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

A Systems Immunology Approach to Plasmacytoid Dendritic Cell Function in Cytopathic Virus Infections

Plasmacytoid dendritic cell (pDC)-mediated protection against cytopathic virus infection involves various molecular, cellular, tissue-scale, and organism-scale events. In order to better understand such multiscale interactions, we have implemented a systems immunology approach focusing on the analysis of the structure, dynamics and operating principles of virus-host interactions which constrain the initial spread of the pathogen. Using high-resolution experimental data sets coming from the well-described mouse hepatitis virus (MHV) model, we first calibrated basic modules including MHV infection of its primary target cells, i.e. pDCs and macrophages (Mφs). These basic building blocks were used to generate and validate an integrative mathematical model for in vivo infection dynamics. Parameter estimation for the system indicated that on a per capita basis, one infected pDC secretes sufficient type I IFN to protect 103 to 104 Mφs from cytopathic viral infection. This extremely high protective capacity of pDCs secures the spleen's capability to function as a ‘sink’ for the virus produced in peripheral organs such as the liver. Furthermore, our results suggest that the pDC population in spleen ensures a robust protection against virus variants which substantially down-modulate IFN secretion. However, the ability of pDCs to protect against severe disease caused by virus variants exhibiting an enhanced liver tropism and higher replication rates appears to be rather limited. Taken together, this systems immunology analysis suggests that antiviral therapy against cytopathic viruses should primarily limit viral replication within peripheral target organs

«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)

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

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

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