Sepsis-3: new edition — old problems. analysis from the perspective of general pathology

Sepsis-3 Guidelines defines sepsis as an organ dysfunction caused by dysregulated host response to infection. To record organ dysfunction, the SOFA/quick SOFA scales were recommended. In fact, in medical practice, sepsis is considered nothing more than a critical infection that requires intensive care. Therefore, sepsis is pathogenetically a nonhomogeneous condition manifested by diverse nosologies and syndromes. Unlike the previous two editions, Sepsis-1 and Sepsis-2 Guidelines, the formal criteria provided in the Sepsis-3 are closer to the de facto position, describe more specific, but less sensitive features to predict mortality. However, the initial, latent manifestations of critical conditions, which can be relatively effectively controlled by intensive therapy, remain outside the Sepsis-3 criteria. Not all signs of multiple organ dysfunctions (according to the Sepsis-3 criteria) will require intensive care. Hence, obviously the presence or absence of formal criteria of Sepsis-3 will not be always taken into account while verifying sepsis. The only relatively pathogenetically homogeneous definition in Sepsis-3 is “septic shock”. However, it also does not fully consider the staging (according to the degree of compensation of hemodynamic disturbances) and the phasing (according to the severity of the proinflammatory response) of the dynamics of the shock condition. From our point of view, a positive result of the Sepsis-3 consensus would be in transition of the systemic inflammatory response syndrome (SIRS) from the main to additional (optional) verifying sepsis criteria. We also believe that the weak side of the Sepsis-3 Guidelines is in underestimated mechanisms of systemic inflammation as a general pathological process in the genesis of developing critical conditions of various origins. From the perspective of general pathology, sepsis is a combination of the three common fundamental pathological processes: classical (canonical) and systemic inflammation (SI), as well as chronic systemic low-grade inflammation (parainflammation), the latter can be considered as an unfavorable background for development of the former two processes. All three processes are characterized by any SIR signs and require to be differentiated on the basis of integral criteria, which reflect specific blocks of the SI complex process. The pathogenesis of the SARS-CoV-2 infection (COVID-19) is a relevant example underlying inevitability of such approach. The systemic microvascular vasculitis, and its main clinical manifestations such as systemic microcirculatory disorders in the form of shockogenic conditions is the SI pathogenetic basis. Apparently, one of the modalities for further evolution of critical care medicine will be coupled to development of a more multilayered but effective methods for assessing pathogenesis of critical states and more differentiated methods of pathogenetic therapy. Therefore, it will require to modernize a number of fundamental premises in our knowledge about pathobiology, pathophysiology, and general pathology

«Сепсис-3»: новая редакция - старые проблемы. Анализ с позиции общей патологии

Sepsis-3 Guidelines defines sepsis as an organ dysfunction caused by dysregulated host response to infection. To record organ dysfunction, the SOFA/quick SOFA scales were recommended. In fact, in medical practice, sepsis is considered nothing more than a critical infection that requires intensive care. Therefore, sepsis is pathogenetically a non-homogeneous condition manifested by diverse nosologies and syndromes. Unlike the previous two editions, Sepsis-1 and Sepsis-2 Guidelines, the formal criteria provided in the Sepsis-3 are closer to the de facto position, describe more specific, but less sensitive features to predict mortality. However, the initial, latent manifestations of critical conditions, which can be relatively effectively controlled by intensive therapy, remain outside the Sepsis-3 criteria. Not all signs of multiple organ dysfunctions (according to the Sepsis-3 criteria) will require intensive care. Hence, obviously the presence or absence of formal criteria of Sepsis-3 will not be always taken into account while verifying sepsis. The only relatively pathogenetically homogeneous definition in Sepsis-3 is “septic shock”. However, it also does not fully consider the staging (according to the degree of compensation of hemodynamic disturbances) and the phasing (according to the severity of the pro-inflammatory response) of the dynamics of the shock condition. From our point of view, a positive result of the Sepsis-3 consensus would be in transition of the systemic inflammatory response syndrome (SIRS) from the main to additional (optional) verifying sepsis criteria. We also believe that the weak side of the Sepsis-3 Guidelines is in underestimated mechanisms of systemic inflammation as a general pathological process in the genesis of developing critical conditions of various origins. From the perspective of general pathology, sepsis is a combination of the three common fundamental pathological processes: classical (canonical) and systemic inflammation (SI), as well as chronic systemic low-grade inflammation (parainflammation), the latter can be considered as an unfavorable background for development of the former two processes. All three processes are characterized by any SIR signs and require to be differentiated on the basis of integral criteria, which reflect specific blocks of the SI complex process. The pathogenesis of the SARS-CoV-2 infection (COVID-19) is a relevant example underlying inevitability of such approach. The systemic microvascular vasculitis, and its main clinical manifestations such as systemic microcirculatory disorders in the form of shockogenic conditions is the SI pathogenetic basis. Apparently, one of the modalities for further evolution of critical care medicine will be coupled to development of a more multilayered but effective methods for assessing pathogenesis of critical states and more differentiated methods of pathogenetic therapy. Therefore, it will require to modernize a number of fundamental premises in our knowledge about pathobiology, pathophysiology, and general pathology. © 2021 Saint Petersburg Pasteur Institute. All rights reserved.This work was carried out within the framework of the state assignment of the Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences (registration number NIOKTR No. АААА-А18-118020590108-7)

Systemic Inflammation: Methodological Approaches to Identification of the Common Pathological Process

We defined Systemic inflammation (SI) as a "typical, multi-syndrome, phase-specific pathological process, developing from systemic damage and characterized by the total inflammatory reactivity of endotheliocytes, plasma and blood cell factors, connective tissue and, at the final stage, by microcirculatory disorders in vital organs and tissues." The goal of the work: to determine methodological approaches and particular methodical solutions for the problem of identification of SI as a common pathological process. SI can be defined by the presence in plasma of systemic proinflammatory cell stress products-cytokines and other inflammatory mediators, and also by the complexity of other processes signs. We have developed 2 scales: 1) The Reactivity Level scale (RL)-from 0 to 5 points: 0-normal level; RL-5 confirms systemic nature of inflammatory mediator release, and RL- 2-4 defines different degrees of event probability. 2) The SI scale, considering additional criteria along with RL, addresses more integral criteria of SI: the presence of ≥ 5 points according to the SI scale proves the high probability of SI developing. To calculate the RL scale, concentrations of 4 cytokines (IL-6, IL-8, IL-10, TNF-α) and C-reactive protein in plasma were examined. Additional criteria of the SI scale were the following: D-dimers>500ng/ml, cortisol>1380 or <100nmol/l, troponin I≥0.2ng/ml and/or myoglobin≥800ng/ml. 422 patients were included in the study with different septic (n-207) and aseptic (n-215) pathologies. In 190 cases (of 422) there were signs of SI (lethality 38.4%, n-73). In only 5 of 78 cases, lethality was not confirmed by the presence of SI. SI was registered in 100% of cases with septic shock (n-31). There were not significant differences between AU-ROC of CR, SI scale and SOFA to predict death in patients with sepsis and trauma

СONCENTRATION OF ANTI-INFLAMATORY CYTOKINES IN CELL CULTURE SUPERNATANTS IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Juvenile idiopathic arthritis is a chronic inflammatory disease of the joints in children, mainly of autoimmune or auto-inflammatory nature. It is a heterogeneous group, which includes different subtypes of the disease. Different mechanisms may play role in the pathogenesis of distinct subtypes of juvenile arthritis. However, a long-term imbalance of pro- and anti-inflammatory cytokines is important for all subtypes of disease. The aim of the present study was to determine spontaneous and stimulated anti-inflammatory cytokines production by peripheral blood cells from the children with juvenile idiopathic arthritis. Patients of 2 to 17 years old with different subtypes of juvenile idiopathic arthritis (n = 99) and healthy children without signs of autoimmune diseases (control, n = 31) were examined. Spontaneous and phytohemagglutinin-stimulated concentrations of IL-1ra, IL-4, IL-10, TGF-β in supernatants of whole-blood cultures were determined by ELISA. Differences in the spontaneous and mitogen-stimulated secretion of the cytokines in patients with different subtypes of juvenile arthritis have not been revealed. The spontaneous IL-1ra, IL-4 and IL-10 production by blood cells in the common group of patients with juvenile idiopathic arthritis was similar to the controls. The median value of spontaneous TGF-β concentration in the patients was below the detection level, whereas blood cells of healthy children had a higher potential of spontaneous TGF-β production. IL-4 and IL-10 production after incubation of peripheral blood cells with phytohemagglutinin in patients and in the control group did not differ from the controls, while IL-1ra and TGF-β synthesis was significantly lower than in healthy children.The spontaneous and/or stimulated production of IL-1ra, TGF-β by blood cells in children with juvenile idiopathic arthritis reflects the pathogenic significance of these cytokines in disease. Stimulation of cells can reveal a latent deficiency in the synthesis of cytokines, which is not evident when determining its concentration in serum or supernatants of spontaneous whole-blood cultures

Physiological and pathogenic role of scavenger receptors in humans

The scavenger receptors (SRs)) include > 30 different molecules structurally classified into 11 classes (A to L). They are expressed mostly on stromal macrophages, and their expression may be augmented in direct dependence with concentrations of their ligands. The SRs are heterogenous by their structure, however, being common in their functional potential. E.g., different SR classes may participate in absorption of modified low-density lipoproteins and glycated proteins, apoptotic and ageing cells, altered erythrocytes and platelets, like as a big variety of other endogenous ligands from metabolic and cellular “trash”. A common property of SRs is their participation in removal of small pathogen amounts from blood circulation, regulation of cell and tissue stress responses, ability to form complicated receptor complexes with other receptor types including integrins and toll-like receptors. Opposite to classic pattern-recognizing receptors, the SR involvement does not always elicit a pronounced cellular activation and development of pro-inflammatory cellular stress. The SR functional effects provide interactions between different physiological events and immune system, including the processes of neuroendocrine and metabolic regulation. These mechanisms provide both homeostatic stability and, likewise, act at the border of normal and pathological conditions, i.e., participating in pathogenesis of transitional processes, e.g., physiological ageing. Moreover, the SR-associated processes represent a key pathogenetic factor in different somatic diseases, e.g., those associated with low-intensity chronic inflammation, including obesity, type 2 diabetes, atherosclerosis, arterial hypertension, various neurodegenerative disorders. Similarly, the SRs are involved into the processes of cancer transformation and antitumor response, different processes of classical inflammation, from antigen presentation to the morphofunctional T cell and macrophage polarization in the inflammation foci and immunocompetent organs. SR are playing a controversial role in development of acute systemic inflammation, the main reason for lethal outcomes in the intensive care wards. Targeted effects upon the SRs represent a promising approach when treating a broad variety of diseases, whereas detection of membrane-bound and soluble SR forms could be performed by means of diagnostic and monitoring techniques in many human disorders. © 2020, SPb RAACI

APPLICATION OF DIFFERENT LABORATORY METHODS FOR ANTINUCLEAR AUTOANTIBODIES INVESTIGATION IN PATIENTS WITH AUTOIMMUNE CONNECTIVE TISSUE DISEASES

1222 patients with suspicion of different autoimmune connective tissue diseases are investigated. Antinuclear antibodies by indirect immunofluorescence reaction, by methods of ELISA and immunoblotting were determined. Laboratory tests results correlated with each other that testifies to satisfactory comparability of different laboratory methods. The most sensitive method for detection of antinuclear antibodies is indirect immunofluorescence. This is a preferable method for screening of autoimmune connective tissue diseases. At comparison of luminescence types in immunofluorescence test and results of immunoblotting was shown that for each type of a luminescence the set of antibody, revealed by immunoblotting, was characteristic. However, the same antibodies can be found in various types of fluorescence that complicates unequivocal interpretation of immunofluorescence test results. Antibodies to Ro-52 were most often found in all types of fluorescence, and also in the absence of that

Role of proinflammatory cytokines in Hashimoto's thyroiditis associated with psychiatric disorders

Mental disorders often accompany autoimmune diseases, for example, since 1949 it has been known about “myxedematous madness”, a psychosis caused by hypothyroidism. The most common cause of hypothyroidism is Hashimoto's autoimmune thyroiditis. It is also known about another neuropsychiatric disorder associated with autoimmune thyroiditis, Hashimoto's encephalopathy. It is a severe dysfunction of the central nervous system, the pathogenesis of which is not associated with hormonal disorders. Cytokines are regulators and participants of inflammation, including autoimmune. Certainly, when we are talking about high concentrations cytokines, we mean systemic inflammation. The minimal or mediocre fluctuations in cytokines within the ranges that are characteristic of healthy status or normergic acute phase response in disease cannot be interpreted from the point of view of binary endocrinological logic. In the CNS, cytokines are able to influence on the neuroendocrine control of systemically regulated functions. It is also important that glial cells (astroglia, microglia) are capable of producing a number of cytokines and can affect neurons and develop behavioral changes. In addition, the ability of a number of cytokines outside the CNS itself to act on vagal afferents and through them to convey information to the CNS, affecting its state and functions, has been proven. It is reasonable to assume that minimal fluctuations in cytokine levels may also affect the state and function of the CNS. The aim of the study was to investigate the levels of cytokines in patients with thyroiditis; in patients with thyroiditis associated with mental disorders; in a group of healthy individuals; and evaluate the effect of cytokine levels on clinical manifestations. In the group of patients with thyroiditis and mental disorders, the levels of CCL20/MIP3α, IL-13, IL-2, IL-27, IL-5 were significantly higher than in other groups. At the same time, no positive correlation was found between the clinical manifestations of mental disorders and the levels of cytokines. A positive correlation was found between the levels of some cytokines and free triiodothyronine, as well as the level of antithyroid antibodies. Mental disorders associated with autoimmune thyroiditis may be associated with changes in the cytokine profile and result from neuroinflammation

ROLE OF INNATE ERRORS OF IMMUNITY IN THE GROUP OF CHILDREN WITH FATAL OUTCOMES DURING THE FIRST YEAR OF LIFE

In the modern world, inborn errors of immunity (IEIs), or primary immunodeficiencies (PIDs), are among of the main causes of childhood disability and mortality, determining the demographic state of mankind not only at present, but also in the future. In the Sverdlovsk Region over the past 5 years, there were about 30% of children who died from severe combined primary immunodeficiency. This retrospective study is devoted to the study of the nosological profile of mortality in the children with immune-dependent disorders in the Sverdlovsk Region, as well as to assess information significance of extrachromosomal circular DNA molecules (TREC and KREC) analysis. Some anamnestic data on the course of prenatal period in the current and previous pregnancies were considered the signs of suggested diagnosis of primary immunodeficiencies, i.e., threats of pregnancy loss at the early terms, documented cases of early childhood death, persistent viral and bacterial infections in the mother, complicated course of pregnancy in the mother, as well as some clinical manifestations, including fungal-bacterial sepsis, generalized viral infection, repair disorders, reduced physiological tolerance accompanied by autoimmune organ damage and uncontrolled systemic inflammation. The study demonstrated a wide range of nosological entities of innate errors of immunity in the structure of early childhood mortality, including both classical forms of primary immunodeficiencies and the disorders not directly related to innate errors of immunity, but those showing phenotypically pronounced immunodeficiency and their immediate role in statistical deviations. Among the main criteria that may presume possible presence of an immune-dependent pathology in the early neonatal period we considered the molecular markers of naive T and B cells (TREC and KREC, respectively) revealed in 70% of the cases studied, with, at least, one of these indexes found to be reduced. It is important to understand that primary immunodeficiencies are not as rare as previously thought. Therefore, it is necessary to carry out timely and high-quality diagnostics, in order to avoid unavoidable deaths. © 2022, RSI

Серосодержащие гетероциклические соединения с потенциальной противодиабетической активностью

The essential link in the pathogenesis of diabetes mellitus and its complications is a non-enzymatic glycosylation of proteins. However, modern endocrinology lacks of clinically effective pharmaceuticals for its correction. The screening of 23 derivatives of 1,3,4-thiadiazine the ability to inhibit the reaction of non-enzymatic glycosylation of proteins in vitro was held, and 11 the most active compounds of them were selected, also the relationship «structure – activity» was investigated. An essential part of the pathogenesis of diabetes mellitus and its complications is non-enzymatic glycosylation of proteins. However, modern endocrinology lacks clinically effective medicines for its correction.Существенным звеном патогенеза сахарного диабета и его осложнений является неферментативное гликозилирование белков (НГБ). Однако современная эндокринология испытывает нехватку клинически эффективных лекарственных средств для его коррекции. Проведен скрининг 23 производных 1,3,4-тиадиазина на способность ингибировать реакцию НГБ in vitro, исследована взаимосвязь «структура – активность». Среди 23 соединений, подвергнутых скринингу, мы выделили 11 наиболее активных веществ, подавлявших накопление ФА на 20–70 %, против контроля. Лидерами среди этих веществ были соединения L-17, 2-Г-5-Ф и Н-10, снижавшие накопление ФА в 2–2,5 раза, по сравнению с контролем, и превосходившие по ингибирующей способности вещество сравнения G-SH. Таким образом, в проведенном исследовании впервые продемонстрирована способность ряда серосодержащих гетероциклических соединений класса 1,3,4-тиадиазинов ингибировать накопление начального продукта НГБ  фруктозамина при инкубации бычьего сывороточного альбумина с глюкозой, проведена оценка взаимосвязи между структурой соединений и противогликозилирующей активностью. Выявленный биохимический механизм может иметь значение в реализации противодиабетической активности производных 1,3,4-тиадиазина