Viral hemorrhagic fevers

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

The diseases are characterized by specific damage to the hemostasis system (vascular, platelet and plasma links) of a person, multiple organ pathology with the development of severe hemorrhagic and intoxication syndromes, and high mortality.

Epidemiology of viral hemorrhagic fevers

Most viral hemorrhagic fevers are transmitted by arthropods (mosquitoes, gnats, ticks) and are arbovirus infections. However, direct transmission from person to person is also possible (Lassa, Sabii, Crimean-Congo, Marburg, Ebola viruses). Animal (rodent) secretions are also important in the spread of viral hemorrhagic fevers (Lassa, Hantaviruses). Rodents (rats, mice) with asymptomatic carriage often 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). The natural reservoir of the disease is not always established ( Ebola, Marburg, Sabik viruses ).

Risk of transmission of viral hemorrhagic fevers through direct person-to-person contact

Arenaviruses: Junin, Machupo, Guanarito, Sabia viruses

Virus	Disease	Human-to-human transmission
1	2	3
ARENAVIRIDAE
Arenavirus Lassa	Lassa hemorrhagic fever	Yes
		Nosocomial cases are rare.
South American hemorrhagic fevers (Argentine, Bolivian, Venezuelan, Brazilian)	Yes, rarely
	Nosocomial cases are rare.
BUNYAVIRIDAE
Phlebovirus Rift Valley fever	Rift Valley Hemorrhagic Fever	No
Crimean-Congo Nairovirus	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	Kyasanur forest disease and Alkhurma hemorrhagic fever	No

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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 viral hemorrhagic fevers, the ability to quickly spread, in accordance with the International Sanitary Rules (WHO, 2005) they are classified as dangerous and especially dangerous infectious diseases of humans. With many viral hemorrhagic fevers, there is a significant risk of transmission of infection through 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 considered potential agents of bioterrorism.

Pathogenesis of viral hemorrhagic fevers

The pathogenesis of viral hemorrhagic fevers remains poorly understood to date. At the same time, similarities in the main pathogenetic and clinical aspects of these diseases have been established, which has allowed them to be combined into one group, despite the fact that the pathogens belong to different RNA-containing families of viruses. When studying pathological processes associated with pathogens of viral hemorrhagic fevers, experimental models (monkeys, rats) are used; there are few clinical observations of patients.

All viruses that cause hemorrhagic fevers are characterized by damage to various cells and tissues of the patient's body. Of particular importance is the ability of viruses to damage immunocompetent cells that play an important role in anti-infective immunity, as a result of which patients develop severe immunosuppression and high viremia. The most severe immunosuppression and viremia are observed in patients with a fatal course of the disease, with the development of fulminant toxic shock, in the pathogenesis of which proinflammatory cytokines play the main role. Low titers of specific antibodies are also associated with immunosuppression in viral hemorrhagic fevers, especially in the early stages of severe diseases.

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

The mechanisms of endothelial damage in viral hemorrhagic fevers remain poorly understood and debatable. Two mechanisms have been established: immune-mediated (action of immune complexes, components of the complement system, cytokines) and direct (cytotoxic) damage to the endothelium as a result of viral replication. Reduced functional state of the endothelium in viral hemorrhagic fevers contributes to the development of a wide range of lesions - from increased vascular permeability to massive bleeding. In Ebola fever, it was shown experimentally that endothelial damage is mainly associated with immunopathological reactions, and viral replication in the endothelium is recorded only at late stages of the infectious process. At the same time, in Lassa fever, it was found 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, which contain a large number of macrophages, important targets for damage by hemorrhagic fever viruses are the cells of the liver, kidneys and adrenal glands. In the development of viral hemorrhagic fevers in monkeys under experimental conditions, various degrees of liver damage have been revealed, but these lesions are rarely fatal. An exception is yellow fever, in which liver damage is an important pathogenetic aspect of the disease. Yellow fever is characterized by a direct correlation between the levels of serum ALT and AST with the degree of liver damage, which has prognostic significance in this disease. All viral hemorrhagic fevers are characterized by a decrease in the protein-synthetic function of the liver, which is manifested by a decrease in the levels of plasma coagulation factors, which contributes to the development of hemorrhagic syndrome. In addition, reduced synthesis of albumin leads to a decrease in the osmotic pressure of plasma, resulting in the development of peripheral edema, which is especially characteristic of Lassa fever.

Kidney damage is mainly associated with the development of serous-hemorrhagic edema of the interstitial substance of the pyramids, tubular necrosis and, as a result, the development of acute renal failure.

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

Experimental studies have shown that viral hemorrhagic fevers are characterized by the development of necrotic processes in the spleen and lymph nodes with minimally expressed phenomena of the inflammatory reaction of tissues. As a result, most viral hemorrhagic fevers are characterized by rapidly progressing lymphopenia (in hantavirus hemorrhagic fevers - more often lymphocytosis). Despite the development of significant lymphopenia, minimal viral replication in lymphocytes has been established. In an experiment with Ebola, Marburg and Argentine hemorrhagic fevers, it was shown that lymphopenia is associated mainly with pronounced apoptosis of lymphocytes due to significant synthesis of TNF, nitric oxide, proinflammatory cytokines. There are few data on the development of neutrophilia with a band shift in the initial period of viral hemorrhagic fever.

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

In recent years, the important role of nitric oxide in the genesis of pathological processes in viral hemorrhagic fevers has been demonstrated. Increased synthesis of nitric oxide leads, on the one hand, to activation of apoptosis of lymphoid tissue, and on the other hand, to the development of pronounced dilation 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. In many viral hemorrhagic fevers, high levels of interferon types 1 and 2 are observed in the blood of patients.

Disturbances in the hemostasis system are characterized by the development of hemorrhagic syndrome: bleeding, the presence of petechiae on the skin and mucous membranes. At the same time, massive blood loss in viral hemorrhagic fevers is rare, but even in these cases, a decrease in blood volume is not the leading cause of death. Hemorrhagic rashes on the skin as manifestations of damage to the microcirculatory bed are usually localized in the armpits, groin, chest, and face, which is more often observed in Ebola and Marburg fevers. All VHFs are characterized by the development of microhemorrhages in many internal organs.

Thrombocytopenia is a common symptom of many viral hemorrhagic fevers (less pronounced in Lassa fever); at the same time, a sharp decrease in the functional activity of platelets is observed in absolutely all fevers. This is associated with a pronounced inhibition of the synthesis of megakaryocytes - platelet precursors. 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.

The issue of the genesis of DIC syndrome development in viral hemorrhagic fevers has not been resolved to date. Most researchers consider disorders in the hemostasis system in viral hemorrhagic fevers as an imbalance in the activation of the coagulation and anticoagulation systems. Many markers of DIC syndrome are determined in the blood serum: increased levels of fibrinogen, fibrin and fibrinogen degradation products (FDP), D-dimers, plasma fibrinolysis activators, decreased protein C, changes in activated partial thrombin time (APTT). The development of DIC syndrome in patients with viral hemorrhagic fever, especially often observed in Ebola, Marburg, Crimean-Congo, Rift Valley, Argentina fever, and hantavirus pulmonary syndrome, is an extremely unfavorable sign.

Symptoms of viral hemorrhagic fevers

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

1. acute onset of the disease, febrile fever, severe symptoms of intoxication (headache, myalgia, joint pain), often abdominal pain, possible diarrhea;
2. signs of damage to the vascular endothelium (postcapillary network) with the appearance of hemorrhagic rash on the skin and mucous membranes, the development of bleeding (gastrointestinal, pulmonary, uterine, etc.), DIC syndrome;
3. frequent development of liver and kidney failure with focal and massive necrosis in the liver and kidney tissue (tubular necrosis), multiple organ pathology - characteristic damage to the lungs and other organs (myocarditis, encephalitis, etc.);
4. thrombocytopenia, leukopenia (less often leukocytosis), hemoconcentration, hypoalbuminemia, increased AST, ALT, albuminuria;
5. the possibility of developing latent forms and subclinical course of the disease with pronounced seroconversion in all viral hemorrhagic 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 viral RNA in PCR; virological studies are performed less frequently. In complex diagnostic cases with a fatal outcome, not confirmed by the results of serological studies, the virus can be isolated from autopsy material. At the same time, it should be borne in mind that if safety measures are not observed, working with infected material can cause subsequent laboratory and nosocomial cases of viral hemorrhagic fevers.

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Treatment of viral hemorrhagic fevers

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

How are viral hemorrhagic fevers prevented?

The following is required: urgent hospitalization of the patient in a special box with reduced atmospheric pressure, isolation of samples of infected biological material obtained from him, timely notification of health authorities about the case of the disease. Care for the patient and work with infected material are carried out in strict compliance with individual universal precautions for personnel. All personnel are also subject to isolation. Some viral hemorrhagic fevers (yellow fever, Crimean-Congo, etc.) can be prevented with the help of possible specific prophylactic vaccination of medical personnel.

When in contact with a patient at a distance of less than 1 meter, medical personnel work in special clothing with glasses and gloves, and also use air respirators if the patient has vomiting, diarrhea, cough, bleeding. Excretions from the patient are processed and not discharged into the general sewage system until 6 weeks of the convalescence period or until negative laboratory test results are obtained for a suspected viral hemorrhagic fever. Used linen is burned or processed in an autoclave (without connection to the general sewage system).