Aspergillus fungus. Aspergillus oryzae micromycete strain - producer of proteolytic and amylolytic enzymes for use in the food industry Aspergillus application

Growth and distribution

Aspergillus is classified as a deuteromycete fungus that does not have a sexual stage of development. With the advent of DNA analysis data, it has become more likely that all members of the genus Aspergillus are closely related to the Ascomycetes, and should be considered members of the Ascomycetes. Representatives of the genus have the ability to grow wherever there is a high osmotic concentration (strong solutions of sugar, salt, etc.), and are very resistant to environmental influences. Aspergillus species are highly aerobic and can be found in almost all oxygen-rich environments, where they typically grow as a mold on the surface of the substrate as a consequence of high oxygen enrichment. Generally, fungi grow on carbon rich substrates such as monosaccharides (eg glucose) and polysaccharides (eg amylose). Aspergillus species are a common contaminant of starchy foods (such as bread and potatoes) and grow in or on the surface of many plants and trees.

In addition to growth on carbon sources, many species of the genus Aspergillus exhibit oligotrophy, that is, the ability to grow in nutrient-poor environments, or in conditions of complete absence of key nutrients. The main example of this is A.niger- it can be found growing on damp walls as a major component of downy mildew (English).

Significance for a person

Aspergillus species are medically and commercially important. Some species can infect humans and other animals. Some infections found in animals have been studied for years; while other species found in animals have been described as new and specific to the disease under study. Others were known as names already in use for organisms such as saprophytes. Over 60 Aspergillus species are significant medical pathogens. There are a number of human diseases such as pinna ear infection, skin lesions, and ulcerations classified as mycetomas.

Other species are important in industry in the manufacture of enzyme preparations. For example, spirits such as Japanese sake are preferred to be made with rice or other starchy ingredients (such as cassava) instead of grapes or malted barley. Typical microorganisms used to produce alcohol, such as yeasts of the genus Saccharomycetes, cannot ferment starch. Therefore, mold is used to break down starch into simpler sugars. koji(for example, Aspergillus oryzae). Aspergillus oryzae, Aspergillus sojae, Aspergillus tamari used to make soy sauce, as well as various types of soy paste - miso, doenjang and others.

Aspergillus fungi are widely used to determine the content of inorganic cations and anions. Representatives of the genus Aspergillus are also sources of natural substances that can be used in the production of medicines for the treatment various diseases person. Perhaps the most widely used Aspergillus niger, as the main source of citric acid. This organism provides 99% of the world production of citric acid - more than 1.4 million tons per year. A.niger also often used to produce true (native) and foreign enzymes, including glucose oxidase and egg protein lysozyme. In such cases, the culture is rarely grown on a solid substrate (although this practice is still common in Japan). More often it is grown as a deep culture in a bioreactor. With this method, you can tightly control important parameters and achieve maximum productivity. This process also greatly facilitates the separation of the target chemical or enzyme from the culture medium and is therefore much more cost effective.

Research

sexual reproduction

Of the 250 Aspergillus species, about 64% have no known sexual stage. However, it is becoming increasingly clear that many of these species likely have an as yet unidentified sexual stage. Sexual reproduction in fungi occurs in two fundamentally different ways. This is outcrossing (cross-crossing) in heterothallomas. (English) fungi, during which two different individuals exchange nuclei, and self-fertilization in homothalloma (English) fungi, where both nuclei come from the same individual. AT last years sexual cycles have been found in a large number of species previously considered asexual. These discoveries reflect the focus of current empirical research on species specifically related to humans. Some species for which sexual reproduction has recently been confirmed are described below.

These results from studies of Aspergillus species are consistent with data accumulated from studies of other eukaryotic species, and indicate the likely presence of sexual behavior in a common ancestor of all eukaryotes. A. nidulans- homothallomic fungus capable of self-fertilization. Self-fertilization involves the activation of the same sexual reproduction pathways as in outcrossing species. It does not mean that self-fertilization takes place necessary steps characteristic of outcrossing, but that instead it requires the activation of these mechanisms within a single member of the species. The vast majority of species Aspergillus, demonstrating sexual cycles, are homothallomic in nature (self-fertilizing). This observation suggests that, in general, species Aspergillus can maintain sexual reproduction, even though the level of genetic diversity of the offspring as a result of homothallomic self-fertilization is low. A. fumigatus- homothallomic (reproducing by outcrossing) fungus, which occurs in areas that differ significantly in climate and environmental conditions. This species also exhibits a low degree of variability both within geographic regions and across the planet, again suggesting that sexual reproduction is this case outcrossing reproduction - can persist even with a low degree of genetic variability.

Genomics

Simultaneous publication of three manuscripts on the topic of the genome Aspergillus in the journal Nature in December 2005 made this genus the leading subject for research in comparative genomics among micellar (filamentous) fungi. Like most genomic projects, these efforts have been undertaken by major sequencing centers in collaboration with the relevant scientific communities. For example, the Institute for Genome Research (TIGR) () has worked with the research community A. fumigatus. A. nidulans was sequenced at the Eli and Edith L. Brad Institute () A. oryzae was sequenced in Japan in National Institute advanced industry and technology. The Joint Genome Institute () of the Ministry of Energy published sequenced data on the genome of the strain A.niger used for the production of citric acid. TIGR, now renamed the Venter Institute (), currently leads the Species Genome Project A. flavus. Sizes of sequenced genomes of species Aspergillus fluctuate within 29.3 MB A. fumigatus and 37.1 MB A. oryzae, while the number of predicted genes varies from ~9926 y A. fumigatus up to ~12.071 y A. oryzae. Genome size in an enzyme-producing strain A.niger medium size and is 33.9 MB.

pathogens

Some species of aspergillus cause serious illness in humans and animals. The most frequently pathogenic species are A. fumigatus and A. flavus that produce aflatoxins, which are both toxins and hepatocarcinogens. They can contaminate food such as nuts, seeds and grains. Common causative agents of various allergic diseases are species A. fumigatus and Aspergillus clavatus (English) . Other species are important as crop pathogens. Representatives of the species Aspergillus cause disease in many cereals, especially corn; some synthesize mycotoxins, including aflatoxin.

Aspergillosis

• Allergic bronchopulmonary aspergillosis affecting patients with respiratory infections such as bronchial asthma, cystic fibrosis, and sinusitis
• Acute invasive aspergillosis, a form of aspergillosis in which fungi grow into surrounding tissues, occurs more frequently in people with a weakened immune system, such as those with AIDS or chemotherapy.
• Disseminated invasive aspergillosis is an infection that has spread widely in the body.
• Aspergilloma is a spherical fungal formation that can form in the sinuses and cavities, for example, in the lungs.

Most often, the fungus enters through the respiratory tract and mouth, and can affect both the respiratory system, and the central nervous system, digestive tract, skin, sensory organs, and reproductive system. Aspergillus meningitis or encephalitis in most cases ends lethal outcome. Aspergillus fungal infections of the spleen, kidneys, and bones also occur, but for the most part they are caused by secondary infection. Respiratory aspergillosis is often diagnosed in birds and certain species are known. aspergillus that infect insects.

see also

Notes

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2. lenta.ru - Mold fungi were able to have sex, (eng.)
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7. Aspergillus niger culture - citric acid producer Archived March 5, 2011.
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9. Descriptions - Aspergillus Comparative (indefinite) . Broad Institute. Retrieved October 15, 2009. Archived from the original on November 22, 2009.
10. Dyer P. S. , O "Gorman C. M. A fungal sexual revolution: Aspergillus and Penicillium show the way. (English) // Current opinion in microbiology. - 2011. - Vol. 14, no. 6. - P. 649-654. - DOI:10.1016/j.mib.2011.10.001 . - PMID 22032932 .[to correct]
11. O "Gorman C. M. , Fuller H. , Dyer P. S. Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus. (English) // Nature. - 2009. - Vol. 457, no. 7228 . - P. 471-474. - DOI:10.1038/nature07528. - PMID 19043401 .[to correct]
12. Horn BW, Moore GG, Carbone I (2009). "Sexual reproduction in Aspergillus flavus". mycology. 101 (3): 423-9. DOI:10.3852/09-011. PMID.
13. Swilaiman SS, O "Gorman CM, Balajee SA, Dyer PS (July 2013). “Discovery of a sexual cycle in Aspergillus lentulus, a close relative of A. fumigatus” . eukaryotic cell. 12 (7): 962-9. DOI:10.1128/EC.00040-13. PMC. PMID.
14. Arabatzis M, Velegraki A (2013). “Sexual reproduction in the opportunistic human pathogen Aspergillus terreus” . mycology. 105 (1): 71-9. DOI:10.3852/11-426. PMID.
15. Malik SB, Pightling AW, Stefaniak LM, Schurko AM, Logsdon JM (2008). “An expanded inventory of conserved meiotic genes provides evidence for sex in Trichomonas vaginalis” . PLOS ONE. 3 (8): e2879.

Aspergillosis is a name given to a number of diseases that are caused by a single pathogen, Aspergillus. These are fungi that grow on a variety of hosts. They are very common around a person - aspergillus are in the ground, in water, in the air. They can often be seen on spoiled products, the walls of wet rooms - this is a light white fluff, dense in composition, which has an island of green or black color inside. The mushroom itself is quite viable, it has a good mycelium. Some types of fungus are used in the food industry for fermentation products.

Aspergillus fungus can cause significant harm to humans and animals and cause aspergillosis. Most often, it affects those people who have weak immunity, people suffering from chronic respiratory diseases. If a person's immunity is strong enough, then contact with aspergillus may look like a carriage or colonization. In some cases, aspergilloma can form - a fungal settlement in the form of a pea on the surface of the mucous membrane (for example, in the oral cavity), in which the fungus does not penetrate into the mucous membrane of the body. May be chronic. In this case, surgery is indicated.

Ways of infection with aspergillosis - through the mouth and nasopharynx. Further, spores can enter the respiratory system, digestive tract, central nervous and reproductive systems, under the skin. Aspergillus affects the spleen, kidneys, bones.

In each individual case, it is said about a specific disease, which has its own characteristics. For example, an allergic component is often added to pulmonary aspergillosis.

Symptoms of aspergillosis

Since the respiratory system takes the first blow, the main symptoms begin to appear precisely from the respiratory system. In a third of cases, the fungus enters the body with blood and lymph and spreads to all organs. With this type of aspergillosis, the mortality rate is high - about eighty percent. The most rare is cutaneous aspergillosis.

If the fungus settled on the surface and did not penetrate the mucosa, as is the case with tracheobronchitis, aspergilloma, then patients notice the following symptoms: chronic cough with sputum, sometimes with blood with a strained cough. Most often in such cases there are pathologies from the lungs.

In response to the penetration of spores, the body's tissues develop certain inflammatory reactions. The two most common types of inflammation are serous-desquamative and fibro-purulent. With serous-desquamative inflammation, aspergillus causes exfoliation of the epithelium, membranes of the stomach, lungs with the release of exudate (plasma with blood elements). In the second type - fibro-purulent - aspergillus causes the release of exudate with fibrin (clotted blood protein) and a purulent component. The most severe reaction to aspergillosis is the formation of granulomas in the lungs.

Otherwise, aspergillosis gives an acute picture - a dense infiltrate is formed in the lungs, which disintegrates. With the blood flow, infection of other organs also occurs. At the onset of acute aspergillosis, the phenomenon of neutropenia is characteristic, which is expressed in sudden weakness, nosebleeds, fever, severe chills, severe sweating, tachycardia, and a sharp decrease in pressure. In this case, a decrease in neutrophils is found in the blood, which makes it difficult for the body to give an inflammatory response to the focus of aspergillosis. Therefore, with neutropenia, it is often not possible to diagnose aspergillosis - all indicators would seem to be normal. However, doctors know from experience that this can signal the beginning of aspergillosis, so additional studies are prescribed. Most often, aspergillus settle in the sinuses. At the same time, red foci appear, after the decay of tissues, they lose their color, and then turn black. This process is very rapid - it usually spreads to the eye sockets, facial tissues, towards the brain. Typical symptoms in this condition are congestion, pain in the nasopharynx, sinuses, swelling of the mucous membrane. The sinuses are filled with pus, but they do not erupt.

Often, allergic aspergillosis is associated with bronchial asthma. At the same time, patients note asthmatic attacks, eosinophils are increased in the blood, dark areas on an X-ray examination, the presence of antibodies in the serum (galactoman). To clarify the diagnosis, a sputum test is taken. In more than half of patients, aspergillus is found during culture. In this case, a secondary seeding is done to clarify the diagnosis (since conidia could have accidentally entered).

Cause of aspergillosis

The immediate cause of aspergillosis is the penetration of the aspergillus fungus into the body. On the outgrowths of the mycelium of the fungus, conidia are formed - spores that enter the air. A person inhales not only aspergillus conidia - there are about forty conidia of various fungi in the air at the same time, but it is aspergillus that is the most dangerous. Conidia can also get on an open wound - then infection will also occur. In addition, conidia can penetrate along with poor-quality food.

An interesting fact is that it is present in the closest environment of a person - an apartment. Aspergillus has been identified in ventilation systems, showers, bathrooms, old pillows, old books, inhalers, air conditioners. If the fungus exists peacefully in the apartment, then it can be “stirred up” by carrying out repairs, when the furniture is transferred, dismantled. Aspergillus is also found in pots of indoor plants, on products (they rot under the influence of aspergillus), in grass.

Diagnostics

If aspergillus is repeatedly detected in the patient's sputum, then this almost completely indicates the presence of invasive aspergillosis. This applies to children and people who do not smoke. If aspergillosis is suspected in other patients, a biopsy is usually done to gain clarity. On sections of materials for research, hyphae - carriers of conidia are clearly visible.

Aspergillosis treatment

The treatment is complex. First of all, you need an effect on the fungus. To do this, prescribe antifungal drugs (antifungal). To a large extent, the success of treatment depends on the right drug and its dose. When treating, it is worth considering that it requires long-term hospitalization, long-term medication. The range of antifungal drugs is large, but not all of them have the same effect on certain types fungi. For example, in Aspergillus meningitis, several drugs are needed to improve the penetration of antifungals into the cerebrospinal fluid. Aspergillus meningitis is one of the most problematic forms; mortality and relapses of the underlying disease are very high here.

Voriconazole relatively new drug, invented in 1995. It is a derivative of fluconazole. In its activity against aspergillus, it is several times higher than the action of fluconazole. Voriconazole can be taken both in the form of tablets and intravenously. This drug perfectly penetrates the brain and spinal cord fluid, which is especially important in the treatment and prevention of Aspergillus meningitis. Side effects drugs are minimal. Most of it binds to serum proteins

Amphotericin B known to medicine for more than half a century. It is a broad spectrum antifungal drug. This drug does not penetrate into the fluid of the spinal cord. Its serious drawback is the negative effect on the kidneys. After using the drug, patients note violations from this organ. After that, doctors reduce the dose or interrupt the administration of the drug for a while. Among adverse reactions rash, heart pain, fever, cardiac arrest, ventricular fibrillation may occur. Usually, almost everyone has a fever, so paracetamol or prednisone is immediately prescribed.

Itraconazole also used against the fungus aspergillus. The drug is applied once a day. Since it is poorly soluble in water, intravenous administration is not possible, it is taken orally with food. If the patient's condition is severe, then doctors may prescribe a larger dosage. The highest concentration is observed in the liver. Itraconazole cannot be used with certain drugs, such as cisapride, terbenafine - this threatens to cause arrhythmias.

There are about 190 species of mold fungi of the genus Aspergillus, about 40 species have a pathogenic effect on the human and animal body, causing infectious diseases. Aspergillus fumigatus is the most common species of this genus, living on the soil in organic residues.

Everyone inhales the spores of this fungus every day, but those whose immune systems are unable to eliminate the pathogen become infected. Consider the types of mold Aspergillus, a potential threat to humans and ways to deactivate this infection.

Aspergillus is a genus of fungi that grows on organic surfaces enriched with oxygen. In urban areas, a mold fungus of this genus is observed on damp walls of houses, on ceilings, on decomposed leaves, and in rural areas - in open ground when the substrate decomposes.

Diseases in humans are caused by several species - A. fumigatus and A. flavus. Other species, such as A. clavatus, can cause an allergic reaction.

Rare species of Aspergillus:

• Aspergilla niger;
• Aspergilla nidulans;
• Aspergilla oruzae;
• Aspergilla terreus.

What is Aspergillus fumigatus? Aspergillus is the most common fungus that causes respiratory disease in humans.
The spores of the fungus, which are in the open ground, when inhaled, enter the mucous tissues of a person. If at the same time the immune system is suppressed, a fungal infection develops.

Aspergillosis often affects people who have the following characteristics:

• violation of the protective properties of the body;
• diseases of the immune system;
• chronic inflammatory diseases;
• farmers;
• people working in the open field;
• workers of poultry farms, dovecotes;
• builders;
• residents of the first floors of the building;
• sewer workers.

Aspergillus is common in fertilized soil, in bird droppings. When harvesting or planting plants in the ground, there is a possibility of infection with this mold, inhaling spores with air flow.
In urban environments, infection can also occur with a stream of air inseminated with mold spores. Especially dangerous in this sense are the first floors of old buildings with basements.

As for the residents of the houses on the first floors, with the development of mold on the walls of the house, there is a risk of its spread in the living quarters and diseases among the residents. To prevent this from happening, it is necessary to repair the sewers, to treat the outer and inner walls with copper sulphate.

Aspergillus fumigatus is a fungus that causes damage to the lung tissue, peritoneum, genital and central nervous system in humans.

The defeat occurs due to a malfunction of the immune system.

The onset of infection with fungi Aspergillus resembles a respiratory tract infection, with the corresponding symptoms:

• fever, chills, fever;
• cough, shortness of breath, shortness of breath;
• chest pain.

Sometimes, the aspergillus fungus can develop against the background of a primary infection - bronchitis or otitis media, during a period of reduced general immunity.

What is an invasive Aspergillus fumigatus infection? This is the development of a mold infection that occurs against the background of diseases of the immune system.

During invasion, conidia germinate into tissues and organs, the lesion spreads throughout the body, not limited to the respiratory tract. Such mycosis of the mold fungus affects people infected with HIV, AIDS patients who have undergone radiation therapy.

Aspergillus species

1. Aspergillus flavus.
   - This fungus is sometimes identified as the cause of the development of otomycosis, aspergillosis.
   - Spores of a carcinogenic fungus are common in warm soil, corn, peanuts, and are observed in dairy products.
   – Some strains of this species are toxic, if swallowed, there is a possibility of infection and damage to liver tissue. Mutogenicity of some flavus strains has been experimentally proven.
2. Aspergillus oriza.
   – Aspergillus oryzae is a filamentous fungus, widely distributed in Asia.
   “It is used to make Japanese and Chinese dishes—soy sauce, fermented to make sake.
   – It is the most domesticated fungus of the genus Aspergillus observed in wild nature infrequently.
3. Aspergillus fumigatus.
   – As mentioned earlier, this species of the mold Aspergillus is the most widespread.
   – The fungus Aspergillus fumigatus is capable of causing secondary, invasive lesions respiratory system and mucous membranes.
   - The growth of conidia is carried out in warm soil on soil fertilized with organic substrates at a temperature of 20-30 degrees Celsius.
   - Food can act as reservoirs for fungal conidia.
   - Moved to human body with the flow of inhaled air, causing infectious pathogenic diseases.
4. Aspergillus black.
   – Black Aspergillus forms predominantly grey-black mold on walls, able to thrive in low nutrient conditions.
   – In animals and humans, the fungus can cause infectious lesions of the respiratory tract.
   – Black fungus is used for fermentation in order to obtain food products and their derivatives.

Mushrooms genus Aspergillus- strong allergens that affect people with an underestimated protective function of the body. The characteristic of the disease caused by aspergillus is similar to the true, primary disease.

The condition is not relieved by standard anti-inflammatory drugs.

Diagnostics

If you have symptoms that indicate the presence of an infectious or inflammatory disease of the respiratory tract, you should consult a doctor for diagnosis. Diagnosis is carried out by collecting blood tests, sputum, a fragment of mucus for culture.

Tests for Aspergillus spp:

1. Bacterial seeding.
2. Microbiological examination of the sample.
3. General blood analysis.
4. Analysis of urine.
5. Phlegm from the nose, on expectoration.

After the tests, treatment is prescribed, consisting of taking antifungal agents, anti-inflammatory, antihistamines. In each individual case, the therapeutic regimen is different, depending on age, the presence of a primary or secondary infection, the state of the immune and endocrine systems, the presence oncological diseases and allergic reactions.

Aspergillosis therapy

1. Some strains of Aspergillus spp are resistant to Itraconazole, so all diagnostic tests should be performed to determine the pathogen and its resistance to drugs. Primary therapy may include amphotericin B.
2. In case of severe infection, it is recommended in a hospital, constant supervision of personnel. If the immune system is not compromised, then most cases of aspergilles spp infection are successfully cured. With HIV infection, the prognosis is poor.
3. Initial therapy is aimed at removing the inflammatory process and inhibiting the growth of fungal spores. For therapy, use Vorikanozol, Amphosetrin B in the form of injections. At the same time, antihistamine therapy is carried out - Zitrek, Diphenhydramine, Claritin and others.
4. After stabilization of the patient's condition, fungicidal and fungistatic therapy of shock type or classical is prescribed, depending on the indications. In parallel, immunosuppressant therapy is carried out, if necessary.
5. The final therapy is characterized by the strengthening of the results obtained, with the reception vitamin complexes drugs that strengthen the immune system. Reception of antifungal drugs is carried out after the removal of symptoms to prevent relapse.

In no case should you carry out therapy yourself, prescribe antibiotics or antimycotic agents for yourself. It's life-threatening.

Prevention

Preventive measures are individual, but come down to simple rules:

• strengthen the immune system;
• monitor the condition of residential premises;
• follow the rules of personal hygiene;
• protection during excavation or rough work.

If a person is infected with HIV, then for such people it is necessary to avoid work and rest in areas with ground lands, and constant monitoring of the state of immunity is necessary.
If mold is seen on the walls of an old building in a house, it should be treated with a special antifungal compound using the work of specialists.

Conclusion

The diseases that Aspergillus mold causes are extremely dangerous for the body and life. Invasive lesions for people with a suppressed immune system end in death, for conditionally healthy people - a significant undermining of immunity, damage to internal tissues and organs.

Aspergillosis is the general name for the diseases that this type of mold causes, so don't underestimate the severity of an infection from a single source. If you experience symptoms that resemble those described, do not waste time - consult a doctor, conduct a diagnosis. This will save health, time and money.

Aspergillosis- a human disease, mycosis, caused by certain types of mold fungi of the genus Aspergillus and manifesting itself mainly by the involvement of the respiratory system as a result of an allergic restructuring or a destructive infectious process, under certain conditions beyond this system with the development of dissemination and specific damage to other organs.

Aspergillosis is the most common mycosis of the lungs. Aspergillus are found everywhere. They are isolated from soil, air, and even sulfur springs and distilled water.

Sources of aspergillus are ventilation systems, shower systems, old pillows and books, air conditioners, inhalers, humidifiers, construction and repair work, houseplant soil, food products (vegetables, nuts, ground black pepper, tea bags, etc.), rotting grass , hay, etc. The disease is often found in millers and fatteners of pigeons, tk. pigeons suffer from aspergillosis more often than other birds.

Regions with high levels of Aspergillus spores in the environment - Sudan and Saudi Arabia. Aspergillus spore concentrations tend to be higher in indoor air than outdoors. Sick diabetes susceptible to aspergillus disease regardless of region. The disease is non-contagious and is not transmitted from person to person.

The respiratory tract is the most vulnerable zone of infection with aspergillosis pathogens, and the lungs and paranasal sinuses are the main sites of damage. Dissemination is observed in 30% of cases, and skin lesions develop in less than 5% of patients. Mortality in disseminated aspergillosis reaches 80%. After organ transplantation, invasive tracheobronchial and pulmonary aspergillosis develops in almost every fifth patient, and more than half of them end in death. In intensive care units of surgical clinics, in patients with AIDS, when using corticosteroid drugs in patients with chronic lung diseases, it occurs in 4% of patients.

Among invasive aspergillosis infections, the first place (90% of lesions) should be occupied by pulmonary aspergillosis, a serious disease with a primary lesion of the lungs and, often, paranasal sinuses nose (in 5-10% of patients), larynx, trachea and bronchi, with possible dissemination to the skin and internal organs. In the CNS, it spreads as single/multiple brain abscesses, meningitis, epidural abscess, or subarachnoid bleeding; also note myocarditis, pericarditis, endocarditis, osteomyelitis and diskitis, peritonitis, esophagitis; primary Aspergillus granulomatosis of the lymph nodes, skin and ear, endophthalmitis, aspergillosis of the external auditory canal, mastoiditis. In addition, aspergillus can cause bronchial asthma and allergic bronchopulmonary aspergillosis, as well as contribute to the development of exogenous allergic alveolitis, sometimes combined with IgE-dependent bronchial asthma (when working with rotten hay, barley, etc.).

Allergic bronchopulmonary aspergillosis (ABPA) is a condition in which a state of lung hypersensitivity develops, induced mainly by A. fumigatus, or a chronic inflammatory lung disease in immunocompetent individuals, caused by a combined allergic reaction of types I, III and IV in response to permanent exhibition Aspergillus antigens (endogenous or exogenous). In the United States, ABPA occurs in 7% to 14% of asthma patients who are chronically treated with corticosteroids. Many patients with cystic fibrosis have colonization of the respiratory tract with aspergillus, and approximately 7% of these patients develop ABPA.

What provokes / Causes of Aspergillosis:

Most often causes pathology A. fumigatus, less often - A. flavus, A. niger, A. terreus, A. nidulans, A. clavatus. These species may be resistant to amphotericin B (especially A. terreus, A. nidulans) but susceptible to voriconazole. A. clavatus and A. niger can cause allergic conditions, A. flavus is a common human pathogen. A. niger often causes otomycosis and, along with A. terreus, colonizes open cavities of the human body.

Patients with ABPA are atopic and have a genetically determined T-cell response.

Pathogenesis (what happens?) during Aspergillosis:

Infection occurs in individuals at risk by inhalation of conidia, as well as when they enter the wound surface and with food. Under favorable conditions, bronchial mucosa is colonized by Aspergilla with possible development their massive vegetation and invasion into the bronchi and lung tissue, often with vascular germination, the formation of inflammatory changes and granulomas, which leads to the development of necrotizing inflammation, bleeding, pneumothorax. With the invasion of mold fungi in the tissues of the body, microscopically distinguish different types tissue reactions, namely, serous-desquamative, fibrinous-purulent, as well as various types of productive reactions, up to the formation of tuberculoid granulomas.

The most common premorbid background for the development of aspergillosis are:
- the use of systemic corticosteroid drugs at a dose of more than 5 mg per day (for collagenoses, including ankylosing spondylitis, rheumatoid arthritis, Raynaud's syndrome), which leads to macrophage dysfunction and inhibition of T-lymphocytes;
- cytostatic chemotherapy, leading to neutropenia in the blood (less than 0.5x109) (with oncohematological diseases, organ transplantation);
- prolonged agranulocytosis in leukemia, aplastic anemia, chronic granulomatosis, etc.;
- dysfunction of granulocytes (chronic granulomatous disease, Chediak-Higashi syndrome, etc.);
- diabetes;
- a decrease in the clearance of fungal spores in lung diseases: chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis and lung cysts, disorders of pulmonary architectonics (cystic hypoplasia of the lung, pulmonary fibrosis), tuberculosis, sarcoidosis, granulomatous lung diseases, conditions after lung resection, etc .;
- chronic peritoneal dialysis (with the development of peritonitis and subsequent dissemination to other organs);
- burn wounds, surgical interventions, injuries;
- placement of venous catheters (with possible local skin contamination), self-adhesive dressings in the area of ​​catheter placement;
- alcoholism with impaired liver function;
- cachexia and severe chronic diseases;
- malignant neoplasms;
- intensive and prolonged antibiotic therapy;
- HIV infection and AIDS;
is a combination of these factors.

Summarizing all the conditions in which Aspergillus is determined and / or plays the role, it is possible to single out carriage / colonization, invasion and an allergic state, while mycosensitization and allergy can acquire a dominant independent character. For patients with defects in the immune system, Aspergillus carriage/colonization is very dangerous and can easily turn into invasion and dissemination.

The risk group for developing mycogenic allergies includes people with bronchial asthma, chronic bronchitis, especially among people associated with mushrooms by genus professional activity(poultry farmers, livestock breeders, workers of microbiological enterprises, workers of pharmacies, libraries, mushroom pickers, etc.).

Symptoms of Aspergillosis:

Aspergillosis is varied clinical manifestations, which is determined by the immune status of the patient. In immunocompetent individuals, aspergillosis can be asymptomatic - in the form of carriage, colonization, aspergilloma. With the deepening of immune disorders, it can transform into an invasive form, which, depending on the degree of immunity defects, has a chronic, subacute or acute course, and the more pronounced the immunological deficiency, the more acute the course of the disease.

For acute invasive sinus aspergillosis(in immunocompromised) penetration of the pathogen into the mucous membrane with the formation of areas of necrosis is characteristic. Non-invasive aspergillosis paranasal sinuses is a relatively rare disease in immunocompetent individuals. It usually manifests itself in one sinus as a spherical fungal formation (aspergilloma), and in this form it can remain for months or years. Chronic subclinical invasive aspergillosis of the nasal sinuses occurs less frequently, develops in immunocompetent individuals in the sinuses, lasts for years and represents a chronic fibrosing granulomatous inflammation with a slow spread to the orbits, skull bones, brain. Its causative agent is usually A. flavus (in contrast to A. fumigatus, the most common causative agent of aspergillosis in immunocompromised individuals). This form of aspergillosis is usually associated with a high content of A. flavus conidia in the environment, especially in countries with a hot dry climate in tropical and desert regions.

In young immunocompetent individuals with nasal congestion and prolonged episodes of allergic rhinitis, asthma, headaches, nasal polyps, allergic fungal sinusitis is not excluded. In advanced cases, erosive damage to the ethmoid bones of the skull is possible.

Aspergilloma of the lungs often considered as benign saprophytic colonization and develops in individuals with an unfavorable premorbid background and impaired lung functions (pulmonary fibrosis, cysts, cavities in sarcoidosis, tuberculosis, emphysema, hypoplasia, histoplasmosis). Pulmonary aspergilloma is defined as a mobile conglomerate of intertwined Aspergillus hyphae located in the lung cavity or bronchiectasis, covered with fibrin, mucus and cellular elements (according to the degree of darkening it corresponds to a liquid), located inside an oval or spherical capsule, separated from it by an air layer, with a thickening of the pleura. With the beginning invasion of micromycetes into the lung tissue, hemoptysis can be observed - a characteristic symptom of aspergilloma, which occurs due to vascular damage due to the action of endotoxins and proteolytic enzymes, the development of thrombosis and mycelium germination in the vascular walls, as well as the formation of necrosis areas. Hemoptysis can cause asphyxia, bleeding, leading to death in approximately 26% of patients with aspergilloma. It can lead to the formation of invasive and chronic necrotizing aspergillosis against the background of a fungal-bacterial mixt infection.

On a radiograph of the lungs, pulmonary aspergilloma looks like a round formation, sometimes mobile, located inside a spherical or oval capsule and separated from the wall of this capsule by an air gap various shapes and size. Aspergilloma corresponds to liquid in intensity of darkening at X-ray. With its peripheral location, a thickening of the pleura is characteristic. An additional diagnostic criterion for establishing the diagnosis is the setting of the precipitation reaction, which in aspergilloma has a sensitivity of 95% (except for patients receiving corticosteroids).

Pulmonary aspergillosis has no pathognomonic features. The diagnosis is difficult to establish.

Chronic necrotizing pulmonary aspergillosis(CNPA) is a chronic or subacute infection most often diagnosed in immunocompetent patients with impaired local protection in the presence of risk factors that change the overall immune status. According to clinical manifestations, CNPA is a borderline form between invasive pulmonary aspergillosis, manifested by pneumonia, and aspergilloma.

A hypothetical mechanism for the formation of CNLA: in patients with moderately severe immunosuppression, after inhalation of spores and their penetration into small bronchi, local damage to the bronchial wall by micromycetes occurs, followed by invasion of micromycetes into the lung parenchyma, which is accompanied by tissue necrosis, thrombosis, phlebitis, arteritis, and an inflammatory reaction. In this case, necrotic tissue and fungal elements are sequestered into the newly formed cavity. Molds also have the ability to grow through tissues and, in the absence of adequate treatment, they penetrate through the walls into the cavity of other alveoli and vessels.

The following clinical forms of CNLA:
- Local invasive lesions of the bronchi, possibly with bronchiectasis and necrotizing granulomatous bronchitis, with greenish-brown or gray mushy or dense sputum, possibly with formations that obstruct the bronchus, which are a fungal conglomerate fixed to the wall of the bronchus, similar in composition to aspergilloma, which can lead to the formation of atelectasis. This form includes aspergillosis of the bronchus stump after a pulmonectomy due to malignant neoplasms in the lungs, which can occur several years after the operation. It is possible that any case of HNLA begins with local damage bronchial wall and either remains a local process, or progresses, turning into pneumonia.
- Chronic disseminated (“miliary”) aspergillosis with clearly defined foci of necrotic Aspergillus invasive process, associated with massive inhalation of Aspergillus spores.
- Chronic destructive pneumonia, in which progressive, of various localization and size are determined, often - upper lobe pulmonary infiltrates with cavities, combined with thinning of the pleura. This form of aspergillosis was previously called "pseudotuberculosis" because of its clinical similarity to tuberculosis. In the presence of this form, concomitant histoplasmosis, chronic granulomatous disease, HIV infection should always be excluded.

Such patients may experience cough with sputum, fever, chest pain, weight loss, hemoptysis (in 10% of patients). However, there is usually no severe intoxication and fever (unlike acute invasive bronchial lesions, for example, in patients with neutropenia), due to a less pronounced degree of immunosuppression. Pneumonia in CNPA does not have the rate of development that is observed in acute invasive aspergillosis, and, at the same time, does not always have a clear picture of aspergilloma. When radiography is determined not changing in time or progressive cavity infiltrates with mycetoma inside or without it, combined with thinning of the pleura, as well as focal dissemination.

CNPA is the rarest and most difficult to diagnose form of aspergillosis.

Acute invasive aspergillosis described in immunocompromised patients, is severe, characterized by the following features:
- persistent fever or its return during therapy with broad-spectrum antibiotics;
- the appearance of new or progression of old infiltrates in the lung tissue against the background of antibiotic therapy;
- pronounced "pleural" pain in the chest;
- clinical signs of pneumonia - "unproductive cough", sputum streaked with blood, there may be pulmonary bleeding, pain in the chest when breathing, wheezing, pleural rub are possible during auscultation;
- signs of sinusitis with destruction of bone tissue, determined by X-ray or computer studies; periorbital pain and swelling, epistaxis;
- maculopapular lesions on the skin with necrosis;
- detection of fungal mycelium during cytological or histological studies;
- isolation of aspergillus culture during cultures from the nasal cavity, sputum, bronchoalveolar fluid, blood and other substrates.

Acute pulmonary aspergillosis can present as:
- hemorrhagic infarction;
- progressive necrotizing pneumonia;
- endobronchial infection.

X-ray of the lungs reveals subpleurally located focal rounded shadows or triangular shadows, the base connected to the pleura; with the progression of the disease, the appearance of cavities is characteristic. Computed tomography of the lungs determines the presence of round-shaped foci surrounded by a corolla (“halo”, a symptom of a halo or corolla - “halo sign”) of less density, which, in fact, is swelling or hemorrhage around the ischemic focus and is observed more often in the first 10 days. The so-called "crescent symptom" or "sickle" ("air crescent sign") is visible later and reflects the formation of necrosis due to the migration of neutrophils to the lesions and the development of an inflammatory reaction. However, similar signs are found in other pathologies.

Immunocompromised patients may develop localized aspergillosis of the larynx, trachea, and bronchi.

Aspergillus tracheobronchitis are a rarer manifestation of acute invasive aspergillosis. Can be observed sequentially: nonspecific reddening of the mucosa, first with mucous plugs, then fibrinous endobronchitis, diffuse hemorrhagic changes in the mucosa, sometimes pseudomembranous tumor-like formations that may contain granulation tissue and hyphae and cause obstruction of the upper respiratory tract. Sometimes there is a profuse secretion. Colonization and damage to the bronchi is the first stage in the development of acute pulmonary aspergillosis. Clinically, fever, shortness of breath, cough, dry wheezing, weakness, fatigue, often weight loss, varying degrees of airway obstruction can be observed.

Allergic bronchopulmonary aspergillosis (ABPA). The following classic ABLA criteria are known:
- the presence of a diagnosis of bronchial asthma / cystic fibrosis;
- persistent and transient infiltrates in the lungs;
- positive skin tests with A. fumigatus antigen;
- eosinophilia of peripheral blood (more than 500 in mm3);
- determination of precipitating antibodies and specific IgG and IgE to A. fumigatus;
- high level of total immunoglobulin E (more than 1000 ng/ml);
- isolation of A. fumigatus culture from sputum or bronchial washings;
- the presence of central bronchiectasis.

A decrease in lung capacity is observed in 60% of patients with ABPA, peripheral blood eosinophilia in 80%, central or proximal saccular bronchiectasis, especially in the upper lobes, in 80% of patients. It has been shown that bronchiectasis can occur due to the release of proteolytic enzymes by micromycetes and eosinophils. In the bronchiectasis cavities, in turn, colonies of fungi can develop, which become a constant source of antigens.

Pulmonary infiltrates are recorded in approximately 85% of patients. So, a typical radiological sign of ABPA is non-permanent one- or two-sided areas of compaction in the lungs, mainly in the upper sections, which is due to obstruction of the bronchi by mucous plugs. The mucus-filled bronchus shows a darkening in the form of a ribbon or a finger of a glove on the radiograph. Such shadows are characteristic of the disease. They can change after coughing up the mucous plug. X-rays may show ring-shaped or parallel shadows ("tram rails"), which are inflamed bronchi. But often there is no change. As ABPA progresses, pulmonary fibrosis (“honeycombing”) develops.

The diagnosis of ABPA should be considered in all patients with hormone-dependent bronchial asthma, cystic fibrosis, with a combination of bronchial asthma with the above radiological signs.

P.A. Greenberger et al. (1986) singled out 5 stages of ABPA.
Stage I - acute (infiltrates in the lungs, high levels of total IgE, blood eosinophilia);
Stage II - remission (there are no infiltrates in the lungs, the level of IgE is slightly lower, there may be no eosinophilia);
Stage III - exacerbation (indicators correspond to the acute stage);
Stage IV - corticosteroid-dependent bronchial asthma;
Stage V - fibrosis ("honeycomb lungs").

The trigger mechanism for the formation of ABPA is probably an acute respiratory infection (ARI, influenza, pneumonia, acute bronchitis), manifested by an increase in body temperature, discharge of a kind of brown, gray or white sputum with mucoid plugs, which was noted in the anamnesis in all patients with ABPA, as well as inhalation of fungal spores Aspergillus spp. in critical quantity.

A variety of ABPA can be classic forms of allergic alveolitis: "farmer's lung", "cheese washer's lung", "malt worker's lung" in brewing, lumberjacks, etc.

Diagnosis of Aspergillosis:

When detecting aspergillus in the sputum of immunocompetent individuals, find out:
- the presence of occupational hazard in history;
- the nature of production and living conditions;
- the presence of symptoms of diabetes;
- condition of the nasopharynx;
- prescription and frequency of antibiotic treatment for other diseases;
- the presence of chronic nonspecific lung diseases, the duration of exacerbation, the presence and nature of anti-inflammatory basic therapy.

When aspergillus is detected in the sputum of immunocompromised individuals, find out:
- the amount and nature of previous antibiotic therapy, corticosteroid and chemotherapeutic agents;
- the level of CD4+ lymphocytes in the blood, the number of neutrophilic granulocytes in the blood;
- the presence of fungal lesions of other organs (ENT pathology, central nervous system, etc.).

Re-isolation of Aspergillus cultures from sputum/ALS in immunocompetent individuals more often reflects the presence of colonization of the respiratory tract. In cases of unclear infiltrates in the lungs in immunocompromised patients in the absence of the effect of antibiotic therapy, the allocation of Aspergillus in the sputum should be considered as an etiological moment and require specific therapy. If there is no dynamics within 7 days of intensive antifungal therapy, then the diagnosis can be considered unconfirmed.

Re-detection of antigenemia (galactomannan) and detection of radiological "corolla sign" in patients at risk is considered equivalent to a biopsy with detection of mycelium, regardless of the isolation or not isolation of a pure culture of Aspergillus.

Laboratory research
Mandatory
- Microscopy (sputum / ALS, biopsy, etc.) for the presence of aspergillus:
- microscopy of unstained preparations by hanging or crushed drop method.
- microscopy of stained preparations (hematoxylin-eosin, Gomorry-Grocott impregnation, white calcofluor, etc.).
- Cultural diagnostics with repeated studies of the material (to exclude false positive results):
- inoculation of the material on the Sabouraud, Chapek-Dox medium (aspergillus is rarely found in the blood, bone marrow and cerebrospinal fluid) - in immunocompromised individuals, the detection of aspergillus culture most likely indicates invasive aspergillosis.
- Serological diagnosis:
- with determination of A. fumigatus galactomannan antigen in blood serum, cerebrospinal fluid, urine, etc.:
using the radioimmunoassay method (RIA-Radioimmunoassay);
ELISA method (Enzyme-Linked Immunosorbent Assay) (true positive results for the determination of galactomannan are more likely with a high titer in adult patients, and false positive results in children).
- Determination of specific antibodies in blood serum:
IgG (in the diagnosis of chronic necrotizing aspergillosis, aspergilloma);
IgG, IgE (diagnosis of ABPA).
- Method of polymerase chain reaction (PCR) - to determine fragments of Aspergillus nucleic acids or their metabolic products, for example, glycan and mannitol (up to 25% of false positive results are possible) (additional diagnostics).

If there are indications
- In order to establish a diagnosis: histological examination of biopsy material with hematoxylin-eosin staining, Gomory-Grocott impregnation, white calcofluor, Gribli, McManus, etc.
- Diagnosis of the intensity of exogenous intake of micromycetes: detection of secretory IgA to fungal antigens and mycotoxins in saliva.

Instrumental and other diagnostic methods
Mandatory
- X-ray examination and computed radiography of the chest to determine the presence of lung damage.
- Bronchoscopy with obtaining bronchoalveolar lavage for microscopic and cultural studies.

If there are indications
- To obtain material for the purpose of cultural and histological diagnosis - biopsy of lesions.

Expert advice
Mandatory
- Otolaryngologist - to exclude fungal infections of the ENT organs.

Treatment for Aspergillosis:

Pharmacotherapy
Due to the low effectiveness of the treatment of invasive aspergillosis, averaging 35% (with amphotericin B), in immunocompromised patients with suspected aspergillosis, even before laboratory evidence is obtained, it often becomes necessary to conduct empirical antifungal therapy. Anti-Aspergillosis treatment should be carried out simultaneously with the normalization of the patient's immune status (with the elimination of neutropenia, CD4+ lymphocytopenia), as well as the treatment of hemoptysis.

The dosage of antifungal drugs and the duration of treatment are determined individually.

For invasive aspergillosis, the drugs of choice are Voriconazole (J02AC03) (initially 6 mg/kg, then 4 mg/kg twice daily, and later 200 mg twice daily orally) and Amphotericin B (J02AA01) (1 .0-1.5 mg/kg/day) or its forms - (J02AA01) (3-5 mg/kg/day), (J02AA01) (0.25-1.0-1.5 mg/kg/day ) and etc.

Second-line drugs include Itraconazole (J02AC02) (dosage when taken per os - 400-600 mg / day for 4 days, then - 200 mg twice a day; intravenously - 200 mg twice a day, then - 200 mg). Its use is preferred in patients with less immunosuppression. Caspofungin (J02AX04) is also used, first at 70 mg once a day, then at 50 mg per day intravenously. It is effective in the absence of the effect of other antifungal agents.

For brain damage, these drugs are used in combination with flucytosine (J02AX01) (150 mg/kg per day), which penetrates into the cerebrospinal fluid.

After stabilization to stable relief of clinical, laboratory and instrumental signs (usually at least 3 months), Itraconazole (J02AC02) 400-600 mg / kg / day is indicated.

Fluconazole (J02AC01) is not active against Aspergillus spp.

Short courses of oral corticosteroids in the treatment of ABPA (prednisone 0.5-1 mg/kg/day) relieve bronchial mucus obstruction in patients with ABPA. Corticosteroid consumption and exacerbations in patients with ABPA may be reduced by prophylactic treatment with itraconazole (200 mg twice daily). Itraconazole may also be used in the treatment of exacerbations of ABPA.

Surgical procedures
Mandatory
Patients with bleeding in the presence of aspergilloma need a lobectomy. When lung function is low, a bronchial artery is ligated or embolized (used as a temporary measure). Systemic therapy is ineffective in endobronchial and cavitary aspergillosis. Surgical excision of the focus or curettage of the affected areas is performed. Surgical intervention is also indicated for a centrally located focus of invasive aspergillosis near the mediastinum, when massive bleeding is possible.

In the treatment of aspergilloma, surgical intervention can be carried out under the protection of intravenous use of amphotericin B or their introduction into the cavity (in the amount of 10-20 mg of amphotericin B in 10-20 ml of distilled water). Serious postoperative complications (life-threatening pulmonary bleeding) are not uncommon. Therefore, the decision on surgical intervention is very difficult: resection of aspergilloma is possible only in patients with massive pulmonary hemoptysis and adequate lung function. There is limited evidence that itraconazole is effective in the treatment of aspergilloma.

Efficiency criteria and duration of treatment
The duration of treatment for aspergillosis is not strictly limited, since the effect of therapy, expressed in the elimination of fever and positive clinical and radiological dynamics, depends on the state of the immune system, background diseases, and the presence of mixt infection (bacterial-fungal). The duration of treatment is individual and ranges from 7 days to 12 months.

Prevention of Aspergillosis:

Primary prevention
for patients with severe immunodeficiency - carrying out measures aimed at preventing the entry of aspergillus conidia into the air, which is achieved by using expensive rooms or chambers with laminar air flows, or by installing various gateways between rooms and air filters.

Since favorable conditions are created in the soil for the development of mold fungi, patients with reduced immunity should not be placed in the wards of patients with reduced immunity. houseplants. At the first manifestations of the disease, the patient should be isolated, indoor flowers should be removed, air ducts, air conditioners and damp surfaces should be checked. If aspergillus is detected, surfaces should be treated with disinfectants.

Prevention of relapses
. For immunocompromised persons - prohibition of earthwork, agricultural work, contact with animals, restriction of stay in dusty and humid places, prohibition of consumption of stale and moldy foods, cheeses, etc.

Which doctors should you contact if you have Aspergillosis:

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The structure of aspergillus is similar to the structure of the fungus penicillium. A vegetative body is distinguished in the form of a branched mycelium penetrating the substrate. Conidiophores, consisting of one cell, less often with septa, depart from the supporting cells of the mycelium. On the upper part of the conidiophores are single-celled conidia in the form of chains. Mold plaque has the same color as the accumulation of mature conidia on the mycelium. After maturation, the conidia break off from the mycelium, are transferred to another place and, under favorable conditions, germinate, giving rise to a new organism of the fungus. This is the asexual reproduction of Aspergillus. Some species reproduce sexually, such as Aspergillus fumigatus.

Aspergillus are active destructive agents of various materials, causative agents of serious diseases and a provoking factor toxic lesions animal and human organisms. These are their negative qualities. But also mushrooms of this genus are capable of producing various enzymes and other substances in the course of their life activity, which are successfully used in various industries. So, aspergillus niger - a biochemically active fungus - produces many enzymes. In particular, the tanase enzyme is used to form gallic acid, which is used in the production of paints, inks, some medical preparations. By means of pectolytic enzymes of Aspergillus black, clarification of wines and juices is carried out, splitting into individual fibers of plant stems. Aspergillus enzymes make it possible to obtain crystalline glucose from starch, fructose from inulin, fumaric, oxalic, citric acid. With the help of some strains of aspergillus black, vitamins are synthesized - biotin, B1, B2, the antibacterial drug fumagillin for the treatment of amoebic dysentery, and other drugs. Species A. Orizae, A. Flavus in Eastern countries used to make soy sauce, in Japan - rice vodka (sake). Beneficial features Aspergillus fungi are extremely diverse.