Viral hemorrhagic fevers

Viral haemorrhagic fevers are a group of special natural focal infectious diseases that are recorded on all continents of the world, except Australia.

Diseases are characterized by specific damage to the system of hemostasis (vascular, platelet and plasma links), multiorgan pathology with the development of severe hemorrhagic and intoxication syndromes, high lethality.

Epidemiology of viral hemorrhagic fevers

Most viral haemorrhagic fevers are transmitted through arthropods (mosquitoes, mosquitoes, mites) and belong to arbovirus infections. However, direct transmission from person to person is also possible (viruses Lassa, Sabii, Crimean-Congo, Marburg, Ebola). Separation from animals (rodents) is also important in the spread of viral hemorrhagic fevers (Lassa, Hantaviruses). Rodents (rats, mice) with asymptomatic carrier play a special role in maintaining the infection in nature. It is possible to maintain the circulation of the virus in wild conditions in monkeys and primates (yellow fever, dengue). A natural reservoir of the disease is not always established ( Ebola, Marburg, Sabik viruses ).

The risk of transmission of viral hemorrhagic fevers with direct contact from person to person

Virus	Disease	Transfer from person to person
1	2	3
ARENAVIRIDAE
Arenavirus Lassa	Hemorrhagic fever Lossa	Yes
		Nosocomial cases are rare
Arenaviruses: Junin, Machupo, Guanarito, Sabia viruses	South American haemorrhagic fevers (Argentine, Bolivian, Venezuelan, Brazilian)	Yes, seldom
		Nosocomial cases are rare
BUNYAVIRIDAE
Phlebovirus Rift Valley fever	Hemorrhagic fever of the Rift Valley (Rift Valley)	No
Nairovirus Crimean-Congo	Crimea-Congo hemorrhagic fever	Usually nosocomial cases
Hantaviruses: Hantaan, Puumala, Dobrava, Seoul and others	Hemorrhagic fever with renal syndrome	No
Hantavirus Sin Nombre and Others	Hantavirus Pulmonary Syndrome	No
FILOVIRIDAE
Filoviruses: Marburg, Ebola	Marburg and Ebola GL	Yes, in 5-25% of cases
FLAVIVIRIDAE
Flavivirus Yellow fever	Yellow fever	No
Flavivirus Dengue	Dengue and dengue GL	No
Flavivirus Omsk hemorrhagic fever	Omsk hemorrhagic fever	No
Flaviviruses: Kyasanur Forest disease, Alkhurma hemorrhagic fever	Kiasanur forest disease and Alkhurma hemorrhagic fever	No

[1], [2], [3], [4], [5], [6], [7], [8],

What causes viral hemorrhagic fevers?

Viral hemorrhagic fevers are caused by RNA-containing viruses that belong to four different families: Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. Currently, this group includes about 20 viruses. Given the severity of the course of viral hemorrhagic fevers, the ability to rapidly spread, in accordance with the International Health Regulations (WHO, 2005), they are classified as dangerous and especially dangerous infectious diseases of man. With many viral haemorrhagic fevers, there is a significant risk of transmission of infection with direct contact with the patient, which can be realized, in particular, in the spread of diseases in hospital settings. The causative agents of viral hemorrhagic fevers are referred to as potential agents of bioterrorism.

Pathogenesis of viral hemorrhagic fevers

The pathogenesis of viral hemorrhagic fevers remains insufficiently studied to the present day. At the same time, the similarity of the main pathogenetic and clinical aspects of these diseases was established, which allowed them to be grouped together, despite the fact that pathogens belong to different RNA-containing families of viruses. In the study of pathological processes associated with pathogens of viral hemorrhagic fevers, experimental models (monkeys, rats) are used, clinical observations in patients are few.

For all viruses that cause hemorrhagic fevers, it is characteristic of the defeat of various cells and tissues of the patient's body. Of particular importance is the ability of viruses to infect immunocompetent cells that play an important role in anti-infectious immunity, resulting in severe immunosuppression and high viremia in patients. The most pronounced immunosuppression and viremia are observed in patients with a fatal course of the disease, while a lightning toxic shock develops, in the pathogenesis of which the main role is played by pro-inflammatory cytokines. Immunosuppression in viral hemorrhagic fevers is associated with low titers of specific antibodies, especially in the early periods of severe diseases.

Like many RNA-containing viruses, the causative agents of hemorrhagic fevers have many pathogenicity factors that ensure adhesion, invasion and replication to different cells. An important pathogenetic aspect of the introduction of viruses into various cells of the human body is the presence on the surface of these cells of various molecules (integrins, lectins, glycoproteins, etc.) that play the role of specific surface receptors. Replication of viruses occurs in monocytes, macrophages, dendritic cells, endothelial cells, hepatocytes, in cells of the adrenal cortex. Experimental studies on monkeys infected with the Ebola virus showed that the causative agent in the early stages mainly affects monocytes, macrophages and dentritic cells; at the same time, endothelial cells are affected at a later date. However, early endothelial damage is characteristic of hantavirus hemorrhagic fevers, although this is believed to be due to indirect infection of viruses. Immunological aspects of the replication of viral hemorrhagic fevers in the human body are currently being studied.

The mechanisms of endothelial damage in viral hemorrhagic fevers remain to the end not studied and discourteous. Two mechanisms have been established: immuno-mediated (the effect of immune complexes, components of the complement system, cytokines) and direct (cytotoxic) damage to the endothelium as a result of viral replication. The reduced functional state of the endothelium in viral haemorrhagic fevers promotes the development of a wide range of lesions - from increased vascular permeability to massive bleeding. With Ebola fever, it was shown in the experiment that endothelial damage is mainly associated with immunopathological reactions, and viral replication in the endothelium is recorded only in the late stages of the development of the infectious process. At the same time, with Lassa fever, it is established that viral replication in the endothelium occurs at the earliest stages of the disease, but without pronounced structural cell damage.

Along with the lymphoid tissues of the human body, containing a large number of macrophages, the liver, kidney and adrenal cells are important targets for the defeat of hemorrhagic fever viruses. With the development of viral hemorrhagic fevers in monkeys, various degrees of liver damage have been identified in experimental conditions, but these lesions are rarely fatal. An exception is yellow fever, in which liver damage is an important pathogenetic aspect of the development of the disease. Yellow fever is characterized by a direct correlation of serum ALT and ACT levels with the degree of liver damage that has prognostic value in this disease. For all viral hemorrhagic fevers, a decrease in protein-synthetic liver function is characteristic, which is manifested by a decrease in plasma coagulation factors, which contributes to the development of hemorrhagic syndrome. In addition, a reduced synthesis of albumin leads to a decrease in the osmotic pressure of the plasma, resulting in the development of peripheral edema, which is especially characteristic of the Lassa fever.

The defeat of the kidneys is mainly due to the development of serous hemorrhagic edema of the interstitial substance of pyramids, tubular necrosis and, as a result, the development of acute renal failure.

The defeat of cells of the adrenal cortex is accompanied by the development of hypotension, hyponatremia, hypovolemia. Reduced function of the adrenal cortex plays an important role in the development of toxic shock in patients with viral hemorrhagic fever.

In experimental studies, it has been established that viral hemorrhagic fevers are characterized by the development of necrotic processes in the spleen and lymph nodes with minimal manifestations of the inflammatory response of tissues. As a result, in most viral haemorrhagic fevers, rapidly progressive lymphopenia is observed (with hantavirus hemorrhagic fevers, more often lymphocytosis). Despite the development of significant lymphopenia, minimal replication of viruses in lymphocytes has been established. In the experiment with Ebola, Marburg and Argentine haemorrhagic fevers, it was shown that lymphopenia is associated mainly with marked apoptosis of lymphocytes caused by a significant synthesis of TNF, nitric oxide, and pro-inflammatory cytokines. There are few data on the development of neutrophilia with a rod-shaped shift in the initial period of viral hemorrhagic fever.

Viruses of hemorrhagic fevers in humans and primates cause the expression of a variety of inflammatory and anti-inflammatory mediators, including interferons, interleukins (lb, 6, 10, 12), TNF-a, as well as nitric oxide, reactive oxygen species. In vitro studies conducted on various human cells, it has been shown that hemorrhagic fever viruses stimulate the release of numerous regulatory mediators. High expression of biologically active mediators in the blood leads to an immunological imbalance and to the progression of the disease. A direct relationship between the level of cytokines (IL-lb, 6, TNF-a) and the severity of the course of viral hemorrhagic fevers was established.

In recent years, the important role of nitric oxide in the genesis of pathological processes in viral hemorrhagic fevers has been shown. The increased synthesis of nitric oxide leads, on the one hand, to the activation of apoptosis of lymphoid tissue, and on the other hand to the development of pronounced dilatation of the microcirculatory bed with arterial hypotension, which plays an important role in the development of pathogenetic mechanisms of toxic shock.

The role of interferons of various types in the pathogenesis of viral hemorrhagic fevers has not been fully studied. With many viral hemorrhagic fevers, high levels of interferon of the 1st and 2nd types are observed in the blood of patients.

Disturbances in the hemostatic system are characterized by the development of hemorrhagic syndrome: bleeding, the presence of petechiae on the skin, mucous membranes. At the same time, massive hemorrhage with viral hemorrhagic fevers is rare, but even in these cases, a decrease in blood volume is not the leading cause of death of the patient. Hemorrhagic eruptions on the skin as manifestations of the lesion of the microcirculatory bed are usually localized in the region of the axillary cavities, in the groin, on the chest, in the face, which is more often observed with Ebola and Marburg fevers. For all VGL, the development of microcirculation in many internal organs is characteristic.

Thrombocytopenia is a common symptom of many viral hemorrhagic fevers (less pronounced with Lassa fever); at the same time, a sharp decrease in the functional activity of thrombocytes is observed with all fevers. This is associated with a pronounced inhibition of the synthesis of megakaryocytes, the precursors of platelets. As a result of a decrease in the number of platelets and their functional activity, the functional state of the endothelium is significantly impaired, which aggravates the development of hemorrhagic syndrome.

To date, the question of the genesis of the development of DIC syndrome in viral hemorrhagic fevers has not been resolved. Most researchers consider abnormalities in the hemostasis system in viral hemorrhagic fevers as an imbalance in the activation of coagulating and anti-coagulation systems. In the blood serum, many markers of the DIC-syndrome are defined: increased fibrinogen levels, fibrin and fibrinogen degradation products (PDF), D-dimers, plasma fibrinolysis activators, protein C decrease, activated partial thrombin time (APTTV). The development of DIC syndrome in patients with viral hemorrhagic fever, especially often observed with Ebola, Marburg, Krym-Congo, Rift Valley, Argentine, hantavirus pulmonal syndrome, is an extremely unfavorable sign.

Symptoms of viral hemorrhagic fevers

The incubation period of viral haemorrhagic fever varies from 4 to 21 days, usually 4-7 days. Symptoms of viral viral hemorrhagic fever are characterized by:

1. acute onset of the disease, febrile fever, marked symptoms of intoxication (headache, myalgia, joint pain), often - abdominal pain, possible diarrhea;
2. signs of damage to the endothelium of the vessels (postcapillary network) with the appearance of hemorrhagic rashes on the skin and mucous membranes, the development of bleeding (gastrointestinal, pulmonary, uterine, etc.), DIC syndrome;
3. frequent development of hepatic and renal insufficiency with focal and massive necrosis in liver and kidney tissue (tubular necrosis), multiple organ pathology - a characteristic lesion of the lungs and other organs (myocarditis, encephalitis, etc.);
4. thrombocytopenia, leukopenia (less often leukocytosis), hemoconcentration, hypoalbuminemia, increased ACT, ALT, albuminuria;
5. the possibility of developing erased forms and the subclinical course of the disease with severe seroconversion in all viral haemorrhagic fevers.

Diagnosis of viral hemorrhagic fevers

Laboratory diagnostics of viral hemorrhagic fever is based on the determination of specific antibodies (to IgM and IgG) in ELISA and the determination of specific RNA viruses in PCR; virological studies are less frequent. In complex diagnostic cases with a fatal outcome not confirmed by serological test results, the virus can be isolated from autopsy material. However, it should be borne in mind that, if safety measures are not taken, working with infected material can cause subsequent laboratory and nosocomial cases of viral hemorrhagic fevers.

[9], [10], [11], [12],

Treatment of viral hemorrhagic fevers

Pathogenetic treatment of viral hemorrhagic fever, aimed at detoxification, rehydration and correction of hemorrhagic syndrome, is the main in most cases of viral hemorrhagic fevers. Antiviral treatment of viral hemorrhagic fever with ribavirin is effective in viral hemorrhagic fevers, caused only by certain viruses from the Arenaviridae and Bunyaviridae families .

How are viral hemorrhagic fevers prevented?

It is necessary: urgent hospitalization of a patient in a special box with reduced atmospheric pressure, isolation of samples of infected biological material received from him, timely notification of health authorities about the case. Care for the patient and work with the infected material are carried out with strict adherence to individual universal precautions for personnel. All personnel are also exposed to isolation. Some viral hemorrhagic fevers (yellow fever, Crimea-Congo, etc.) can be prevented with the help of a specific preventive vaccination of medical personnel.

When in contact with the patient at a distance of less than 1 meter, medical personnel work in special clothing with glasses and gloves, and also uses air respirators when the patient has vomiting, diarrhea, coughing, bleeding. Allocations from the patient are processed and do not merge into the system of general sanitation until 6 weeks of the reconvalescence period or until negative results of laboratory tests are obtained from the suspect for viral hemorrhagic fever. Used linen is burned or processed in an autoclave (without connection to a common sewage system).