Fungal allergic asthma

　　I. Causes of Disease

　　1. Classification and characteristics of fungi:There are many types of fungi, widely distributed, with approximately more than 100,000 species in nature. Affected by factors such as geography and climate, the types and content of fungi in the atmosphere vary greatly. Influenced by living conditions and customs, the concentration of indoor fungi also varies greatly. There are hundreds of types of fungi with strong allergenicity and a large number of airborne spores, and the main cause of human sensitization is indoor fungi. Although the number of fungi in the air is extremely large and their shapes vary, they all have common characteristics. They are filamentous branching nutritional structures with cell nuclei and cell walls, without chlorophyll, and are typical organisms that undergo sexual and asexual reproduction, containing substances such as polysaccharides and proteins. According to modern taxonomic methods, the phylum of fungi is divided into 5 classes, and there are 4 classes related to变态反应 allergic reactions.

　　(1) Zygomycetes: This class is a lower category of fungi and also the least numerous. Among them, the Mucoraceae is the largest family in this class, including Mucor, Rhizopus, Mucor plumbeus, and Allomyces, which are both opportunistic pathogens and important allergenic fungi causing allergic reactions.

　　① The hyphae are mostly tubular, usually without transverse septa, branched, and have a larger diameter.

　　② During asexual reproduction, spores are produced in the sporangium.

　　The sporangia are usually located at the top of the nutrient hyphae or at the top of special reproductive hyphae called sporangiophores. In the early stage of the sporangium, it is filled with multinucleated protoplasm. As it develops, the entire protoplasm splits into many small pieces, each of which develops into a sporangiospore. Sporangiospores are mainly spread by wind, and under appropriate conditions, the spores germinate into a germ tube, which then develops into new hyphal bodies.

　　③ During sexual reproduction, the gametes or gametangia mate, and then form resting spores or zygospores.

　　(2) Basidiomycetes: This is a larger class among fungi. From their complex structure, they are more evolved than zygomycetes and are very likely to have evolved from zygomycetes. Examples include common ascospore-forming fungi such as Trichoderma, Aspergillus, and Phomopsis in the air.

　　① Most species produce fruiting bodies that contain asci. The asci are usually elongated rod-like or cylindrical sac-like structures, with a few being spherical, ovoid, or rectangular. Usually, the ascus is a cavity where ascospores are formed, and some are segmented asci.

　　② The asci contain a certain number of spores, usually 8, but due to differences in species, the number of spores is not always the same. The size, shape, color, and other characteristics of the spores vary greatly. Generally, the characteristics of the ascospores are used as the basis for classifying ascomycetes.

　　③ Asexual reproduction can occur through fission, budding, fragmentation, powdery spores, chlamydospores, or conidia, etc.

　　④ Sexual reproduction involves the combination of male and female nuclei, which gather in a single cell to form a pair, known as the diploid stage. Continuous diploid fission produces many diploid cells. After the diploid nuclei combine in the ascus mother cell that is about to develop, meiosis immediately occurs, producing 8 nuclei, thereby forming the typical 8 ascospores.

　　⑤ Many ascomycetes only appear once a year in the sexual stage, and the most commonly encountered stage is the conidial stage.

　　(3) Basidiomycetes: This is the highest level among all fungal classes. Mushrooms, wood ear, Ganoderma lucidum, and very common powdery mildews and rusts in the air all belong to this class.

　　① There are special sporangia called basidia, which have four basidiospores. The karyogamy, nuclear pairing, and meiosis of basidiospores occur within the basidium. Basidiospores can be round, elliptical, elongated, or sausagelike. They may be colorless or pigmented with light colors, and can only be identified when they are clumped together.

　　② There are no obvious reproductive organs, and the fusion of the sexes is achieved by the fusion of undifferentiated hyphae or spores. During the fusion, only karyogamy occurs, not nuclear pairing, resulting in a binucleate cell phase, and new binucleate cells are formed in a special clamp connection manner. Nuclear pairing occurs before the formation of spores, followed by meiosis, producing haploid basidiospores.

　　③ Asexual reproduction is achieved through budding, the fragmentation of hyphal bodies, or the production of conidia and aecidia. Ustilago often produces conidia, which are formed by the budding of both basidiospores and hyphal bodies. Uredinales produce aecidia, which are essentially conidia in origin and function. Many other basidiomycetes also produce conidia. Some basidiomycetes have hyphal bodies that usually fragment into single-celled segments, and the fragments of these hyphal bodies are aecidia.

　　④ Sexual reproduction is achieved through somatic pairing or fertilization. In the species that produce cells, two monokaryotic hyphae come into contact, the cell walls at the contact points dissolve, the nucleus of one cell pierces and enters the other cell, making it become binucleate. This binucleate cell continuously divides to produce secondary binucleate hyphal bodies. In the species that produce spores, the process of karyogamy often occurs at the junction of spores and nutrient hyphae. In summary, the formation of basidia, binucleate hyphal bodies, and clamp connections are the three typical characteristics of basidiomycetes.

　　(4) Fungi Imperfecti: This class includes the ascomycetes and a few basidiomycetes that have not yet been found to have a sexual stage, as well as the asexual stages of known ascomycetes and basidiomycetes described and named before the discovery of their sexual stages. Examples include Aspergillus, Penicillium, Cladosporium, Alternaria, Trichoderma, etc.

　　① They reproduce solely by means of spores or fragments of hyphae. Spores are usually produced on the conidiophores, which have various morphologies. Their production can come from ordinary nutrient hyphae without any obvious organs, or they can form certain fruiting bodies, the most common of which are conidiophores and conidial disks.

　　② Only the asexual stage was found in their life cycle, so they are called hemibiotrophic fungi.

　　③ The hyphae are all segmented. Many are saprophytic, but many are extremely important to humans and are parasitic fungi that cause diseases in plants, animals, and humans.

　　2. Airborne fungal survey:The investigation of fungi in the air is an important method to identify the types, quantities, and seasonal distribution of common fungi in various regions. This is of great significance for selecting allergenic fungi and guiding the diagnosis and treatment of patients with fungal变态反应. The selection of the strain for preparing fungal allergens is determined based on air survey data and the allergenicity of fungi. By isolating and screening the most common fungi in the air with the largest spore dispersal and the strongest allergenicity, pure strains are retained, cultured in the laboratory, and can be prepared into various fungal allergen extracts for clinical diagnosis and immunotherapy.

　　It is generally believed that fungal surveys are conducted simultaneously with exposure and exposure dishes. Since the exposure survey is difficult to observe and distinguish certain smaller fungal spores, the exposure dish survey is also very important. Generally, the survey should last at least one year to have a relatively comprehensive understanding of the main allergenic fungi in the region.

　　(1) Air exposure and microscopic counting method:

　　①Exposure method: Expose the slide coated with soft lanolin adhesive agent (25mm×75mm) in the air. Place the slide coated with the adhesive in the sampler, and take out the slide at a fixed time every day. The slide is exposed in the air for 24 hours. Place a piece of glycerol gel stain on the retrieved slide, cover it with a clean 22mm×22mm cover glass after micro-dissolving. Generally, microscopic examination is performed the next day.

　　(1) Air exposure and microscopic counting method:

　　①Exposure method: Expose the slide coated with soft lanolin adhesive agent (25mm×75mm) in the air. Place the slide coated with the adhesive in the sampler, and take out the slide at a fixed time every day. The slide is exposed in the air for 24 hours. Place a piece of glycerol gel stain on the retrieved slide, cover it with a clean 22mm×22mm cover glass after micro-dissolving. Generally, microscopic examination is performed the next day.

　　②Mycological counting method: During microscopic examination, place the slide on the microscope stage, move the pusher from left to right, gently lift the pusher after reaching the end, push the slide onto a new microscopic section, and then move the pusher from right to left. Proceed in this manner to cover the entire range of the cover glass. Record in detail the species and quantity of fungi. A certain hospital exposed a slide coated with lanolin adhesive agent every morning at 10 am from August 1, 1989, to July 31, 1990. The slide was retrieved after 24 hours, added with one drop of neutral tree resin, covered with a 22mm×22mm cover glass, and the entire cover glass was examined under the microscope, recording the number of fungal spores and hyphae. A total of 365 slides were exposed in a year, collecting 101,112 fungal spores, 2,367 hyphal sections, 101,089 identified fungal spores, and a total of 37 species and genera.

　　(2) Air exposure and microscopic counting method:

　　①Exposure method: Expose the flat dish (diameter 10cm) with disinfected culture medium to the air for 3 to 5 minutes. The exposure location can be determined as needed. After exposure, place the flat dish in a room temperature or 25℃ constant temperature box for culture. Observe and record the growing colonies and identify their names every day. The flat dish should be placed in a fixed location, and it should be gently picked up and placed to prevent the fungal spores from being shaken off, which may cause contamination of the culture medium and affect the accuracy of the survey count. Generally, expose the flat dish once a week or a month, and the time should be consistent with the exposure time, at least for one year.

　　②Mycological counting method: In order to prevent certain fungi from growing rapidly and quickly filling the culture dish, affecting the growth of other fungi, spores should be separated, identified, and recorded immediately once they are formed. Each colony is recorded as a single species of fungus. When counting, the colonies and the species of fungi should be calculated separately. Our hospital uses 11cm culture dishes, potato glucose, Czapek, and Saccarose three kinds of agar medium, and sets up 3 fixed points for exposing dishes at the exposure location, hospital front square, and ward. There are three dishes at each point, exposed once every two weeks, for 3 minutes at 10 am every day, and cultivated in a 25℃ biochemical incubator. Every day, observe and record the number of colonies until no new colonies appear. Select colonies and identify them under the microscope using the direct pressing or culture dish method. Take microphotographs of the identified fungi and transfer them to tube agar slant culture and preservation. There are 24 exposures in a year, a total of 216 agar plates. 3012 colonies were collected.

　　3. Research on the allergenicity of fungi:Fungi and fungal spores, as antigenic substances, have a relatively low ability to produce antibodies in the human body. This may be due to the fact that fungi and fungal spores do not produce exotoxins and do not have surface antigens; or it is believed that there is a layer of chemically stable substances on the cell membrane of fungal spores, which makes it difficult for the antigenic components inside the cell to be released, so the function of inducing antibody production is low. In clinical practice, the intensity and positive rate of fungal antigen extract skin tests are significantly lower than those of pollen antigen extract.

　　The process of fungi-induced hypersensitivity is similar to that of tuberculosis-induced hypersensitivity, so when using fungal antigen extracts for skin tests, both immediate phase skin reactions and delayed phase skin reactions can occur, and sometimes biphasic reactions can occur. We have observed the results of skin tests in 75 cases of allergic conjunctivitis and found that the positive rate of delayed-phase reactions to fungi is significantly higher than that of immediate reactions.

　　So-called allergenic fungi mainly include some plant pathogenic fungi and saprophytic fungi. In the past, most people believed that the main antigenic effective components of fungi were present in fungal spores. Later, it was found that both mycelium and spores contain allergens, and many foreign laboratories have studied the allergenic components of several species of fungi, including antigen purification, immunodetection analysis, and so on. Gravesen, in 1979, discovered that Alternaria contains more than 10 antigenic components through cross-radial immunoelectrophoresis analysis. In 1980, Yunginger and others conducted biochemical analysis on Alternaria and found a strongly antigenic glycoprotein, called Alt-1, with a molecular weight between 25,000 and 50,000. Aukrust and others analyzed the antigenicity of Cladosporium in 1979 and found it contains more than 60 protein components, of which 4 belong to the main antigenic determinants, and the rest are minor antigenic determinants. Purification of 2 antigenic determinants resulted in a molecular weight of 13,000 and 25,000. Antigenicity comparison of 10 different strains of Cladosporium showed that the content of the main antigenic determinants varies greatly among different strains. In 1980, Kauffman and others analyzed the antigenic components of Aspergillus fumigatus and found that the antigenicity of the longer-cultured bacterial colonies was higher than that of the shorter-cultured bacterial colonies. In 1969, Pepys discovered that after allergenic Aspergillus fumigatus, it can not only induce the body to produce specific IgE but also produce specific IgG, which becomes an important basis for the occurrence of allergic bronchopulmonary aspergillosis induced by Aspergillus fumigatus. A hospital in Beijing started to conduct immunoelectrophoresis and agar diffusion tests on Penicillium, Alternaria, Aspergillus, and so on in 1984, and found some different bands. In 1986, the antigen of Penicillium citrinum was preliminarily separated and purified. In 1986, Peking University Medical College conducted a preliminary activity identification of Alternaria allergens and found a strongly antigenic component. In 1987, Reed found that there is a high antigen cross-reactivity between Aspergillus fumigatus and Aspergillus terreus (A. Terreus), Aspergillus clavatus (A. clavatus), Aspergillus niger (A. niger), and Aspergillus flavus (A. flavus).

　　From the above information, we can see that the antigenic issue of airborne allergenic fungi is an extremely complex issue. Not only does it vary greatly among different species of fungi, but it may also exist different antigenic determinants within the same species. In the future, how to study the antigenic issues of common allergenic fungi in China will require a large amount of exploration.

　　Due to the complex genetic characteristics, various morphologies, and variability of fungi, its allergenic complexity is determined. The antigenic substances of fungi are mainly derived from their spores and hyphae. Different fungal strains show distinct morphological differences between the two stages of sexual and asexual reproduction. The allergenicity of different fungi often exhibits relative cross-reactivity. At the same time, the same fungal allergen can produce completely different reactions when acting on different patients with fungal变态反应. The morphology and development of fungi are also affected by the environment and can vary. Different inoculation conditions, culture medium components, culture temperature, and humidity can all lead to spontaneous variation in fungal morphology, thereby affecting its antigenicity. According to Hoffman (1981), eight important allergen components were found in the allergens prepared from Alternaria alternata spores, several of which were not present in the allergen extracts prepared from Alternaria alternata hyphae, suggesting that the allergen components of fungal spores and hyphae are different.

　　In the late 1970s, in patients with bronchial asthma, it was found that 16% to 28% had positive skin test reactions to the allergen extract of Aspergillus fumigatus, and it was considered that such patients may belong to a special type of allergic reaction, known as allergic bronchopulmonary aspergillosis. Subsequently, the allergen components of Aspergillus fumigatus and other fungal species such as Alternaria, Cladosporium herbarum, etc. were purified and separated, and the results are shown in Table 1.

　　Since the separation chromatography of the allergen of Aspergillus fumigatus has been carried out and combined with clinical comparative analysis, significant progress has been made, such as the discovery that Ag3 of Aspergillus fumigatus is a non-heat-resistant component, which can significantly degrade the allergenicity after heating. Ag7 is the most important allergen component causing allergic bronchopulmonary aspergillosis. Currently, more in-depth research is being conducted on the separation and purification of fungal allergens. In terms of separation methods, cross-immunoelectrophoresis is used: it can perform finer chromatography on different zones to obtain purer allergen components. Then, by using cloning technology, high-titer and highly specific fungal allergens are prepared. This may make breakthroughs at the molecular level in guiding the diagnosis and treatment of fungal变态反应, and even in elucidating the pathogenesis and prevention and treatment mechanisms of fungal变态反应.

　　For the determination of fungal allergenicity, one method is the biological method, which estimates the intensity and activity of allergens through skin tests with fungal allergens or other provocation tests. Another method is radioimmunoassay, which uses the radioallergosorbent test (RAST) to measure the intensity and activity of allergen extracts in vitro. Due to the need for certain instruments and equipment, some reagents are lacking in China, and the cost is high, making it somewhat difficult to use this method for large-scale allergen screening of sensitizing fungi. In the 1960s, Shelley and others discovered that basophils or mast cells from patients with immediate-phase reactions could cause these cells to degranulate when they interacted with specific antigens in vitro. Since then, the human basophil degranulation test (HBDT) method has been continuously improved and gradually perfected. We have used the HBDT and Xu's improved method, replacing toluidine blue with alizarin red for staining to reduce staining errors, and observed the results with a hemocytometer, which is simple and time-saving, and has a good correlation rate with skin tests (87%). The combination of skin testing and HBDT methods for the determination of fungal allergenicity can reflect the intensity of fungal allergens from both in vivo and in vitro aspects, which is helpful to obtain correct results. Antigen and antibody binding can occur at any ratio, but there is an optimal ratio (equivalence point) at which the binding reaction is strongest. In the HBDT test, several single fungal allergen dilutions (protein content) were tested, and the results showed that the 10-4 allergen dilution was the best for basophil degranulation. Because of the diversity of fungal species and their characteristics, the effective allergen components and contents in their extracts may also vary. For each fungal allergen, selecting its optimal dilution (protein content) for the HBDT test may yield better results.

　　In summary, the vast variety and wide distribution of airborne fungi make them one of the important allergens that induce bronchial asthma. It is reported that there are more than 280 commercial fungal allergen extract preparations on the market in the United States, while in China, only 20 to 30 types of fungal antigens are currently used for clinical diagnosis and treatment. Therefore, the in-depth separation and purification of allergens is an important task for the future research on fungal allergies in China.

　　2. Pathogenesis

　　After fungal spores enter the airways of normal people, the barrier function of the intact airway mucosal epithelium plays an important defensive role in preventing the inhaled fungal spores from entering the body. At the same time, the phagocytic function of macrophages in the airways also plays an important role in clearing the inhaled fungi and their spores, so fungi are rarely able to become pathogens. Because the barrier function of the airway mucosal epithelium effectively limits the contact between fungal antigens and lymphoid tissues related to the airways, the specific IgE levels in the blood circulation against fungi are usually low, and precipitation is negative when measured by double immunodiffusion method and ELISA-IgG titration method. For patients with atopic constitution, when the airways are repeatedly and continuously exposed to fungal spore or hyphal antigen, while the airway macrophages phagocytize fungi, the immune system in the airways also presents them as foreign antigens, which can lead to the production of specific IgE against fungi, resulting in airway sensitization and the induction of respiratory allergic reactions causing asthma attacks. Spores of fungi such as Aspergillus, Penicillium, Botrytis, Alternaria, Trichoderma, Mucor, Rhizopus, Mucor circinelloides, Mucor hiemalis, Ustilago, and Candida can all act as antigens to produce specific IgE and can cause allergic inflammation of the airways.

　　Incidence of Fungal Allergic Asthma

　　1. Overview of Incidence:Due to the limitations of experimental technology and the lack of corresponding diagnostic criteria, there is no precise data on the incidence of fungal allergic asthma in China. Fungal allergies have a more complex clinical manifestation than pollen allergies, and they do not necessarily have a clear seasonal pattern. There is a high cross-reactivity among various fungi, and the incidence statistics vary greatly from place to place. The rate of positive fungal skin tests in hospitals in Beijing is 21%, and some reports in China indicate that the positive rate of fungal allergen skin tests can reach as high as 70%. In recent years, the incidence of occupational fungal allergies has increased. According to the U.S. Census Bureau, the total agricultural population in the United States is over 8 million, of which 1/4 frequently come into contact with grains, and 1/2 to 3/4 of the patients are exposed to grain dust. Since the grain dust stored for a long time contains a lot of fungi, many of them can cause fungal asthma, acute or chronic farmer's lung, and so on. The agricultural population in China is dozens of times larger than that in the United States, and manual operations are the main way, so fungal allergies must be a very important issue. In the future, with the development of agriculture, animal husbandry and breeding, brewing and fermentation, food processing, mushroom cultivation, and the pharmaceutical industry, as well as the use of air conditioners and the increase in sealed buildings in living environments, it is possible to further lead to an increase in fungal allergies.

　　Jimenez Diaz and Sanchez Cuenca found that in Spain, most of the patients allergic to indoor dust are actually allergic to fungi in the dust. In 1939, Wittich discovered that the spores of rust fungi and smut fungi in grain dust were the main sensitizing pathogens for asthmatic patients in Minnesota. Bruce found that in 24 patients allergic to Alternaria, 15 cases of onset were consistent with the peak period of Alternaria counts in the air. Since the 1970s, Reed and Salvaggio et al. have done a lot of work on the antigen separation and purification of sensitizing fungi. They have conducted in-depth research on various fungal occupational allergies. In 1983, Crook discussed the impact of Candida on human immune function and the issue of Candida allergy from various aspects. In 1957, Beijing area hospitals began clinical and laboratory research on fungal hypersensitivity. Over the past 30 years, through the clinical diagnosis and treatment of tens of thousands of patients and the survey of fungal exposure films, exposure dishes in the laboratory air, etc., a lot of work has been done on the types, dispersion laws, inspection methods, antigen preparation, fungal identification, strain preservation, and antigen purification of sensitizing fungi in China. Some practical experience has been gained in the treatment of bronchial asthma, allergic pneumonia, alveolitis, and allergic bronchopulmonary aspergillosis caused by fungi, which has created necessary conditions for the comprehensive research on fungal hypersensitivity in the future.

　　2. The relationship between age and the incidence of fungal allergy:The study finds that the incidence of fungal allergy is closely related to the age of patients. A survey with a 10-year age segment as a unit confirms that the incidence of fungal allergy in children under 10 years old is the highest, usually the younger the age, the higher the incidence of allergy to fungi, and with the increase of age, the sensitivity to fungi can decline rapidly. This phenomenon forms a sharp contrast with pollen allergy. The positive rate of various fungal skin tests in the low-age group is usually consistent with the types and content of fungal spores in the local air, indicating that the results of the local air fungal survey can be used as a reference for fungal skin tests in children under the age of 5. Koivikko et al. confirmed that the incidence of fungal allergy in asthmatic children is relatively high, and this result is also consistent with the relatively high specific IgE titer of allergens in children's serum. Fungal antigens can sometimes pose a serious threat to severe asthmatic patients, and they are an important trigger factor for asthma. In severe cases, they can lead to sudden asthma death in children and young adults. Beaumont et al. conducted a skin test survey on the extract of fungal allergens in adult asthmatic patients, and the positive rate was less than 5%, and it often occurred in asthmatic patients who were also allergic to other airborne allergens.

　　The reason why the incidence of fungal allergy in the low-age group is higher may be related to the widespread presence of fungi in the air (especially in poorly ventilated indoor air), and there is a high antigen cross-reactivity among various fungi. Therefore, there is always an opportunity for fungal sensitization from newborns. At the same time, due to the higher indoor activities of infants and young children, the opportunity for sensitization is even greater than that of pollen. As age increases, sensitivity to fungi quickly decreases. This can partly explain the large differences in the incidence of fungal allergies in various parts of the world. Immune memory cells can produce specific antibodies against fungi in the airway, such as secretory immunoglobulin A (sIgA), which causes the body's sensitivity to fungi to decrease rapidly. The timely removal of fungal spores in the airway reduces the exposure of these antigens to bronchial-associated lymphoid tissue, thereby reducing the immune response.

　　Severe attacks may be complicated by pneumothorax, mediastinal emphysema, and atelectasis. In the late stage, pulmonary heart disease may also occur.

　　1. Pneumothorax:It refers to the entry of gas into the pleural cavity, causing a state of air accumulation, known as pneumothorax. It is usually divided into three major categories: spontaneous pneumothorax, traumatic pneumothorax, and artificial pneumothorax.

　　2. Mediastinal emphysema:It is the accumulation of gas in the connective tissue spaces of the mediastinum.

　　3. Atelectasis:It refers to a decrease in the volume or gas content of one or more pulmonary segments or lobes. Due to the absorption of gas in the alveoli, atelectasis is usually accompanied by a decrease in opacity in the involved area. Adjacent structures (bronchi, pulmonary vessels, pulmonary interstitium) gather in the atelectasis area. Sometimes, there may be实变 of the alveolar cavity, and other lung tissues may develop compensatory emphysema. The collateral gas communication between pulmonary acini and segments (occasionally pulmonary lobes) allows the completely blocked area to still have a certain degree of translucency.

　　4. Pulmonary heart disease, abbreviated as pulmonary heart disease:It is mainly caused by heart disease due to pulmonary hypertension caused by lesions in the bronchopulmonary tissue or pulmonary artery vessels. According to the severity of onset and the duration of the disease, it can be divided into acute and chronic types. Clinically, the latter is more common.

　　1. Clinical symptoms of fungal allergic asthma

　　Fungal allergic asthma is a relatively common type of bronchial asthma, mainly caused by hyperallergic constitution patients who develop high airway reactivity and allergic airway inflammation after inhaling or ingesting fungal allergens, leading to a widespread reversible respiratory obstruction syndrome. Since the invasion of this fungus is non-infectious, the fungus stays in the airway for a short time and can be engulfed by macrophages in the airway, so the symptoms are often transient and reversible. However, it can trigger a series of immune reactions, such as allergic airway inflammation in the delayed phase asthma reaction.

　　The onset of fungal asthma has a certain seasonal variation, but it is not as obvious as pollen-induced allergic asthma. Patients usually suddenly develop symptoms after contacting fungal allergens, with prodromal symptoms such as nasal itching, sneezing, clear nasal discharge, cough, chest tightness, etc. If not treated in time, asthma attacks may occur due to the exacerbation of bronchial obstruction. During mild asthma attacks, patients are conscious, can lie flat, without cyanosis, and have slight limitations in activity. During moderate attacks, patients may experience shortness of breath after slight exertion, cannot lie flat, often require assistance in breathing, increased respiratory rate, and may have mild cyanosis. During severe attacks, patients are forced to sit up, with hands supporting the shoulders, and profuse sweating or cold sweat on the forehead, cyanosis. The frequency and duration of asthma attacks vary greatly, and cough is often the prominent symptom, with sputum or white phlegm, sometimes with fever. Some patients may present with chronic paroxysmal cough without typical asthma attacks, which is currently referred to as cough variant asthma.

　　During the remission period of asthma or in patients with atypical asthma, there may be no obvious signs. During an attack, the chest is full and presents as inspiratory, with hyperresonant percussion, a reduced cardiac dullness, and wheezing can be heard during expiration. If the asthma attack is severe, the respiratory distress may worsen while the wheezing sound may decrease. An asthma attack that lasts for more than 24 hours is called a status asthmaticus, in which the patient experiences extreme difficulty breathing, restlessness, excessive sweating, cyanosis, and may progress to hypotension, confusion, or coma, respiratory failure. Patients with recurrent and persistent attacks and infections may develop chronic bronchitis, emphysema, etc. In severe attacks, complications such as pneumothorax, mediastinal emphysema, atelectasis may occur, and in the late stage, pulmonary heart disease may occur.

　　2. Other fungal allergic respiratory diseases

　　Fungi can not only induce allergic asthma but also induce other allergic bronchopulmonary diseases of pulmonary parenchyma, such as allergic pneumonia induced by fungi (also known as extrinsic allergic alveolitis), which is a group of non-IgE-mediated fungal hypersensitivity reactions in the lungs. Its pathogenesis, pathophysiology, and clinical course are quite different from those of bronchial asthma. As asthma prevention and treatment workers, one should also understand this disease for the purpose of differential diagnosis and treatment in clinical work.

　　These patients often become ill due to the inhalation of various fungal spores from living or occupational environments. Some non-fungal inorganic or organic dust, chemical or drug particles, etc., can also cause disease after inhalation, but fungi are the main pathogen.

　　This type of disease can be divided into two categories in clinical practice. One is the acute type, known as acute allergic pneumonia, with symptoms appearing within 4 to 8 hours after a large amount of allergenic fungal inhalation, including chills, fever, cough, sputum, shortness of breath, fatigue, headache, moist rales at the base of the lung, increased peripheral blood leukocytes, and in severe cases, there may be infiltrative lesions in the lung tissue. Pulmonary function may show insufficient ventilation. The other type is the latent type, also known as subacute or chronic allergic pneumonia, which is caused by long-term inhalation of certain fungal spores without symptoms in the short term, but symptoms such as cough, shortness of breath, fatigue, weight loss, and significant dyspnea after exertion gradually appear. There may be moist rales at the base of the lung, clubbing, and an increase in pulmonary markings on chest X-ray. In the late stage, there may be widespread pulmonary fibrosis, limited ventilation insufficiency in pulmonary function, irreversible changes in lung tissue, and poor prognosis.

　　1. Try to keep the air in the living room or work environment dry, clean, sunny, and well-ventilated. An air filter can be used when necessary to keep the air in a state of circulation and filtration. The commonly used filtering methods currently include a high-efficiency particle air filtration system, which is a type of microporous mechanical filtration device. It uses activated carbon microporous filter membranes to remove more than 99.97% of particles suspended in the air that are larger than 2μm (the diameter of most fungal spores in the air is larger than 2μm). The activated carbon filter membrane not only filters out fungal spores and particles but also absorbs the fungal mold smell molecules in the air. Another method is the electrostatic adsorption filtration method, which uses a static generation device to adsorb the suspended particles in the air through electrostatic adsorption.

　　2. The living environment of fungal allergic asthma patients should be as simple as possible. The walls and floors should be paved with tiles. The bedroom should be chosen on the upper floor, and the bed should have a high bed frame. It is not advisable to pile up things under the bed.

　　3. For severe allergic patients, consider alternative treatment. Those confirmed to have occupational fungal变态反应 should leave the work environment as soon as possible.

　　4. Fungal allergic asthma patients should avoid going to dark and damp environments such as cellars, granaries, swamps, and places where firewood is stacked or rotten.

　　5. Try to avoid the intake of fermented foods and the consumption of fungi.

　　1. Radioallergosorbent Test (RAST)

　　Adsorb the fungal allergen on a solid-phase support, add the patient's serum. If the patient's serum contains specific IgE antibodies against the fungus, they will bind together and cannot be washed off. When the serum of the horse anti-human IgE labeled with isotopes is added, the three will combine to form a radioactive complex, which can be measured for specific radioactivity on the gamma counter. The radioactivity is proportional to the amount of specific IgE in the patient, and it can be used to judge whether the patient has a fungal变态反应 and the degree of allergy.

　　2. Enzyme-Linked Immunosorbent Assay (ELISA)

　　The principle is to first adsorb the fungal allergen on the pores of polystyrene plastic plates, then add the serum of the patient to be tested, followed by adding sheep anti-human enzyme-labeled IgE antibody, and then adding the substrate of the enzyme. Stop the reaction, use its colorimetric reaction, and determine the OD value on the enzyme-linked immunosorbent assay (ELISA) instrument to judge the sensitivity and degree of sensitivity of the patient to fungi.

　　3. Basophil Degranulation Test

　　Collect the patient's venous blood, after anticoagulation treatment, centrifugal chromatography is used to extract basophils. Transfer the patient's basophils into two test tubes, respectively add fungal allergen and blank allergen solvent. After incubating at 37℃ for 30 minutes, stain with Alcian blue, and count the number of basophils under a blood cell counter. If the number of basophils counted in the sample co-incubated with the fungal allergen is less than 30% of the sample co-incubated with the blank allergen solvent, it indicates that more than 30% of the basophils have undergone degranulation due to specific antigen-antibody reaction, which cannot be detected under the microscope, i.e., a positive reaction. The higher the percentage of degranulation, the more severe the allergic degree.

　　4. Histamine Release Test

　　The principle of this test is to detect the amount of histamine released after the patient's blood cells are treated with fungal allergens. The higher the sensitivity of the patient to fungi, the higher the amount of histamine released, thereby determining the degree of sensitization of the patient to fungi.

　　5. Fungal culture

　　Agar diffusion test for fungal antigens and antibodies. This test can be used for specific diagnosis of fungal allergic pneumonia, alveolitis, or allergic bronchopulmonary aspergillosis. Generally, the double diffusion method is used, and the patient's serum is diffused with different concentrations of fungal allergens to observe the appearance of precipitin lines. This method has obtained positive results for antigens such as Aspergillus fumigatus and Penicillium in China, and is a good objective basis for identifying the pathogenic strain of the patient.

　　6. Direct smear examination of the patient's sputum or bronchial secretions for fungi

　　Take a small amount of sticky gray-brown material from the fresh sputum coughed up by the patient, spread it thinly on a glass slide, and before it dries, add one drop of 0.05% lactophenol blue. After 5 minutes, examine the blue-stained fungal spores or hyphae under a microscope. If multiple checks are positive, it can be used as a reference basis for the diagnosis of fungal变态反应.

　　7. Antigen intradermal test

　　This is the most widely used routine detection method in the specific diagnosis of fungal allergic asthma. Generally, 1:100 fungal antigen extract is used, and a 1ml syringe is used with a 4号 needle, and 0.01-0.02ml is gently injected into the dermis on the lateral side of the patient's upper arm. Observe the skin reaction for 15-20 minutes. In addition to the immediate phase reaction, the fungal allergen skin test often shows a delayed phase reaction, which should be noted.

　　8. Bronchial provocation test

　　The results are accurate and reliable. Since symptoms can be induced by the use of fungal allergen preparations for inhalation challenge tests, they should be carried out under strict observation. Due to the frequent occurrence of a delayed phase reaction, asthma reactions may reappear within 6 to 24 hours after the test, which should be noted. Detailed test methods can be referred to in the chapter on airway reactivity testing.

　　9. Pulmonary function examination

　　In some asthmatic patients during the clinical remission period, there may be abnormalities in the closing volume (CV)/vital capacity (VC) %, closing capacity (CC)/total lung capacity (TLC) %, mid-expiratory flow (MMEF), and Vma×50%, and during asthma attacks, all indicators of expiratory airflow will significantly decrease, such as the forced expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC) %, and MMEF. Due to gas blockage and overinflation of alveoli, the residual volume (RV), functional residual capacity (FRC), and RV/TLC ratio increase. After inhaling 1% isoproterenol or 0.2% salbutamol aerosol solution, the above indicators can be improved. If FEV1 increases by more than 15%, it will be helpful for the diagnosis of bronchial asthma, moderate or severe asthma. The distribution of inhaled gas in the lungs is uneven, the ventilation/perfusion ratio is disordered, physiological dead space and physiological arteriovenous shunting increase, leading to a decrease in PaO2, but PaCO2 is normal or slightly reduced. In severe asthma or asthma status, PaO2 further decreases, and due to respiratory muscle fatigue, PaCO2 can increase, with concurrent respiratory acidosis, predicting severe condition.

　　10. Airway reactivity measurement

　　Inhalation of histamine, acetylcholine, sulfur dioxide, prostaglandin F2α, β-blocker medication, exercise stress, and other factors can trigger asthma. The detection can be done by measuring FEV1, peak expiratory flow rate, airway resistance, etc., immediately and every 15-30 minutes after inhalation of the provoking agent. Acetylcholine is generally used because it has a fast reaction and short duration, starting from 0.05mg/L and gradually increasing until the FEV1 decreases by more than 20% or the airway conductance decreases by more than 35%, which is called the threshold of the drug. The sensitivity of asthma patients to acetylcholine-induced airway spasm is 100 to 1000 times higher than that of normal people. The slope of the drug dose-response curve is called reactivity. Asthma patients have increased reactivity, and smokers also have higher reactivity than non-smokers. The airway obstruction induced can disappear naturally within 15-30 minutes, but in patients during an attack, it can cause severe asthma, even asphyxia. Therefore, it is necessary to strictly control the indications and prepare bronchodilators, antishock drugs, and other rescue measures. In recent years, the airway reactivity meter has been used to continuously record airway resistance. When the resistance rises twice or remains elevated for 2 minutes, the cumulative amount of the drug at that time is used as a sensitivity indicator. The airway resistance when inhaling normal saline is called the initial resistance; the minimum cumulative amount of the drug inhaled when the airway resistance rises is called the response threshold; the rise in airway resistance per unit of acetylcholine is called the resistance rise degree; one milliliter containing 1mg of the drug, inhaled for 1 minute is one unit. A reactivity threshold below 3 units indicates increased sensitivity, with the mean of asthma patients being 1.08 units. A resistance rise degree greater than 0.5cmH20/L per unit per second indicates increased reactivity. Therefore, the sensitivity and reactivity of asthma patients are both increased, and airway reactivity measurement is very valuable for the diagnosis of covert asthma, which can be diagnosed when the patient is breathing quietly.

　　1. What foods are good for allergic asthma patients with fungal allergies

　　They can eat more radishes, luffa, Job's tears, tangerines, ginkgo biloba, and other expectorant and diuretic foods; they can also eat mung beans, rapeseed, bitter melon, and pomelos that clear heat. The diet should be warm, light, and soft, and can be eaten in small portions and more frequently.

　　2. What foods should allergic asthma patients with fungal allergies avoid

　　Patients with allergic asthma should not eat pork, fish, or greasy and sweet foods, as they can promote dampness and phlegm. It is not advisable to eat spicy and刺激性 foods such as chili, Sichuan pepper, mustard, and fennel.

　　(The above information is for reference only, please consult a doctor for details.)

　　1. Treatment

　　1. General treatment

　　(1) Sympathomimetic drugs: β-adrenergic receptor agonists have a strong bronchodilatory effect. This class of drugs mainly acts by exciting β-receptors, activating adenylate cyclase, increasing the synthesis of cyclic adenosine monophosphate (cAMP), raising the concentration of intracellular cyclic adenosine monophosphate (cAMP), dilating the bronchial smooth muscle, and stabilizing the mast cell membrane. Due to the multiple effects of ephedrine, adrenaline, isoproterenol, and other drugs on α, β1, and β2 receptors, they are gradually replaced by β2 receptor agonists, which can selectively dilate the bronchial smooth muscle and greatly reduce the side effects on the cardiovascular system. Currently, commonly used drugs include salbutamol, terbutaline, chlorpheniramine, dyclonine, procaterol, etc. They are usually administered orally or inhaled, and inhaled administration is divided into aerosols, nebulized solutions, and dry powder inhalers, etc., which have the advantages of low dosage, rapid onset, and few side effects. Oral formulations include sustained-release and controlled-release preparations, which can extend and maintain effective blood drug concentration well. When β2 receptor agonists are used, some cases may cause symptoms such as tachycardia and hand tremors, but these symptoms gradually diminish or disappear with prolonged use.

　　(2) Theophylline drugs: The effect of aminophylline in relieving bronchospasm has been confirmed by more than half a century of clinical practice. Studies have shown that theophylline has anti-inflammatory effects, can stabilize and inhibit mast cells, basophils, neutrophils, and macrophages, can antagonize bronchospasm caused by adenosine, can stimulate the adrenal medulla and chromaffin tissue outside the adrenal glands to release catecholamines, and increase the contractility of the diaphragm to low-frequency stimulation in healthy or fatigued individuals.

　　(3) Anticholinergic drugs: Isopropylthiopropamine (isopropyl bromide) can be inhaled, 20-80 μg per time, 3-4 times a day. Local use has no systemic side effects and has a relatively long-lasting antispasmodic effect.

　　(4) Glucocorticoids: Glucocorticoids can prevent and suppress airway inflammatory reactions, reduce airway reactivity, and inhibit the late-phase asthma reaction. Their mechanism is to inhibit phospholipase A2, prevent the synthesis of LTs, PGs, TXs, and PAF; inhibit histidine decarboxylase, reduce the formation of histamine; increase the number of β-receptors and PGE receptors; reduce the release of plasminogen activators and the secretion of elastase and collagenase; inhibit the synthesis of acidic mucopolysaccharides in bronchial glands; promote vasoconstriction of small blood vessels, increase the tension of their endothelium, thereby reducing exudation and infiltration of inflammatory cells. In summary, the efficacy of glucocorticoids in asthma is the result of a comprehensive action, and they are currently the most effective drugs for the treatment of asthma. However, due to the potential for numerous side effects with long-term use, they should not be used abusively. Currently, it is generally advocated to use inhaled corticosteroids or dry powder inhalers as much as possible, with a daily dose of 400-800 μg. Its greatest advantage is that it exerts a unique therapeutic effect in the bronchus while avoiding systemic side effects. Systemic application of glucocorticoids is mainly used for patients with acute severe asthma attacks or those in a persistent asthma state. To avoid or alleviate the side effects of systemic application of glucocorticoids, the maintenance dose of prednisone should be taken once a day or every other morning.

　　2. Non-specific immunotherapy:When the allergen cannot be determined, non-specific immunotherapy can be performed to change the patient's reactivity so that they can tolerate the stimulation of allergens. Common drugs include histaglobin and freeze-dried BCG vaccine (BCG vaccine).

　　(1) Freeze-dried histamine gamma globulin (histamine gamma globulin): Also known as histaglobin, it can be used to treat bronchial asthma. The therapeutic mechanism of histaglobin is still not fully understood. It can be肯定 not a simple immunological effect of human blood gamma globulin (gamma globulin), because the content of human blood gamma globulin (gamma globulin) in histaglobin is very low. Shiffarth's experiment has shown that injection of human blood gamma globulin (gamma globulin) alone cannot induce protective immunity against histamine in guinea pigs, while the same dose of histaglobin is effective. Most people believe that histaglobin is a complex antigen that can stimulate the body to produce antibodies against histamine, thereby eliminating the pathogenic effects of endogenous histamine. Some people also believe that histaglobin is attached to the surface of mast cells, forming a high concentration state of histamine around it, which inhibits the degranulation process of mast cells. The general administration is to inject subcutaneously 1 to 2 times a week, 1ml each time, and efficacy appears around 10 times, and then changed to once a month. Adverse reactions include mild dizziness, headache, and rash. These reactions occur within the first 4 injections, and can be spontaneously relieved about 20 minutes after injection.

　　(2) Freeze-dried BCG vaccine (BCG vaccine, BCG-E): It is a heat-phenol ethanol extract of the BCG bacterium, mainly composed of freeze-dried BCG (BCG) polysaccharide nucleic acids and more than 10 other components. The current dosage form is 1ml per vial, containing 0.5mg of freeze-dried BCG (BCG vaccine), which is a good pure biological preparation and an ideal immunostimulant. Animal pharmacological experiments have shown that freeze-dried BCG (BCG vaccine) can effectively activate macrophages and T lymphocytes, enhance the phagocytic function of alveolar macrophages, and have the effects of anti-asthma, anti-allergic reactions, enhancing the body's cellular and humoral immunity, and promoting the proliferation and vitality of mononuclear macrophages. It can also activate T lymphocytes to release various lymphokines. The injection of 1ml to 2ml of freeze-dried BCG (BCG vaccine) is intramuscularly administered every other day, with 30 times as a course of treatment. Side effects are rare, and may include fever, general fatigue, joint pain, and hard nodules at the injection site.

　　3. Specific immunotherapy:The simplest specific immunotherapy is to avoid contact with fungal allergens. However, it is impossible to completely avoid contact with fungi, so the commonly used treatment method is specific immunotherapy (i.e., desensitization therapy). Desensitization therapy usually starts to take effect when the level of blocking antibodies rises after about 3 months, and the antibody level continues to rise, and the effect is also relatively stable. Generally, desensitization therapy is required for 2 to 3 years, and some patients may need a longer time. During the desensitization treatment, if asthma attacks occur, symptomatic treatment drugs can be used as usual. For mild attacks, desensitization therapy can continue, but for severe attacks, desensitization therapy should be paused. Desensitization therapy is generally safe, and a few patients may experience local or systemic reactions. Local redness and swelling reactions that resolve within 24 hours can continue treatment, but the development should be closely monitored; if local hard nodules form and do not resolve for more than 48 hours or even form sterile necrosis, consider the occurrence of type III hypersensitivity reaction, and desensitization therapy should be discontinued and other therapies should be used. Systemic reactions are often caused by excessive dosage, and the injection dose should be appropriately reduced to prevent reactions.

　　4. Preventive treatment

　　(1) Cromolyn (sodium cromoglycate): It has the effect of stabilizing mast cells, preventing their degranulation and release of mediators, and can reduce airway hyperreactivity and inhibit both the early and late phases of asthma. It is recommended to start medication 2 weeks before the peak season, 20mg per inhalation, 3 to 4 times a day. It is generally effective for allergic asthma caused by fungi. For patients with asthma dependent on corticosteroids, the use of this product may reduce the dose of corticosteroids.

　　(2) Ketotifen: It can inhibit the release of histamine and slow-reacting substances by mast cells and neutrophils, counteract the inflammatory effects of histamine, bradykinin, 5-HT, PAF, leukotrienes, and other substances, reduce airway hyperreactivity, enhance the effect of β-receptor agonists in dilating the airways, prevent and reverse the rapid tolerance to β-receptor agonists, and have inhibitory effects on both the early and late phases of asthma. It is generally started 2 weeks before the onset, 2 times a day, 1mg per time. The main side effects are drowsiness and fatigue.

　　II. Prognosis

　　Late-stage extensive pulmonary fibrosis, with restricted ventilatory function of the lung, irreversible changes in lung tissue, and poor prognosis.