Chronic Pulmonary Aspergillosis: Literature Review and Demonstration of Own Observations

Chronic pulmonary aspergillosis (CPA) is a severe disease that develops mainly in patients without obvious immune disorders. Computed tomography is the main instrumental method in the diagnosis of CPA, which is necessary to determine the form of the disease, to choose treatment policy, to combat complications, and to monitor therapy. This makes it important for a radiologist to understand the main aspects of timely and differential diagnosis. There are insufficient Russian studies on this problem. This paper analyzes the 2014–2020 Russian and foreign publications available in PubMed, Web of Science, Elsevier, and eLibrary electronic databases. When searching for information, the following keywords were used: “computed tomography”, “chronic pulmonary aspergillosis”, “aspergilloma”, “air-crescent symptom”, “differential diagnosis”

Optical spectroscopy of single beryllium acceptors in GaAs/AlGaAs quantum well

We carry out microphotoluminescence measurements of an acceptor-bound exciton (A^0X) recombination in the applied magnetic field with a single impurity resolution. In order to describe the obtained spectra we develop a theoretical model taking into account a quantum well (QW) confinement, an electron-hole and hole-hole exchange interaction. By means of fitting the measured data with the model we are able to study the fine structure of individual acceptors inside the QW. The good agreement between our experiments and the model indicates that we observe single acceptors in a pure two-dimensional environment whose states are unstrained in the QW plain

Инвазивный кандидоз у детей

The prevalence of invasive candidiasis (IC) in pediatric hospitals is from 4,3 to 15,2 per 10,000 hospitalized, in ICU – from 3,5 to 7 cases per 1,000, with HSCT – 2,9%. The average length of stay of a patient in the hospital before the development of IC varies from 21 to 56 days, in the ICU – more than 15 days. Knowledge of risk factors (ICU stay for ≥15 days, use of antibacterial drugs and parenteral nutrition, active malignant neoplasm, etc.) makes it possible to identify patients with a high (10-46%) risk of developing IC. Candida albicans remains the leading causative agent of IC in children, but infections with non-albicans Candida spp. have increased and an increase in the resistance of IC pathogens to azole antimycotics was noted. The main clinical variant of IC in children is candidemia, other forms include the central nervous system, abdominal organs, eyes, heart, bones and joints, kidneys, skin and subcutaneous tissue involvement, as well as chronic disseminated (hepatolienal) candidiasis. Blood culture, the main method of laboratory diagnostics of IC, is characterized by low sensitivity and requires a long time. Methods of noncultural diagnostics of IC (1,3-β-D-glucan, mannan and antimannan antibodies, T2 Candida etc) in children have not been sufficiently studied. The main drugs for the treatment of IC in children are echinocandins (anidulafungin, etc.), and CVC removal/replacement is necessary. The overall mortality rate in pediatric patients within 30 days after the diagnosis of IC is 37% to 44%.Распространенность инвазивного кандидоза в педиатрических стационарах составляет от 4,3 до 15,2 на 10 000 госпитализированных, в отделениях реанимации и интенсивной терапии – от 3,5 до 7 случаев на 1000, при проведении трансплантации гемопоэтических стволовых клеток – 2,9%. Средний срок пребывания пациента в стационаре до развития инвазивного кандидоза варьирует от 21 до 56 дней, в отделениях реанимации и интенсивной терапии превышает 15 суток. Знание факторов риска (пребывание в отделениях реанимации и интенсивной терапии ≥15 дней, применение антибактериальных лекарственных средств и парентерального питания, активное злокачественное новообразование и пр.) позволяет выявить пациентов с высоким (10– 46%) риском развития инвазивного кандидоза. Сandida albicans остается ведущим возбудителем инвазивного кандидоза у детей, но увеличилось количество инфекций, вызванных не-albicans Candida spp. и отмечен рост устойчивости возбудитетей инвазивного кандидоза к азольным антимикотикам. Основной клинический вариант инвазивного кандидоза у детей – кандидемия, возможно поражение центральной нервной системы, органов брюшной полости, органов зрения, сердца, костей и суставов, почек, кожи и подкожной клетчатки, а также хронический диссеминированный (гепатолиенальный) кандидоз. Посев крови (основной метод лабораторной диагностики инвазивного кандидоза) отличается низкой чувствительностью и требует длительного времени. Методы некультуральной диагностики ИК (определение 1,3-β-d-глюкана, маннана и антиманнановых антител, Т2 Candida) у детей изучены недостаточно. Основные препараты для лечения инвазивного кандидоза у детей – эхинокандины (анидулафунгин и пр.), кроме того, необходима замена центрального венозного катетера. Общая летальность педиатрических пациентов в течение 30 дней после диагностики инвазивного кандидоза составляет от 37% до 44%.

MOLECULAR GENETIC AND IMMUNOLOGICAL ASPECTS OF INVASIVE ASPERGILLOSIS

Aspergillus is very widely spread in nature. Daily people inhale to several thousand spores of micromycetes, however, an effective immune response prevents to development of the disease. In case of violation the mechanisms of innate and adaptive immune response as a result of genetic defects or iatrogenic immunosuppression Aspergillus spp. become pathogenic and can cause severe invasive infections in immunocompromised patients. Until now there are no reliable biomarkers for the risk prediction of invasive aspergillosis and monitoring the effectiveness of treatment of infectious process. In our review, we are considering the most important genetic and immunological factors affecting susceptibility to Aspergillus spp., The analysis of which can provide an individual approach to antifungal therapy / prevention in immunocompromised patients

INVASIVE ASPERGILLOSIS IN AN ADOLESCENT

The article presents the clinical case of invasive aspergillosis in a 15-year-old adolescent with lesions in the spine, ribs and both lungs, and primary immune deficiency which was not diagnosed earlier. In order to diagnose this disease it was necessary to differentiate it from the generalized form of tuberculosis and to perform integral X-ray examination and surgery with consequent morphological and bacteriological examination of the surgical samples

Тромбоциты при инвазивном аспергиллезе: роль в патогенезе и иммунной защите

Invasive aspergillosis (IA) is a serious disease, with mortality rate up to 80%. A. fumigatus is an angiovasive pathogen, fragments of its hyphae can detach and circulate in the bloodstream. Platelets are activated by surface structures, metabolites and soluble fungal complexes, resulting in adhesion to conidia and fungal hyphae. The melanin and hydrophobin contained in the conidia, as well as the galactosaminogalactan contained in the hyphae and the glyphotoxin secreted by the hyphae, suppress phagocytic cells, but activate the platelets. Activated platelets show direct antifungal activity by releasing microbicidal proteins and serotonin. In addition to direct antifungal effect, platelets form an interactive network with cellular components of the immune system and a complement system, increasing the response of neutrophils and monocytes. In the presence of platelets, the efficacy of antimycotics is greatly enhanced. The adverse effects of platelet activation in IA are associated with clinical conditions such as hemoptysis, pulmonary hemorrhage and infarctions of various organs. Another danger associated with IA is the development of thrombocytopenia. Thrombocytopenia is defined as an independent risk factor of mortality in IA in oncohematological patients after allogeneic transplantation of hematopoietic stem cells. Numerous evidences of the important role of platelets in protection from A. fumigatus suggest that the study of the number and functional state of platelets will provide a new data, which will help develop new methods for prediction and treatment of IA.Инвазивный аспергиллез – тяжелое заболевание, при котором летальность может достигать 80%. Aspergillus fumigatus – самый частый возбудитель заболевания, ангионвазивный патоген, фрагменты гифов которого могут циркулировать в кровотоке. Тромбоциты активируются поверхностными структурами, метаболитами и растворимыми грибковыми комплексами, после чего наблюдается их адгезия к конидиям и гифам гриба. Содержащиеся в конидиях меланин и гидрофобин, а также содержащийся в гифах галактозаминогалактан и секретируемый гифами глиотоксин подавляют фагоцитирующие клетки, но активируют тромбоциты. Активированные тромбоциты проявляют прямую противогрибковую активность путем высвобождения микробицидных белков и серотонина, а также формируют интерактивную сеть с клеточными компонентами иммунной системы и системой комплемента, увеличивая ответ нейтрофилов и моноцитов. В присутствии тромбоцитов существенно усиливается эффективность антимикотиков. Неблагоприятные эффекты активации тромбоцитов при инвазивном аспергиллезе связаны с развитием легочного кровотечения и инфарктов различных органов. Другой опасностью, связанной с инвазивным аспергиллезом, является развитие тромбоцитопении. Тромбоцитопения определена как независимый фактор риска летальности при инвазивном аспергиллезе у онкогематологических больных после аллогенной трансплантации гемопоэтических стволовых клеток. Изучение количества и функционального состояния тромбоцитов позволит создать новые методы прогнозирования и лечения инвазивного аспергиллеза

Comparative pharmacoeconomic analysis of posaconazole therapy in tablet form and in suspension for invasive fungal infections prevention

The objective of the study was to conduct a comparative pharmacoeconomic analysis of the treatment with posaconazole in a tablet form for the prevention of invasive fungal infections in patients aged 13 years and older with prolonged neutropenia and hematopoietic stem cell transplant recipients.Study design: pharmacoeconomic study, cost–effectiveness analysis; budget impact analysis; sensitivity analysis to changes in the initial parameters of the model.Results and conclusion. A literature review has shown that the use of the compared drugs for the prevention of invasive fungal infections is effective, with posaconazole being the most effective. Based on pharmacokinetic studies data, we can state the equivalence of the action of various drug forms of posaconazole. A cost analysis of drugs showed that the lowest total costs were for the prevention of invasive fungal infections in patients with acute myeloid leukemia with posaconazole tablets (197,149.37 rub.) and posaconazole suspension (215,911.53 rub.). The lowest cost for the prevention of invasive fungal infections in patients with hematopoietic stem cell transplant was shown by posaconazole in tablets (505,070.37 rub.) and posaconazole in suspension (616,652.01 rub.). Budget impact analysis in acute myeloid leukemia patients showed that with a possible cohort size of 2288 people an increase in the share of posaconazole in tablets from 5 to 15 %, in suspension from 20 to 35 % and with a decrease in the share of voriconazole from 25 to 15 %, and the share of fluconazole from 50 to 35 % in public procurement will reduce budget costs by 30,441,219.72 rub., and in patients with hematopoietic stem cell transplant ‒ by 11,219,243.54 rub. (per 100 patients)

Possibilities of Discriminant Analysis in the Differential Diagnosis of Chronic Aspergillosis and Nonmicotic Lung Lesions

Objective: to improve the efficiency of differential diagnosis of chronic pulmonary aspergillosis (СPA) based on the assessment of its probability using a discriminant mathematical model. Material and methods. The prospective study included 74 patients with CPA (57% women, median age 53 years) meeting the ERS/ESCMID criteria (2016). The control group consisted of 35 patients with lung diseases without CPA. Clinical and anamnestic data, the results of computed tomography (CT), laboratory and instrumental methods of research were analysed. By means of stepwise discriminant analysis, the model was created in order to differentiate compared groups. Results. The main forms of CPA were simple solitary aspergilloma (n = 30, 40%) and cavitary CPA (n = 21, 28%). On CT scans, in patients with CPA pulmonary emphysema (n = 50, 74%; 95% CI 63–83), bronchiectasis (n = 42, 56%; 95% CI 44–67), pleura thickening (n = 40, 56%; 95% CI 42–65) were detected with a high frequency. The sensitivity and specificity of typical for CPA air sickle symptom were 66.2% and 74.29%, respectively. The diagnostic informativeness of laboratory methods was characterized by high specificity (85–100%), however, it had sensitivity 40–60%. A discriminant model was worked up. It included five variables: mycological confirmation of the diagnosis (р < 0.001), air sickle symptom on CT (p = 0.03), ground glass opacity sympton on CT (p = 0.017), accompanying rheumatological diseases (p = 0,031), positive Aspergillus antigen in bronchoalveolar lavage (p = 0.036). The resulting model of differential diagnosis is statistically significant (F = (5.102) = 27.291; p < 0.001). Conclusion. CT-patterns of CPA include typical (air sickle symptom) and nonspecific (pleura thickening, emphysema, bronchiectasis) changes. Separately taken laboratory indicators and CT-symptoms are not always the determining criteria for diagnosis; an integrated approach is required to make a diagnosis. The proposed model improves the accuracy of differential diagnosis between CPA and nonmycotic lung diseases: increases sensitivity to 82.43%, specificity to 94.28% in comparison with separately analyzed laboratory data and typical CT-pattern of air sickle symptom. As a whole this model allows to classify the CPA and nonmycotic lung disease in 86,23% of cases

РОЛЬ ТРОМБОЦИТОВ В ПАТОГЕНЕЗЕ БАКТЕРИАЛЬНЫХ ИНФЕКЦИЙ

In recent years, a critical mass of information has accumulated, which has made it possible to equate platelets to the cells of innate immunity, which ensures the initiation of inflammation and the reactions of innate immunity. In the presented review platelets were examined from the point of view of antibacterial immune reactions. Mechanisms that allow platelets to recognize bacteria and their soluble products as characteristic of immune cells (via TLR2, TLR4, TLR7 and TLR9, FcγRIIa and receptors for complement components), as well as the mechanisms involved in the hemostasis process (GPIb, GPIIb-IIIa). The consequence of the recognition of bacteria is the activation of platelets, the initiation of hemocoagulation and the innate immune response. The ability of platelets to phagocyte bacteriae and stop their growth due to the pronounced microbicidal potential (thrombocidins or microbicidal proteins of platelets and human β-defensins hBD-1, -2 and-3), which these anucleate cells possess, is shown. Discussed that bacteria actively oppose antimicrobial reactions, including using various toxins. Several groups of bacterial toxins have been isolated that activate platelets, destroying the electrochemical gradient of the plasma membrane through membrane perforation. A number of toxins cause the activation of platelets and cells of the immune system, acting as superantigens. In the antibacterial immunity, platelets attract neutrophils, monocytes and activate the complement system. In this case, platelets act together with these cells and proteins, promoting the full disclosure of the microbicidal potential of phagocytes and complement. This is especially important for bacterial infections, which monocytes / macrophages or only platelets cannot control, but, combining, they create the necessary conditions for the clearance of pathogenic bacteria from circulation.За последние годы скопилась критическая масса информации, которая позволила определить тромбоциты как клетки врожденного иммунитета, обеспечивающие инициацию воспаления и защитных иммунных реакций. В представленном обзоре литературы тромбоциты рассмотрены с точки зрения их участия в реакциях антибактериального иммунитета. Описаны механизмы, позволяющие тромбоцитам распознавать бактерии и их растворимые продукты, характерные как для клеток иммунной системы (через рецепторы TLR2, TLR4, TLR7 и TLR9, FcγRIIa и рецепторы для компонентов комплемента), так и для структур, задействованных в процессе гемостаза (через рецепторы GPIb, GPIIb-IIIa). Следствием распознавания бактерий является активация тромбоцитов, инициация ими гемокоагуляции и врожденного иммунного ответа. Показана способность тромбоцитов фагоцитировать бактерии и останавливать их рост за счет выраженного микробицидного потенциала (который описывается как тромбоцидины, или микробицидные белки тромбоцитов, и β-дефензины человека hBD-1, -2 и -3), которым обладают эти безъядерные клетки. Обсуждается, что бактерии активно противодействуют антимикробным реакциям тромбоцитов, в том числе используя различные токсины. Выделено несколько групп бактериальных токсинов, которые активируют тромбоциты, разрушая электрохимический градиент плазматической мембраны, перфорируя ее. Ряд токсинов вызывают активацию тромбоцитов и клеток иммунной системы, действуя как суперантигены. В реакциях антибактериального иммунитета тромбоциты привлекают нейтрофилы, моноциты и активируют систему комплемента. При этом тромбоциты действуют совместно с этими клетками и белками, способствуя полному раскрытию микробицидного потенциала фагоцитов и комплемента. Особенно это важно при инфекциях бактериями, контролировать которые не способны только моноциты/макрофаги или только тромбоциты, но, объединяясь, они создают необходимые условия для клиренса патогенных бактерий из циркуляции