What is Pneumocystosis (Pneumocystis Pneumonia)?
Pneumocystosis is a protozoal disease caused by Pneumocystis carinii, which is one of the most common causes of pneumonia in people with weakened immune systems.
Causes of Pneumocystosis (Pneumocystis Pneumonia)
The causative agent of pneumocystosis is Pneumocystis carina (Delanoe M., Delanoe P., 1912) – a unicellular microorganism. According to morphological characteristics and sensitivity to antiprotozoal drugs, they have long been classified as protozoa. Gradually, pneumocysts began to reveal features characteristic of fungi. Attempts to attribute them to mushrooms or protozoa encountered a vague systematic criteria. In some respects, they are close to Protozoa: in morphology, the presence of meiosis, the presence of cholesterol in the cell membrane (rather than ergosterol, as in fungi, which makes them sensitive to antiparasitic drugs and insensitive to the antifungal agent amphotericin B), and the impossibility of their cultivation on nutrient environments for mushrooms. The fact that pneumocysts contain structures similar to ascospores in fungi, as well as phytosterols, which animal cells lack, is similar to mushrooms.
Metabolism in P. carinii (synthesis of aromatic amino acids, thymidine, etc.) occurs, as in fungi; in addition, pneumocysts lack sporogonia characteristic of protozoa. In 1988, Edman and Stringer, using molecular genetics methods, showed that the pneumocyst c-nucleotide sequence in t-RNA has a high degree of homology with the yeast-related t-RNA nucleotide sequence (Saccharomycetes serevisiae). For comparison, similar sequences were also studied in different species of protozoa: toxoplasma, plasmodium, acantameb, etc. By genetic characteristics, pneumocysts were closest to fungi. But these are mushrooms that have a number of features that bring them closer to the simplest. Thus, P. carinii m-DNA contains dehydrogenase and cytochrome oxidase genes, which are 60% similar to fungal genes and only 20% to protozoan genes. Similar properties were found in other species of fungi.
According to the latest data, pneumocysts are classified as fungi, possibly actinomycetes or higher fungi – asko- or basidomycetes. At the same time, some researchers consider P. carinii to be a phylogenetically ancient causative agent of an uncertain systematic position, which during evolution lost characteristic taxonomic features (T.V. Beyer, 1989). Modern molecular biological and molecular genetic analysis cannot definitively determine their species affiliation. To solve this problem, an ultrastructural study of the pathogen, a study of its phylogenesis and improvement of the pneumocyst cultivation technique are necessary.
P. carinii is an extracellular parasite tropic to the lung tissue. In the development cycle, pneumocysts secrete a vegetative form (trophozoite), a cyst and a cyst with intracystic bodies.
Trophozoites – cells with a size of 1-8 microns, coated with a thin membrane. Their form is diverse and mobile (oval, amoeba-like, etc.). It depends on the shape of the structures to which they are adjacent. Microgrowths and long processes in the form of filopodia depart from the surface of the trophozoite. At their expense, pneumocysts are interconnected and attached to the host cells. The core is limited to two membranes. Mitochondria, free ribosomes, small and large vacuoles, polysaccharides, lipid drops are detected in the cytoplasm. Sometimes there are dual cells, which may indicate division or copulation. According to electron microscopic studies, trophozoites adhere closely to the first order alveolocytes. Filopodia can penetrate into the cell of the lung of the host, without breaking its shell. At the same time, the membrane of the alveolocyte can enter the body of the trophozoite without damaging it. The physiological contact of the pathogen with the host is through a system of micropinocytic vesicles.
Precysts are oval cells with a diameter of 2-5 microns, devoid of pellicular outgrowths. The fission of nuclei occurs in them. Cysts of P. carinii are round or oval in size from 3.5 to 10 microns, sometimes up to 30 microns (Fig. 20). They are covered with a dense three-layer shell and an outer membrane. The cytoplasm contains from 1 to 8 intracystic bodies, which enter the lumen of the alveoli after rupture of the cyst membrane. Empty cysts have an irregular shape, often in the form of a crescent, sometimes intracystic bodies are detected in them. The size of the latter is 1-2 microns. The pellicle of intracystic bodies is formed again after exiting the destroyed cyst. They become extracellular trophozoites and begin a new round of the life cycle.
Among AIDS patients, pneumocystosis is one of the most common opportunistic infections (over 80%) and, if untreated, almost always leads to death. In other patients with a weakened immune system, a pneumocyst is excreted in 40% of cases. According to animal experiments, the incubation period lasts from 4 to 8 weeks.
Pathogenesis during Pneumocystosis (Pneumocystis Pneumonia)
The pathogenesis of pneumocystosis is determined by the biological properties of the pathogen and the state of the host’s immune system. Propagative forms of pneumocysts that have not yet been described, bypass the upper respiratory tract, reach the alveoli and begin the life cycle in the body of the new host. The attachment of trophozoites to first-order alveolocytes is mediated by many mechanisms, in particular, a large number of surface glycoproteins in P. carinii, which interact with lung tissue proteins through mannose receptors on host cells, especially macrophages. Superficial pneumocystis glycoproteins are highly immunogenic. Attachment of a pneumocyst is accompanied by proliferation of the pathogen, its interaction with a surfactant, and the release of toxic metabolites. The host organism is protected from P. carinii by T-lymphocytes, alveolar macrophages, specific AT. The interaction of micro and macro organisms remains at a subclinical level until the immune system is compromised. The compromise of the immune system stimulates the growth of the number of pneumocysts.
In a healthy person, P. carinii reproduce slowly, however, the disease sharply activates when the immune response is suppressed and during the incubation period the number of pneumocysts in the lungs increases from 10,000 to more than 1,000,000,000 cells. They gradually fill the alveolar space. This leads to the appearance of foamy, “honeycomb” exudate, damage to the membrane of the alveolar leukocytes, an increase in their permeability, and destruction of the first order alveolocytes. The tight fit of the pneumocyst to the alveolocytes leads to a reduction in the respiratory surface of the lungs. Mechanical damage to the interstitial tissue of the lung by the pathogen and inflammatory cells, infiltration of the alveolar wall by mononuclear cells, and interstitial cells by plasma cells lead to a 5-20 times thickening of the alveolar wall, as a result of which the alveolar-capillary block develops.
With AIDS, the number of parasites in the alveoli and bronchi is so large that alveolar ventilation is disrupted, and the patient dies from increasing pulmonary insufficiency. The destruction of the alveolar-capillary membrane can lead to dissemination of pneumocysts from the main location.
On histological sections of the lungs affected by pneumocysts, a picture appears that is characteristic only of pneumocystosis. Expanded bronchioles, alveoli and small bronchi are filled with eosinophilic foam mass. The alveolar epithelium in contact with the pathogen is hypertrophied, the walls of the alveoli are thickened due to the expansion of capillaries and infiltration of lymphoid-histiocytic elements. Abundant accumulations of plasmocytes are observed around the vessels. On the walls of the bronchi and alveoli, individual round forms and pneumocyst layers are visible, creeping along the walls of the alveoli. Broken P. carinii cysts are revealed with the release of intracystic bodies into the surrounding space, which build up the cytoplasm and turn into trophozoites, and then mature into cysts. The histological picture of the lungs resembles alveolar lipoproteinosis with the phenomena of exudation, leukocytosis and net sclerosis. Alveoli and alveolar passages filled with foam mass alternate with areas of compression atelectasis and emphysema.
P. carinii uses the phospholipids (unsaturated phosphatidylcholine) of the host surfactant to build its own cell wall. This leads to a general damage to surfactant metabolism: an imbalance in the levels of surfactant phospholipids and proteins, hypersecretion of surfactant. The pronounced reproduction and maturation of P. carinii directly correlates with the peak activity of the surfactant system. Hyperproduction of surfactant against the background of developing dysfunction of the alveolar macrophages leads to the filling of the alveoli with a relatively homogeneous foam mass. Mechanical destruction and inactivation of surfactant by exudate proteins exacerbate the hypoxic state of tissues, activate fibrosis of interalveolar septa. There is a decrease in the secretory function of second-order alveolocytes and an increase in their proliferative activity. The flat alveolar epithelium is replaced by a cubic. In patients with AIDS, reproduction in P. carinii alveoli often occurs as part of a mixed infection (bacterial flora, fungi). This creates a pathomorphological picture of pneumocystosis.
After treatment and recovery, complete recovery of the surfactant lung system does not occur. This is the reason for the colonization of the respiratory system of AIDS patients with nosocomial strains of microorganisms resistant to broad-spectrum antibiotics. Therefore, recurrent pneumonia in AIDS patients is a common occurrence.
It has been shown that in HIV-negative patients with chronic non-specific lung diseases, there is also a tendency to increase the degree of contamination of the respiratory tract with microflora. With an increase in the number of P. carinii cysts in sputum, the species composition of microflora expands and the frequency of isolation of microbial associations from the lungs increases (Yu. I. Feshchenko et al., 2003). Our data also indicate that in patients with acute and chronic non-specific! / Lung diseases infected with P. carinii, microbial associations, which include coccal flora (cocci diplococci, streptococci), are detected in large numbers in 77% of cases, in insignificant and moderate amount – i 15%. In patients without pneumocystosis – in 65% and 28%, respectively. These data may be evidence of the role of pneumocia as a component of lung microbiocenosis in the pathology of the respiratory system.
In severe forms of immunodeficiency in HIV-infected patients, generalization of pneumocystosis with the development of a disseminated form is possible. In such individuals, P. carinii is detected in the bone marrow, heart, kidneys, appendix, lesions of the skin, joints, and organ of hearing. In some cases of extrapulmonary pneumocystosis, patients do not have lung pathology or symptoms of pneumocystis damage of internal organs are ahead of lung pathology, which develops later. This may indicate the persistence of certain forms of P. carinii in the reticuloendothelial system.
Pneumocystis pneumonia develops in individuals with suppressed cellular immunity, as well as in cases of impaired humoral immunity. An experimental model of pneumocystis pneumonia is obtained by prolonged administration of corticosteroids to laboratory animals (rats, rabbits, ferrets, etc.). The paramount importance in the pathogenesis of pneumocystosis is given to the reduction of T-helper lymphocytes (CD4 +). More than 90% of all cases of pneumocystis pneumonia develop with a decrease in CD4 + in the peripheral blood of less than 200 cells in 1 μl (at a rate of 640 – 1360 cells in 1 μl). The function of killer T-lymphocytes (CD8) is also significantly inhibited.
The importance of humoral immunity in protecting the body against pneumocystosis is also noted. Corticosteroids indirectly reduce the phagocytic and cytolytic activity of alveolar magcrophages, damaging the Fc receptor on their membrane. Macrophages digest, destroy and kill pneumocysts, realizing the cytokine mechanism and including reactive oxidants.
In preterm infants with protein deficiency, a specific synthesis of immunoglobulins is impaired and pneumocystis pneumonia develops, which also indicates the role of humoral immunity in the pathogenesis of the disease. In the foamy exudate of patients with pneumocystic pneumonia, a complex of specific IgG, IgM, IgA is detected. In peripheral blood serum, there is no general deficiency of antibodies, but a deficiency of some isotypes of antipneumocystic antibodies is detected. When experimental animals are prescribed hyperimmune serum, a positive therapeutic effect is noted. Stopping the administration of corticosteroids to laboratory animals leads to the reverse development of the disease.
Symptoms of Pneumocystosis (Pneumocystis Pneumonia)
Pneumocystosis in children usually develops at the 4-6th month of life (premature, sick with rickets, malnutrition, central nervous system lesions) and in older age groups (with hemoblastosis, malignant neoplasms, AIDS). The disease begins gradually – the child’s appetite decreases, the increase in body weight stops, pallor and cyanosis of the nasolabial triangle appear, mild coughing. Normal temperature at the onset of the disease is replaced by subfebrile with rises to febrile. In the lungs appear inconsistent small and medium bubbling rales. Shortness of breath appears (up to 50-70 in 1 min), cyanosis, cough of pertussis character. Often a cough is accompanied by the release of foamy sputum, in which pneumocysts can be detected. X-ray focal shadows of different sizes and densities are recorded, giving a picture of a “cloud-like” lung. Leukocytosis, moderate eosinophilia and an increase in ESR are detected in the blood.
Sometimes pneumocystosis in children occurs under the guise of acute laryngitis, obstructive bronchitis or bronchiolitis. In some cases, a lethal outcome occurs with the clinical picture of pulmonary edema.
In adults, pneumocystosis develops in individuals receiving immunosuppressive therapy (usually corticosteroids) and in patients with AIDS. With drug immunosuppression, the disease often manifests itself against the background of a reduced dose of corticosteroids. The prodromal period usually lasts 1-2 weeks, and in patients with AIDS it reaches 10 weeks. Subfebrile condition, moderate shortness of breath during physical exertion, dry cough, chest pain appear gradually. After 1-2 weeks, fever, shortness of breath at rest, dry cough intensifies (productive cough is rare). On examination, tachypnea, tachycardia, cyanosis are found. Dry, less often wet rales are often heard in the lungs. The white blood cell count usually depends on the background disease. A gas blood test reveals progressive hypoxemia, an increase in the alveolar-arterial oxygen gradient and respiratory alkalosis.
Pneumocystis pneumonia in AIDS is usually characterized by a sluggish chronic course. Initially, auscultatory symptoms are not detected, the radiological picture may also remain without pathological changes. As the disease progresses, bilateral radical infiltrates appear, then transforming into either focal or interstitial changes. Occasionally, solitary nodules are found that can be cavernous with the formation of an extensive central cavity. The cause of abscess formation is probably the attachment of bacterial and mycotic infections.
Complications. The leading complication, most often causing mortality, is respiratory failure associated with a sharp violation of ventilation and gas exchange. Complications such as abscesses, spontaneous pneumothorax (against the background of the formation of small pulmonary cysts), and exudative pleurisy are also possible.
Diagnosis of Pneumocystosis (Pneumocystis Pneumonia)
Considering that the clinical manifestations of pneumocystis pneumonia are not very specific, and the detailed clinical and radiological picture appears significantly delayed from the onset of the disease (especially in AIDS), early etiological diagnosis is of great importance, since it allows timely initiation of appropriate treatment.
Pneumocysts in the sputum of patients are extremely rare, and methods of cultivation of human pneumocysts have not yet been developed. Serological methods are considered highly unreliable. For these reasons, the main possibility of identifying the pathogen is a histological examination of the fluid of bronchoalveolar lavage (ZhBAL) and transbronchial biopsy specimens carried out using fibrobronchoscopy. An open lung biopsy is currently being used less and less.
Differential diagnosis in the early stages of the disease is usually carried out with other interstitial pneumonia. However, the presence of usually background underlying disease and the high reliability of histological studies (90% in AIDS and 40% in other immunocompromised patients) greatly simplifies this task.
The moderate degree of invasiveness and the relative simplicity of fibrobronchoscopy make it possible to consider this method as a mandatory study when examining patients with various disorders of the immune system and with interstitial pneumonia of an unclear genesis.
Treatment of Pneumocystosis (Pneumocystis Pneumonia)
The main drugs for the treatment of pneumocystic pneumonia are trimethoprim-sulfamethoxazole (bactrim, biseptol) and pentamidine isothionate. Bactrim is an inhibitor of the folic acid system, and pentamidine damages the reproductive system of pneumocysts.
Trimethoprim-sulfamethoxazole is prescribed orally or intravenously (at a dose of 20 mg / kg – trimethoprim and 100 mg / kg – sulfamethoxazole per day for 2 weeks, maximum 1 month). The drug is well tolerated and preferably pentamidine when prescribed to patients not suffering from AIDS. Pentamidine is administered intramuscularly or intravenously (slowly, over 1-2 hours in 100 ml of 5% glucose solution) at a dose of 4 mg / kg per day for 2-3 weeks. Side effects are noted in approximately 5% of patients and are characterized by infiltrates at the injection site, hypoilia hyperglycemia, hypocalcemia, azotemia and impaired liver function.
It was noted that the combination of bactrim and pentamidine does not increase the effectiveness of therapy and enhances the toxicity of pentamidine. One drug is replaced by another if one of them does not cause significant positive dynamics of clinical manifestations within 5-7 days.
Chloridine and sulfazine previously used are practically not used now because their effectiveness is lower than bactrim, and toxic manifestations are more pronounced.
For the treatment of pneumocystosis in AIDS patients, alpha-difluoromethylornithine (DFMO) has been increasingly used recently. The drug is well tolerated, low toxicity. In addition to acting on pneumocysts, DFMO blocks the replication of retroviruses and cytomegaloviruses, also has an immunomodulating effect (restores the functions of T-suppressors and increases the immunoregulatory index OKT4 / OKT8).
Prescribe the drug in a dose of 6 g per 1 m2 of body surface per day in 3 divided doses for 8 weeks.
With a favorable course of the disease, the condition begins to improve on average 4 days after the start of therapy. The body temperature is gradually normalizing, objective indicators of high-pressure function and x-ray picture are improving. After 3-4 weeks, in 20-25% of patients, pneumocysts are not detected.
Forecast. Among premature babies, mortality from pneumocystis pneumonia is 50%, but there is practically no relapse. With pneumocystic pneumonia in adults not suffering from AIDS, the prognosis is more favorable and is determined more by the severity of the background disease, the content of leukocytes, the nature of the associated opportunistic infection.
In patients with AIDS, if untreated, pneumocystis pneumonia always leads to death. With late diagnosis, the detail in the primary disease is about 40%, timely treatment can reduce mortality by 25%. However, even after a few months, relapses (from 10 to 30%) of pneumocystis pneumonia are possible.
Relapse treatment is much more difficult, as 50-80% of patients with C develop severe adverse reactions to bactrim and pentamidine and mortality increases to 60%.
The prognosis of pneumocystis pneumonia.
Among premature babies, mortality from pneumocystis pneumonia is 50%, but there is practically no relapse. With pneumocystis pneumonia in adults who do not have AIDS, the prognosis is more favorable and is determined by the severity of the background disease. In patients with AIDS, in the absence of treatment for pneumocystis pneumonia, it is always fatal. With late diagnosis, mortality in the initial episode is about 40%, timely treatment can reduce mortality to 25%. However, even after a few months, relapses (from 10 to 30%) of pneumocystis pneumonia are possible. Relapse treatment is much more difficult, since 50 – 80% of patients develop severe adverse reactions to bactrim and pentamidine, and mortality increases to 60%.
Prevention of Pneumocystosis (Pneumocystis Pneumonia)
Measures to identify the source of infection should be carried out in risk groups, families of patients infected with P. carinii, according to clinical indications among medical workers of departments where patients from risk groups are staying. If the listed persons have subclinical or clinically expressed symptoms from the respiratory organs, they should be examined for pneumocystosis. In the future, depending on the severity of the pathological process in the lungs, the degree of immunodeficiency, concomitant diseases or epidemic danger, a selection of therapeutic and preventive measures is made.
In severe cases of illness, individuals with pneumocystis pneumonia are placed in boxes or semi-boxes and specific treatment is prescribed. Medical workers and staff with clinically pronounced forms of pneumocystosis are treated. In a subclinical course – reorganization.
Chemoprophylaxis of pneumocystis pneumonia is prescribed for HIV-infected patients according to the following indications: when the content of T4 lymphocytes is less than 200 cells in 1 μl of blood in adults and less than 450 in children; with thrush of the oral cavity; with fever of unknown etiology lasting more than 2 weeks; children born to HIV-infected mothers from 4 to 6 weeks of age before being diagnosed with HIV infection.
Chemoprophylaxis of pneumocystis pneumonia is recommended for the contingent of patients with immunodeficiency of different origins: with primary immunodeficiency, with low-calorie protein nutrition, recipients of transplanted organs; in the treatment of cytostatics, corticosteroids, irradiation of the corresponding groups of patients.
Prevention prevents the disease only while taking the drug. Chemoprophylaxis of pneumocystis pneumonia is carried out by an AIDS patient throughout his life; patients after bone marrow transplantation – at least 1 year.
Measures to break the transmission mechanism do not differ from measures for other drip infections. These include strict adherence by doctors, medical personnel and patients to the hospital regimen, ventilation, quartzing and wet cleaning twice a day in wards and other rooms where patients are located. Of great importance is the improvement of the ventilation system in medical institutions.