Symptoms of Aspergillosis and Pathogenesis during Aspergillosis

What is Aspergillosis?

Aspergillosis is 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 rearrangement or a destructive infection process, under certain conditions, beyond the scope of this system with the development of dissemination and specific damage to other organs.

Aspergillosis is the first most common pulmonary mycosis. Aspergillus are ubiquitous. They are isolated from soil, air, and even sulfur sources and distilled water.

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

Regions with high aspergillus spores in the environment are Sudan and Saudi Arabia. Higher concentrations of aspergillus spores are usually detected in residential air than outdoors. Patients with diabetes are affected by aspergillus, regardless of region. The disease is non-contagious and is not transmitted from person to person.

The most vulnerable area of ​​infection with aspergillosis pathogens is the respiratory tract, and the lungs and paranasal sinuses are the main lesion sites. 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 fatally. In resuscitation departments of surgical clinics, in patients with AIDS, when using corticosteroid drugs for patients with chronic lung diseases, it occurs in 4% of patients.

Among invasive aspergillosis infections, lung aspergillosis should be put first (90% of lesions) – a serious disease with primary damage to the lungs and, often, sinuses (in 5-10% of patients), larynx, trachea and bronchi, with possible dissemination to the skin and internal organs. The central nervous system spreads in the form of single / multiple abscesses of the brain, meningitis, epidural abscess or subarachnoid hemorrhage; myocarditis, pericarditis, endocarditis, osteomyelitis and diskitis, peritonitis, esophagitis are also noted; primary aspergillosis granulomatosis of 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 (ABA) is a condition in which a state of pulmonary hypersensitivity develops, induced primarily by A. fumigatus, or a chronic inflammatory disease of the lungs in immunocompetent individuals due to a combined allergic reaction of types I, III, and IV in response to a continuous exposure of Aspergillus antigens (endogenous or exogenous). In the United States, ABA is observed in 7-14% of patients with bronchial asthma who are constantly receiving treatment with corticosteroids. Many patients with cystic fibrosis have airway colonization with aspergillus, and about 7% of these patients develop ABA.

Causes of Aspergillosis

Most often causes pathology of 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 sensitive to voriconazole. A. clavatus and A. niger can be the cause of allergic conditions, and A. flavus is a common pathogen in humans. A. niger often acts as the cause of otomycosis and, along with A. terreus, colonizes the open cavities of the human body.

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

Pathogenesis during Aspergillosis

Infection occurs in people at risk from inhalation of conidia, as well as when they enter the wound surface and with food. In the presence of favorable conditions, Aspergilla bronchial mucosa is colonized with the possible development of their massive vegetation and invasion into the bronchi and lung tissue, often with vascular sprouting, the formation of inflammatory changes and granulomas, which leads to the development of necrotizing inflammation, bleeding, pneumothorax. With the invasion of molds in the body tissue, different types of tissue reactions are microscopically distinguished, 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 in 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 0.5×109) (for hematologic diseases, organ transplantation);
– prolonged agranulocytosis with leukemia, aplastic anemia, chronic granulomatosis, etc .;
– granulocyte dysfunction (chronic granulomatous disease, Chediak-Higashi syndrome, etc.);
– diabetes;
– reduction in clearance of fungal spores in lung diseases: chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis and lung cysts, impaired 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;
– staging of venous catheters (with possible local contamination of the skin), self-adhesive dressings in the staging area of ​​catheters;
– alcoholism with impaired liver function;
– cachexia and severe chronic diseases;
– malignant neoplasms;
– intensive and prolonged antibiotic therapy;
– HIV infection and AIDS;
– a combination of these factors.

Summarizing all the conditions in which aspergillas are determined and / or play a role, carriage / colonization, invasion and an allergic state can be distinguished, 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 go into invasion and dissemination.

The risk group for the development of mycogenic allergies includes people with bronchial asthma, chronic bronchitis, especially among people associated with mushrooms by occupation (poultry farmers, livestock breeders, workers in microbiological enterprises, pharmacy workers, libraries, mushroom pickers, etc.).

Symptoms of Aspergillosis

Aspergillosis is diverse in 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.

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

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

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

On a chest x-ray of the lungs, the 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 of various shapes and sizes. According to the intensity of the darkening during radiography, aspergilloma corresponds to a liquid. With its peripheral location, thickening of the pleura is characteristic. An additional diagnostic criterion for establishing a diagnosis is the formulation of a precipitation reaction, which with aspergilloma is 95% sensitive (except for patients receiving corticosteroid drugs).

Aspergillosis of the lungs has no pathognomonic features. The diagnosis is difficult to establish.

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

Presumptive mechanism of KNLA formation: in patients with moderate immunosuppression after inhalation of spores and their penetration into the small bronchi, local damage to the bronchial wall with micromycetes occurs, followed by invasion of micromycetes into the pulmonary parenchyma, which is accompanied by tissue necrosis, thrombosis, phlebitis, arteritis, and an inflammatory reaction. At the same time, necrotic tissue and fungal elements are sequestered in the newly formed cavity. Mold fungi also have the ability of through growth through tissues and, in the absence of adequate treatment, they penetrate through the walls into the cavity of other alveoli and blood vessels.

The following clinical forms of KNLA are described:

Local invasive lesions of the bronchi, possibly with bronchiectasis and with necrotic granulomatous bronchitis, with mushy or dense sputum of greenish-brown or gray color, possibly with formations that obstruct the bronchus, which is a fungal conglomerate fixed to the bronchial wall, similar in composition to aspergillus , which can lead to the formation of atelectasis. This form includes aspergillosis of the bronchus stump after undergoing pulmonectomy for malignant neoplasms in the lungs, which can occur several years after surgery. Perhaps any case of KNLA begins with local damage to the bronchial wall and either remains a local process or progresses, passing 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 ones of various localization and size are determined, often upper lobar 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 such a form, concomitant histoplasmosis, chronic granulomatous disease, and HIV infection should always be excluded.

Such patients may experience cough with sputum, fever, chest pain, weight loss, hemoptysis (in 10% of patients). However, pronounced intoxication and fever are usually not observed (in contrast to acute invasive lesions of the bronchi, for example, in patients with neutropenia), which is due to a less pronounced degree of immunosuppression. Pneumonia with KNLA does not have the rate of development that is observed with acute invasive aspergillosis, and, at the same time, does not always have a clear picture of aspergilloma. When x-rays are determined do not change in time or progressive cavity infiltrates with mycetoma inside or without it, combined with thinning of the pleura, as well as focal dissemination.

KNLA is the most rare and difficult to diagnose form of aspergillosis.

Acute invasive aspergillosis is described in immunocompromised patients, is severe, characterized by the following symptoms [Ruhnken M., 1999]:

– persistent fever or its return on the background of broad-spectrum antibiotic therapy;
– the appearance of new or the progression of old infiltrates in the lung tissue against the background of antibiotic therapy;
– expressed “pleural” pain in the chest;
– clinical signs of pneumonia – “unproductive cough”, sputum with streaks of blood, there may be pulmonary hemorrhage, chest pain when breathing, wheezing, pleural friction noise are possible with 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 mycelium of fungi in cytological or histological studies;
– isolation of aspergillus culture during inoculation from the nasal cavity, sputum, bronchoalveolar fluid, blood and other substrates.

Acute pulmonary aspergillosis can occur in the form of:

– hemorrhagic heart attack;
– progressive necrotizing pneumonia;
– endobronchial infection.

Radiography of the lungs reveals subpleurally located focal rounded shadows or triangular shadows, the base connected with the pleura; with the progression of the disease, the appearance of cavities is characteristic. Computed tomography of the lungs determines the presence of foci of a rounded shape surrounded by a corolla (“halo”, symptom of a halo or corolla – “halo sign”) of lower density, which, in essence, is edema or hemorrhage around the ischemic focus and is noted 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 migration to the foci of neutrophil lesions and the development of an inflammatory reaction. However, similar signs are found in other pathologies.

In immunocompromised patients, the development of localized aspergillosis of the larynx, trachea and bronchi is possible.

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

Allergic bronchopulmonary aspergillosis (ABA). The following classic ABA criteria are known:

– the presence of a diagnosis of bronchial asthma / cystic fibrosis;
– persistent and transient lung infiltrates;
– 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 against A. fumigatus;
– a high level of total immunoglobulin E (more than 1000 ng / ml);
– isolation of A. fumigatus culture from sputum or bronchial lavage;
– the presence of central bronchiectasis.

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

Pulmonary infiltrates are recorded in approximately 85% of patients. So, a typical radiological sign of ABA is unstable one- or two-sided areas of compaction in the lungs, mainly in the upper sections, due to obstruction of the bronchi with mucous plugs. The bronchus filled with mucus on the x-ray gives a blackout in the form of a tape or finger of a glove. Such shadows are characteristic of the disease. They can change after coughing up the mucous plug. On the pictures can be observed ring-shaped or parallel shadows (“tram rails”), which are inflamed bronchi. But often no change is observed. With the progression of ABA, pulmonary fibrosis develops (“cell lungs”).

The diagnosis of ABA should be assumed 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) identified 5 stages of the course of ABA.
Stage I – acute (infiltrates in the lungs, high levels of total IgE, blood eosinophilia);
II stage – remission (there are no infiltrates in the lungs, the level of IgE is slightly lower, eosinophilia may not be);
Stage III – exacerbation (indicators correspond to the acute stage);
Stage IV – corticosteroid-dependent bronchial asthma;
Stage V – fibrosis (“cell lungs”).

The trigger mechanism for the formation of ABA is probably an acute respiratory infection (acute respiratory infections, influenza, pneumonia, acute bronchitis), manifested by an increase in body temperature, the discharge of a kind of brown, gray or white sputum with mucoid plugs, which is noted in the history of all patients with ABA, as well as Inhalation of Aspergillus spp. in critical quantities.

A variation of ABA can be the classic forms of allergic alveolitis: “farmer’s lung”, “cheese washer’s lung”, “lungs of a worker engaged in obtaining malt” in brewing, lumberjacks, etc.