What is Hemorrhagic Fever?
The group of hemorrhagic fevers includes acute febrile diseases of viral etiology, in the pathogenesis and clinical manifestations of which the leading role is played by vascular lesions, leading to the development of thrombohemorrhagic syndrome.
For the first time as an independent nosological form, hemorrhagic fever (hemorrhagic nephrosonephritis) was described in 1941 by A.V. Churilov (Professor of the Department of Infectious Diseases of the Military Medical Academy). In the following years, a number of hemorrhagic fevers in various countries of the world were described. The group of hemorrhagic fevers included some diseases that were described earlier (dengue, yellow fever).
Causes of Hemorrhagic Fever
The causative agents of hemorrhagic fevers belong to 4 families of viruses: togaviruses, bunyaviruses, arenaviruses and filoviruses, a common property of which is high tropism to the vascular endothelium.
Hemorrhagic fevers are natural-focal infections, in which the main reservoir and sources of the disease are various animal species, and carriers for a significant proportion of them are arthropods (ticks, mosquitoes). In other cases, the transmission of infection is carried out in other ways – air-dust, alimentary, water, with zoonotic contact, parenterally. In accordance with the peculiarities of the pathogen, they provide a ticker Argentine, Bolivian, Venezuelan, Brazilian, Marburg and Ebola). Although the susceptibility to these infections is quite high, most often the disease is registered among persons who have professional contact with animals and or objects of the wild. In cities, hemorrhagic fever with renal syndrome mainly affects household workers and homeless persons who have contact with synanthropic rodents or their secretions.
Pathogenesis During Hemorrhagic Fevers
Pathogenesis of hemorrhagic conditions in hemorrhagic fevers. Thrombohemorrhagic syndrome (Machabeli syndrome) is an important link in the pathogenesis of many infectious diseases. Thrombohemorrhagic syndrome is a symptom complex caused by the universal and nonspecific properties of blood, lymph, tissue fluid, cellular and intercellular structures to reversibly and irreversibly thicken due to the activation of their ability to coagulate and, as a result of retraction, stratify into components of different aggregative state. Thrombohemorrhagic syndrome in its development passes through 4 stages.
The stage of hypercoagulation begins in the cells of the tissues of the damaged organ, which leads to the release of coagulation-active substances, the reaction of activation of coagulation spreads to the blood. This stage is usually short-lived.
Stage of increasing consumption coagulopathy, intermittent fibripolytic activity. It is characterized by a decrease in the number of platelets and the level of fibrinogen, as well as the consumption of other plasma factors of the coagulation and lymphatic system of the body. This is the stage of the beginning and progressive ICE (incomplete ICE syndrome).
Stage of defibrinogenesis and total, but not permanent fibrinolysis (defibrinogen-fibrinolytic). A synonym for this stage is a complete syndrome of DIC.
The recovery stage or the stage of residual thrombosis and occlusion. With a favorable course of the syndrome, a return to the physiological norms of all factors of the coagulation and lymphatic system of the body is noted.
According to clinical manifestations, there are various forms of thrombohemorrhagic syndrome (fulminant, acute, chronic, latent, hemorrhagic, hyperergic, etc.). Thrombohemorrhagic syndrome is observed in injuries, surgical diseases, in oncology, obstetric pathology, sepsis and many infectious diseases. In this chapter, we consider only the features of the pathogenesis of hemorrhagic syndrome in hemorrhagic fevers.
In hemorrhagic fevers, the primary pathology of suffering develops at the cellular-molecular level, with the obligatory involvement of the endothelial cells of the circulatory system and stem cells of potent bone marrow in the infectious process. The speed of development of the process is due to the aggressiveness of the pathogen and its tropism and to other sensitive cells, for example, macrophage-monocytes, as well as the degree of maturity of the immune system of the individual affected by a specific pathogen. As a result, the normal physiological level of functioning of the endothelium and hematopoietic organs dynamically changes. In the midst of an infection, a total change occurs in the anatomical and morphological integrity and, accordingly, of the functions of the blood microcirculation system. It is accompanied by the deterioration of the trophism of all organs and tissues, hypoxia and their functional insufficiency develops. The process is accompanied by a violation of the thermoregulatory and coordinating centers of the central nervous system, cardiovascular and excretory systems, pulmonary or other organ pathology develops and often patients die in a comatose state. Life-threatening volumetric blood loss is rare, although increased bleeding, as a sign of changes in vascular permeability, is one of the leading symptoms of hemorrhagic viral fevers.
Among the causes of hemorrhagic syndrome, which develops rather quickly and often ends in the death of patients, viruses of five families are known: Arena-, Bunya-, Filo-, Flavi- and Togaviridae. These include the Lassa, Junin, Machupo, Guanarito, Sabia viruses (arenavir-family) viruses – the causative agents of Lassa, Argentinean, Bolivian, Venezuelan and Brazilian fevers, respectively; rift valley fevers and Crimea Congo (Bunyavirus family); yellow fever (flavivirus family); Marburg and Ebola fevers (family of filoviruses), dengue fever, Qasanur forest disease and hemorrhagic fever with renal syndrome (family of togaviruses). The causative agents of tick-borne rickettsiosis, ehrlichiosis and groups of typhus, on the contrary, are involved in hemorrhagic syndrome with a slower and more benign course. Consequently, by attachment to the causative agent of an infectious disease, hemorrhagic syndrome is etiologic.
A wide range of pathogens causing a single clinical complex of symptoms, due to the same type of mechanism of its formation. From the data of morphological and immunohistological studies of the above diseases, it is known that the main pathology develops in the endothelial cells of the microdirculatory system, bone marrow cells and for some infections (Marburg, dengue fever) mononuclear phagocytes, both circulating in the bloodstream and tissue, are involved in the process. This is reflected in the cellular, protein and peptide (kinins, leukotrienes) composition of the blood and the balance of its biologically active components. It affects the activity of the systems of complement, kinin, coagulation and anticoagulation. The latter regulate the vascular tone, their permeability, the secretory activity of the endothelium, the rheological properties of the blood and are responsible for the subjective sensations of pain, fatigue and other symptoms of diseases.
Despite the etiological diversity of pathogens associated with the development of hemorrhagic syndrome, they are united by an identical or very close mechanism for delivering the pathogen to target cells at the initial stage of the infection process. Fever pathogens, transmitted with the participation of blood-sucking carriers, contact through skin scratching or aerogenic through the alveolar-capillary membranes of the lungs, are essentially mechanically transferred to endothelial cells and tissue sedentary macrophages sensitive to the pathogen in places of microtraumas caused by the flow-sucking device. It is at these points or in the alveolar-capillary membranes, at which the infectious aerosol particles are delayed, the primary local process is formed. A protective reaction at the entrance gate is accompanied by simultaneous generalization of the infectious process due to dissemination of the pathogen with blood-lymphatic drainage with a subsequent successively increasing lesion of target cells in organs and tissues remote from the entrance gate of the infection. At the same time, part of the pathogen particles is absorbed by macrophages and other blood cells, for example, by erythrocytes in rickettsiosis and bartonellosis, but is not inactivated due to an insufficient concentration of cytokines, such as interferon gamma (INF-y), tumor necrosis factor alpha (TNF-a), other monokins and the absence of specific neutralizing antibodies in the blood plasma at the time of infection and in the initial period of the disease.
Local damage to physiologically highly active hemostasis-regulating cells in the gateway area of the pathogen and simultaneous generalization of infection with a transmissible mechanism of transmission are predetermined by the characteristics of the bloodsucking of ticks and mosquitoes, carriers of the pathogens of most hemorrhagic fevers, and the features of the anatomical structure of tissue and alveolar capillaries. The synchronicity of the formation of local and generalized processes is explained by the fact that the sucking of the carriers lasts long and intermittently, especially in ticks (up to several days). Periodic suction of blood is accompanied by periodic injection into the capillary of saliva, and in some cases, coxal fluid containing the pathogen, anticoagulants and bloodsucker enzymes.
The infection process at the level of the causative agent begins according to the usual pattern for intracellular parasites: attachment to the surface membrane and its loosening, penetration into the cytoplasm, reproduction or death (in case of an abortive infection), exit into the surrounding intercellular space or channel of the blood, with infection of the adjacent and remote intact cells. The last stage of cell-pathogen interaction is accompanied either by destruction and necrolysis of the first, or by enhancement of intracellular physiological processes with increased production of cytokines and other metabolites of their normal functioning.
The process of overcoming the cell wall by the pathogen is not indifferent for the macroorganism: membrane lipopolysaccharides are split by the carrier phospholipases and the pathogen. As a result, arachidonic acid is released – the precursor substrate of the biologically most active eicosanoids (prostaglandin E2 (PGE9), thrombooxanes, platelet activating factor (PAF), interleukin-I (IL-1) and others), which are responsible in the macroorganism for tonus and permeability of small arterioles and precapillaries, leukocyte chemotaxes, thermoregulation, the feeling of pain and other reactions of the body, united by the common name “endogenous toxicosis.”
Reproduction of the pathogen in endothelial cells by electron-microscopic observations is accompanied by their swelling and vacuolization, and then an obvious pathology – detachment from the basement membrane in the capillary segments or from the underlying cells in larger vessels and the appearance of part of the endothelium cells in the bloodstream. Anatomical defects appear at the junction of the capillary with the exposure of a part of the basement membrane. The weakness of the vascular walls in these loci with a progressive excess of PGE2, PAF and other cytokines causes a persistent dilation of the venule lumen with an increase in their blood supply; blood flow slows down, leukocyte-platelet stasis forms, peripheral-type hypotension, and then edema and hemorrhage due to plasma exudation and migration of blood cells into the perivascular space from postcapillary venules. Initially, the process of exudation is compensated, but the growth of the infectious process as a whole with the expansion of destructive-inflammatory changes in the vascular and macrophage systems overcomes the “threshold” of compensatory protective reactions of the body. The latter is obviously determined by the peculiarities of the constitutional immunity of the sick person, the age degree of maturity of his immune system, and the virulence of the pathogen. The time of overcoming the threshold of the compensatory response is most likely determined (coincides) with the end of the next cycle of reproduction of the pathogen, manifested by an increase in structural and functional cellular changes of a negative nature and the appearance of the pathogen in the blood and exudates on the surface of mucous membranes and skin. The number of peroxides increases in cells, and eicosanoids in plasma. As the pathogen disseminates, the severity of local processes and the multiplicity of infection of the microorganism progressively increase, accompanied by the appearance and development of the infected unspecified symptoms of the disease, creating a general feeling of discomfort. In this initial period of the disease, in addition to quantitative changes in the mediators and cytokines, an imbalance in the blood coagulation-anticoagulation system begins to manifest itself; a sharp deterioration occurs in the patient’s condition, which is usually felt as the onset of the disease. Since that time and in the midst of illness, dramatic changes have occurred in the tissues and blood of the patient. The outflow of plasma into the intercellular spaces is decompensated, perivascular leukocyte infiltration, erythrocyte diapedesis and blood clots increase, and sludge symptoms are formed.
Increased platelet aggregation and leukocyte-neutrophil migration into the vessel walls and perivascular cracks activate the Hagemann factor (factor XII), the “trigger” component of the coagulation cascade. Against the background of thrombocytopenia and leukopenia, symptoms of hypercoagulation develop, characteristic of stage I DIC.
Further progressive structural and functional disorganization of the endothelium, the germinative points of the bone marrow stem cells and others (in yellow fever and Marburg fever – hepatocytes and mononuclear phagocytes) leads to an increase in capillaropathy and, consequently, toxicosis, up to the development of the infectious toxicity, to the development of the infectious toxic syndrome, complete loss of consciousness and perception of the environment, i.e. the state of coma develops (synonym, IET, grade III. The level of cytokines and mediators involved in pyrogenesis (PGEZ, IL-1, leukotrienes) dynamically fluctuates, coagulation – anticoagulation, synthesis of colony-stimulating factors (CSF) begins to decrease. Reduction of CSF is accompanied by suppression of the process self-renewal of potent stem cells; the direction of differentiation of blood cells, in particular neutrophils, and their maturation change.
The unusual against the physiological norm content of the decay products of cells affected by the pathogen, and increased synthesis and secretion of eicosanoids at the initial stage of the infectious process is accompanied by increasing insufficiency of the excretory function of the kidneys and the neutralizing activity of the liver due to ischemia, and in some hemorrhagic infections and due to its direct damage by the pathogen, synchronously flowing with the affected endothelium and other cells. For HFRS with a slower compared with Marburg and Ebola fevers, vascular thrombus and necrosis of endothelial cells are not typical, and the clinic is due to generalized dilation of the capillaries, edema, granulocytes infiltration of large organs and lymph nodes. For this nosoform, the increased permeability of capillaries, including nephrons, reflecting endothelial dysfunction in combination with an imbalance of mediators and other regulatory components of hemostasis, is most noticeable.
At the final stage of viral haemorrhagic fevers with an unfavorable outcome, thrombocytopenia persists due to the loss of platelets in the aggregates and microthrombi, Hagemann factor deficiency, A2 thromboxane and other mediators, the hypocoagulation phase smoothly goes into a state of deep hypocoagulation with the development of symptoms, and the drivers have lost the test patterns, and the hypocoagulation phase gradually goes into a state of deep hypocoagulation with the development of symptoms, and the levels have decreased; and leukocyte count is as low as possible, bleeding reaches a maximum, while body temperature decreases.
Thus, the pathogenesis of hemorrhagic conditions in hemorrhagic fevers reflects a complex of dynamically flowing conjugate processes that overlap each other, the basis of which is:
- deregulation of the normal physiological ratio of the components of the systems providing hemostasis (see above), due to changes in the secretory activity of the cells involved in hemostasis;
- anatomical and morphological exposure of the walls of blood vessels in the most active (in the aspect of its functional activity) parts, namely in the microcirculation areas (arteriole-capillary-venule);
- increase of vascular permeability due to the violation of their integrity and the changing content of vasoactive components in the blood (platelets, eicosanoids, kinins, adrenaline and other pharmacologically active compounds);
- the lag of immunologically important defense reactions of the macroorganism, including in the form of the formation of specific antibodies, from the growth of destructive changes during the generalization of the infectious process;
- the total formation of DIC-symptomatology of varying severity.
At the same time, changes in the blood sequentially develop through the phase of hypercoagulation in the hypocoagulation stage with mandatory thrombosis and leukopenia consumption and a shift of the neutrophil formula to the left. The rate of development of symptoms and the outcome of the disease is determined by the degree of pathogenicity of the pathogen, constitutional features and the immune status of the patient.
Symptoms of Hemorrhagic Fever
Most hemorrhagic fevers are characterized by the same staging of the course of the disease, reflecting the main phases of the pathogenesis of these infections. The incubation period for hemorrhagic fever averages 1-3 weeks. The initial period of the disease has a duration of 2 to 7 days. It is characterized by general toxic phenomena – fever, headache, myalgia and arthralgia, signs kapillyarotoksikoz – flushing of the face, neck, injection vessels sclera and hyperemia of conjunctiva ( “rabbit eye”), hemorrhagic enanthema on the soft palate, positive endothelial symptoms often – bradycardia and hypotension , changes in peripheral blood (leukopenia until the 3-4th day of illness, increasing neutrophilic shift to the left, thrombocytopenia). The peak of hemorrhagic fever lasts 1-2 weeks. It often develops after a short-term decrease in body temperature and is accompanied by a sharp increase in intoxication, hemodynamic disturbances, hemorrhagic syndrome and organ lesions characteristic of a particular nosological form. In this period, severe (often fatal) complications often occur: toxic shock, acute renal failure, cerebral coma, etc. The recovery period lasts several weeks and is characterized by a long-standing astheno-vegetative syndrome and slow recovery of impaired functions of various organs.
Diagnosis of Hemorrhagic Fever
Diagnosis of hemorrhagic fevers is based on clinical, epidemiological and laboratory data. In specific diagnostics, serological (RSK, RNIF, etc.), immunochemical (ELISA), molecular biological (PCR, hybridization), and sometimes virological methods are used.
Differential diagnosis is influenza, leptospirosis, rickettsial diseases, a number of arboviral infections, non-hemorrhagic fever, meningococcal infection, sepsis, purpura trombogemorragichesky (Verlgofa disease), hemorrhagic vasculitis (Henoch-Schonlein purpura disease) and others.
Hemorrhagic Fever Treatment
All patients should be hospitalized and they need careful care. Assign semi-liquid, easily digestible and high-calorie foods with a maximum enrichment of the diet with vitamins, especially C and B (fresh vegetables and fruits, natural fruit and berry juices, dogrose infusion, yeast). It is recommended to give the patient up to 600-800 mg of ascorbic acid by mouth daily, vitamin P; due to the presence of hemorrhagic phenomena, prescribe vitamin K (vikasol) of 0.015 g 4 times a day for 4 days.
It should be borne in mind that hemorrhagic manifestations can reach the greatest development not in the febrile period of the disease, but after its termination.
Intravenous glucose infusions are also used (40% solution of 40-50 ml daily). In the febrile period of the disease, blood transfusions of 125–150 ml every other day, intramuscular injections of campolone or anti-anemone (2 ml daily for 5–7 days), and oral iron preparations are recommended. As an auxiliary therapeutic agent, a desensitizing (antihistamine) drug Dimedrol is given by mouth at 0.08 g 4 times a day for 4-6 days. The convalescent needs bed rest until the clinical symptoms disappear; after discharge, medical supervision is required. Forecast. The severity of the clinical course of hemorrhagic fevers varies widely. Far Eastern nephrosonephritis is significantly more severe than the other hemorrhagic fevers described here, and in some cases it ends in death.
Prevention of Hemorrhagic Fevers
The success of the fight against the spread of hemorrhagic fevers is determined primarily by the results of activities for the destruction of vectors of infection and for protecting healthy people from their bites. In areas where there are diseases, careful clearing of land for residential and industrial premises is needed: mowing grass, destroying shrubs, burning fallen leaves.
Persons working or living in areas where hemorrhagic fevers are encountered should wear boots, gloves, and special overalls; impregnation of industrial clothing with tick repellent preparations is obligatory. The need for these activities depends on the specific epidemiological situation. These tools provide protection for the person from the bites of infected ticks, which are carriers of hemorrhagic fevers.
For the purpose of specific prevention of Omsk hemorrhagic fever in natural foci of this disease, prophylactic vaccination of the population is used with an emulsion of a virus killed by formalin (vaccinations are made according to a special instruction).
The main role in the prevention of hemorrhagic fevers does not belong to vaccination, but to the systematic implementation of the above measures.