is still not very clear at present. Some scholars believe that the increase in mast cells may be related to the stimulation of IL-3, and its possible role is to regulate the inflammatory response.

　　4. Pathology Most 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 (usually within 2 weeks of onset), the lesions mainly involve respiratory bronchioles and adjacent blood vessels and alveoli, with obvious infiltration of lymphocytes, plasma cells, and activated alveolar macrophages in the alveoli and interstitium. The cytoplasm of macrophages usually shows characteristic vacuolar changes, and fused giant cells can sometimes be seen. Some bronchioles may become blocked, with wall destruction, and 25% to 50% of cases may develop obstructive bronchiolitis (BO). 15% to 25% of cases may be accompanied by obstructive bronchiolitis with organizing pneumonia (BOOP). Vasculitis may occur in alveolar capillaries, with fibrin deposition, small thrombus formation, and infiltration of neutrophils, eosinophils, and mononuclear cells. The above pathological manifestations can completely regress without trace upon separation from the allergen. In the subacute stage (usually a few months later), non-caseating granulomas may appear, which are very similar to sarcoidosis, but the granulomas of EAA are often located near bronchioles and exist singly, while sarcoidosis granulomas are often located in bronchial and subpleural sites. In chronic cases, the main pathological change is pulmonary interstitial fibrosis, and granuloma lesions may exist or disappear. The differences in pulmonary interstitial fibrosis among various cases are very large, but most occur in the upper lobe of the lung. Fibrosis can be localized or diffuse, and immunofluorescence examination may show that IgG, IgA, and IgM are deposited on the surface of plasma cells and lymphocytes in the wall of the involved bronchioles, while C3 staining on histiocytes is positive.

　　Exogenous allergic alveolitis can be caused by various antigens and the sources of multiple allergens are different, most of which are caused by occupational exposure to antigens. In late cases, respiratory failure and pulmonary heart disease are usually present.

　　Respiratory failure is a clinical syndrome caused by severe impairment of lung ventilation and (or) gas exchange function due to various causes, leading to ineffective gas exchange and resulting in hypoxemia with (or without) carbon dioxide retention, thereby causing a series of physiological and metabolic disorders. Under sea-level atmospheric pressure, when breathing indoor air at rest, and excluding conditions such as intracardiac anatomical shunts and primary decrease in cardiac output, the partial pressure of oxygen in arterial blood (PaO2) is below 8 kPa (60 mmHg), or accompanied by a partial pressure of carbon dioxide (PaCO2) higher than 6.65 kPa (50 mmHg), it is considered respiratory failure (abbreviated as RF).

　　The most common type of chronic pulmonary heart disease is chronic hypoxic-ischemic pulmonary heart disease, also known as obstructive emphysema pulmonary heart disease, abbreviated as pulmonary heart disease. It refers to a type of cardiovascular disease caused by chronic changes in the chest wall or pulmonary artery, leading to increased pulmonary circulation resistance, resulting in pulmonary hypertension and hypertrophy of the right ventricle, with or without right heart failure. Pulmonary heart disease is a common and frequently occurring disease in China.

      Exogenous Allergic Alveolitis, although EAA ((Exogenous Allergic Alveolitis). The clinical manifestations are complex, and the causative antigens are diverse. Overall, exogenous allergic alveolitis can be divided into three types: acute, subacute, and chronic.

　　1. Acute type

　　Acute cases usually have a clear history of antigen exposure, with typical symptoms including fever (sometimes up to 40℃), cough, aversion to cold, fatigue, and dyspnea. Symptoms often appear 4-6 hours after exposure to the antigen and last about 18-24 hours. Physical examination may reveal fever, dyspnea, even cyanosis, and wet rales in both lungs, but wheezing is rarely seen. Some cases may only have fever, so they are often misdiagnosed as viral or bacterial pneumonia. The histological response associated with acute symptoms is inflammation of the alveoli and pulmonary interstitium, with lymphocytes as the main inflammatory cells, most of which are cytotoxic CD8 T lymphocytes, which is opposite to the case of sarcoidosis, where CD4 T lymphocytes are predominant. In addition to lymphocytes, the number of plasma cells and activated alveolar macrophages also increases significantly, and inflammatory exudates may be seen in the alveolar cavity. Immunofluorescence staining methods can show antigen deposition in the pulmonary interstitium and alveolar septum, but immunoglobulins or complement are rarely seen. Obstructive bronchiolitis (OB) has also been reported, and histological changes can gradually return to normal with the relief of acute symptoms.

　　2. Subacute type

　　Clinical symptoms are usually concealed, and cough, sputum, fatigue, dyspnea, decreased appetite, easy fatigue, and weight loss can also be seen. Double lung base crackles are usually the main physical examination finding, and generally no fever.

　　3. Chronic type

　　It can transform from acute type or show no acute type symptoms. Pulmonary fibrosis can be caused by repeated high-dose inhalation of antigens, or by long-term low-dose inhalation of antigens. The latter is more common in pigeon breeders' lung, air conditioning pneumonia, and other chronic diseases related to indoor environment and antigens. The clinical manifestations are usually progressive dyspnea, fatigue, decreased appetite, and weight loss, which often appear in the late stage of the disease. Usually, after the irreversible pulmonary interstitial fibrosis occurs, in chronic cases without acute type, there are generally no early symptoms and signs, except for possible chronic cough, physical examination may find diffuse crackles. In late cases, signs of respiratory failure and pulmonary heart disease are usually present.

　　For patients in the acute stage, due to the frequent history of clear antigen contact, further examination is not necessary. As long as the symptoms gradually alleviate after the patient stops contacting the antigen, the diagnosis can be established. However, if there are no clear allergens in the patient's living and working environment, inhalation challenge tests can be used to determine the relationship between allergens and clinical symptoms. Although inhalation challenge tests are helpful in clarifying the relationship between allergens and clinical symptoms, they are harmful to patients. Since clinical application can lead to EAA symptoms in patients, their clinical use is limited.

　　For patients with respiratory symptoms and restrictive ventilation dysfunction, EAA should be suspected. For the prevention of pulmonary interstitial fibrosis, early diagnosis is important. It is very important to inquire about the medical history carefully, not only for the diagnosis but also for finding the predisposing factors for EAA. When there is no clear clue in the medical history and the clinical suspicion is EAA, laboratory tests can be helpful for diagnosis.

　　Avoiding the inhalation of antigens is the best measure to prevent exogenous allergic alveolitis. Farmers should wait until the grains are dried before storing them in the granary to prevent mildew. To keep poultry and birds in clean and hygienic pens to prevent mildew or other contamination. Molds like warmth and humidity and also consume oxygen. For most stored goods, considering the storage cost, it is impossible to store them in a sealed anaerobic environment. Therefore, the effective way to reduce the loss caused by the mildew and decay of goods is to change their environmental temperature and humidity conditions. Therefore, it is particularly important to study the mildew meteorological index of the storage space and make forecasts.

      Exogenous allergic alveolitis, also known as 'allergic pneumonia', can be caused by various different antigenic substances, but its pathology and clinical manifestations are similar or identical. The main examinations for exogenous allergic alveolitis include:

　　1. BALF examination

　　It is of great significance to clarify the pathogenesis of EAA. Although BALF analysis has certain significance for the overall patients, its diagnostic significance is not great for individual patients. In normal people, alveolar macrophages are the main components in BALF (more than 90%), followed by lymphocytes (6% to 8%). In EAA, sarcoidosis, and other respiratory system diseases, the number of lymphocytes in BALF is significantly increased. However, in EAA, the lymphocytes are mainly CD8 lymphocytes, while in sarcoidosis, they are mainly CD4. The number of CD8 lymphocytes is highly correlated with acute symptoms. Marayama et al. found that with the prolongation of the course of EAA, the number of CD8 gradually decreases. In addition, the timing of BALF examination is also closely related to the course of the disease. In the early stage, the number of neutrophils, complement, and mast cells in BALF is significantly increased. Yoshizawa et al. reported that the number of CD8 in the BALF of non-fibrotic EAA patients is higher than that in patients with fibrotic EAA.Overall, the analysis of BALF cell composition is very helpful in distinguishing between normal individuals, those who have not been exposed to allergens, and patients, but it has no diagnostic significance in distinguishing between symptomatic and asymptomatic allergen exposed individuals..

　　2. Serum Immunoglobulin G

　　Although EAA patients have high levels of specific IgG antibodies against specific antigens in the systemic circulation, most individuals who have been exposed to antigens but have no symptoms also have high levels of specific IgG. Therefore, the elevation of specific IgG only indicates a history of chronic antigen exposure in patients, which is not of great diagnostic significance.

　　3. Skin Antigen Testing

　　Due to the various forms of skin test reactions such as immediate, delayed, and biphasic, skin antigen testing is not very helpful for the diagnosis of EAA.

　　4. Chest X-ray Examination

　　The typical manifestation during the acute phase is patchy infiltrative shadows in both lungs, with the shadows showing interstitial or alveolar nodule-type changes. These shadows are usually bilateral and symmetrical in distribution, with some cases showing indistinct hilum, which is often easily confused with acute pulmonary edema. Some cases may appear completely normal on chest X-ray in the early stages of onset. The subacute phase is characterized by linear and small nodule shadows, showing a reticular nodular change, without mediastinal or hilar lymphadenopathy, and generally not accompanied by pleural effusion or pleural thickening. The chronic phase is mainly manifested by diffuse pulmonary interstitial fibrosis, which may develop into 'cystic lung' in the late stage.

　　5. Pulmonary Function Examination

　　Most cases present with restrictive ventilatory dysfunction, manifested by a decrease in VC and other lung volumes, a decrease in pulmonary diffusion function and lung compliance, but the airway resistance is usually normal.

　　Blood gas analysis shows a decrease in arterial oxygen saturation, exacerbated after exercise, and a slight decrease in arterial carbon dioxide. In some cases, pulmonary function may return to normal as acute symptoms subside, and a few cases may show obstructive ventilatory dysfunction early on after exposure to the antigen.

　　6. Inhalation Challenge Test

　　This challenge test must be conducted in a special laboratory. Before the test begins, the patient's baseline pulmonary function is measured first, followed by the administration of an extract of the suspected allergen through a mechanical nebulizer. Subsequently, the patient's symptoms, signs, pulmonary function, and blood leukocyte count are recorded until 24 hours. The most common positive reactions occur 4 to 6 hours after inhalation of the antigen, with the patient experiencing chills, fever, cough, and difficulty breathing. On physical examination, fine moist rales may be heard in the lungs, and pulmonary function shows restrictive ventilatory dysfunction, manifested by a decrease in FVC and DLCO, with a few cases showing bronchospasm. This challenge test is not only used to identify allergens but also serves as a method that can directly prove the relationship between allergens and the onset of disease. However, caution is required when interpreting the results of the challenge test, as some patients may experience feverish reactions due to the endotoxins and other components in the antigen extract. Another potential risk factor is the possibility of causing severe pneumonia symptoms and leading to permanent pulmonary function damage.

　　The samples extracted for provocation tests are usually collected from the work environment and home, and provocation tests must be carried out under strict supervision. The patient needs to be monitored for at least several hours, with a typical method being to start continuous monitoring for 12-24 hours after 15 minutes of antigen inhalation.

　　Patients with extrinsic allergic alveolitis should eat more nutritious foods, mainly to supplement the nutrients lacking in the body. It is advisable to eat light and balanced meals, and low-salt diet is preferable. Pay attention to sufficient nutrition, eat more vegetables and fruits, kelp, nori, mushrooms, and more bean products and coarse grains. Patients with extrinsic alveolitis should absolutely not smoke or drink alcohol in their daily life.

　　The most effective and reliable treatment for extrinsic allergic alveolitis is to avoid contact with antigens, such as changing the work environment, using respiratory protective equipment, cleaning air conditioners and humidifiers, etc. For severe cases, adrenal cortical hormones can be administered, and the specific dose and treatment time are not yet conclusive, but most scholars give prednisone (Prednisone) orally, starting with a dose of 40-60mg/d, gradually reducing the dose after 2 weeks, and the total course of treatment is 4-6 months. Prednisone (Prednisone) can reduce the duration and mortality rate during the acute phase, but cannot prevent the occurrence of chronic EAA. Small-dose hormone therapy can also be given to patients with chronic EAA, but the clinical effects vary greatly. Other non-steroidal anti-inflammatory drugs or systemic immunomodulators are ineffective for the treatment of EAA.

　　If the patient can avoid contact with the allergen before the appearance of permanent radiological or physiological abnormalities, the prognosis of the patient is good. If the patient cannot avoid the allergen at this time, the use of a mask to prevent the occurrence of acute EAA will still have a good prognosis. If the patient continues to be exposed to the allergen, 10% to 30% of the patients will develop interstitial pulmonary fibrosis. It is reported that the mortality rate can reach 20% five years after the onset of farmer's lung. Overall, long-term low-dose exposure is worse than short-term intermittent exposure to allergens.