Rabies (hydrophobia) in adults: clinical guidelines

List of Abbreviations

RIG – rabies immunoglobulin**

WHO – World Health Organization

GGT – gamma-glutamyl transferase

D.Sc. in Medicine – Doctor of Medical Sciences

DNA – deoxyribonucleic acid

IMV – invasive mechanical ventilation

EIA – enzyme immunoassay

Ph.D. in Medicine – Candidate of Medical Sciences

LDH – lactate dehydrogenase

Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation

CBC – complete blood count (differential)

UA – urinalysis

BV – blood volume

PT – prothrombin index

ARDS – acute respiratory distress syndrome

DFA – direct fluorescent antibody test

RCT – randomized controlled trial

NT – neutralization test

IFA – indirect fluorescent antibody assay

RNA – ribonucleic acid

CFT – complement fixation test

RF – Russian Federation

CSF – cerebrospinal fluid

ESR – erythrocyte sedimentation rate

CNS – central nervous system

Terms and Definitions

Aerophobia – a pathological reaction to air movement accompanied by fear, anxiety, and convulsions.

Hydrophobia – pathological fear of water, accompanied by convulsive attacks, observed only in humans.

Evidence-based medicine – an approach to medical practice in which decisions regarding the use of preventive, diagnostic, and therapeutic interventions are made based on available evidence of their efficacy and safety, with such evidence being sought, compared, synthesized, and widely disseminated for use in the best interest of patients.

Disease – a disturbance of bodily function, working capacity, and the ability to adapt to changing environmental conditions arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Instrumental diagnostics – diagnostics performed by examining a patient using various devices, apparatuses and instruments.

Quality of medical care – a set of characteristics reflecting the timeliness of medical care, the correctness of the choice of prevention, diagnostic, treatment and rehabilitation methods during the provision of medical care, and the degree of achievement of the planned result.

Clinical guidelines – a document based on proven clinical experience, describing the physician's actions regarding the diagnosis, treatment, rehabilitation and prevention of diseases, and helping them make correct clinical decisions.

Laboratory diagnostics – a set of methods aimed at analyzing the test material using various specialized equipment.

Lysophobia – the fear of contracting rabies; it is a specific type of phobia.

Medical worker – an individual who has a medical or other education, works in a medical organization and whose labor (job) duties include the implementation of medical activities, or an individual who is a sole proprietor directly engaged in medical activity.

Working group – two or more people of the same or different professions working together and in a coordinated manner to create clinical guidelines, and bearing joint responsibility for the results of this work.

Syndrome – a set of symptoms sharing a common etiology and pathogenesis.

Guillain-Barré syndrome – an acute autoimmune inflammatory polyradiculoneuropathy manifested by flaccid paresis, sensory disturbances, and autonomic disorders.

Condition – changes in the body arising due to the exposure to pathogenic and (and/or) physiological factors and requiring medical care.

Level of evidence certainty – reflects the degree of certainty that the found effect of a medical intervention is true.

Grade of recommendation – reflects not only the certainty in the reliability of the intervention's effect, but also the certainty that following the recommendations will bring more benefit than harm in a specific situation.

Encephalitis – inflammation of the brain tissue.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Rabies (hydrophobia, lat. – rabies, gr. – lyssa) is a viral zoonotic natural-foci and anthropurgic disease with a contact transmission mechanism that affects all warm-blooded vertebrate animals, proceeds with severe damage to the nervous system and results in a fatal outcome for humans [1, 2, 3, 10].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causative agent of rabies is the RNA-containing virus Neuroryctes rabid from the Rhabdoviridae family, genus Lyssavirus. Currently, the International Committee on Taxonomy of Viruses recognizes 14 species of lyssaviruses, which initiate clinically indistinguishable diseases, leading in some cases to overdiagnosis of rabies [1, 3, 4, 6]. In nature, lyssaviruses are associated with specific reservoirs, predominantly predators and bats. The circulation of four lyssavirus species has been proven on the territory of the Russian Federation: Rabies lyssavirus, European bat 1 lyssavirus, Irkut lyssavirus, and West Caucasian bat lyssavirus.

The virus has a cylindrical shape resembling a rifle bullet, with sizes ranging within 90-200 nm [1, 3, 4, 6]. There are seven genotypes of the rabies virus, combined on the basis of phylogenetic relationship and antigenic characteristics into three phylogroups. The classical (street) rabies virus (RABV, genotype 1) is part of phylogroup I, is widespread in Europe, Asia, North and South America, and is highly pathogenic for all types of warm-blooded animals and humans. The fixed strain was obtained artificially (by repeated passage of the wild virus through rabbit brains), is non-pathogenic for humans, and is used in the production of antirabic vaccines (J07BG) [3].

In the environment, the rabies virus is unstable and dies quickly. The pathogen is resistant to temperatures below 0°C, is destroyed at 60°C within 10 minutes, and instantly at 100°C. The virus is sensitive to ultraviolet and direct sunlight, antiseptics and disinfectants (including chlorine-containing agents, ethanol**, formaldehyde) and drying [1, 3, 4, 6].

Lyssaviruses are exclusively neurotropic pathogens causing acute progressive encephalomyelitis (animal rabies and human hydrophobia).

Typically, transmission of the pathogen occurs via vector-type epizootic chains exclusively through traumatic contacts with a sick source animal (bites, scratches, and occasionally through contamination of damaged external and internal integuments) by intraneural entry of virus-containing saliva.

As a result of injection transdermal infection, the pathogen penetrates into motor or sensory neurons and spreads centripetally to the central nervous system (CNS) using retrograde axonal transport along neural pathways [1, 3, 4, 6].

Active reproduction of the virus occurs in the medulla oblongata, cerebral aqueduct, horns of Ammon of the hippocampus, centers of the vagus nerve ($n.vagus$) and glossopharyngeal nerve ($n.glossopharyngeus$), causing spasms of the pharynx and vocal cords. The virus also actively multiplies in the cardiac ganglia and the Gasserian ganglion of the trigeminal nerve. Then the rabies virus spreads in the reverse direction centrifugally along autonomic nerve fibers to the periphery. By the same perineural pathway, it enters the salivary glands (being excreted in the saliva of a sick individual starting from the end of the incubation period), lacrimal glands, cornea, kidneys, lungs, liver, intestines, pancreas, skeletal muscles, skin, heart, papillae of the tongue, adrenal glands, hair follicles, etc. The role of hematogenous and lymphogenous pathways of virus spread in the body cannot be ruled out either [4-5].

Multiplying in nervous tissue, the virus causes specific meningoencephalitis with moderate inflammatory changes, relatively mild destruction of nerve cells, accompanied by edema and swelling of the brain tissue. Death occurs due to asphyxia and cardiac arrest resulting from damage to vital centers – the respiratory and vasomotor centers [6]. Worth noting is the discrepancy between the severe neurological manifestations of the disease and the scanty pathomorphological changes in the brain tissue. The histological picture resembles that of other viral CNS infections: hyperemia, moderate chromatolysis, nuclear pyknosis and neuronophagia, infiltration of perivascular spaces with lymphocytes and plasma cells with the formation of lymphoid "sleeves" around brain venules, proliferation of microglia, and hydropic degeneration. Destruction of neurons is observed in the cerebral cortex and cerebellum, thalamus, subthalamic region, substantia nigra, cranial nerve nuclei, midbrain, basal ganglia, and pons. However, maximum changes are present in the medulla oblongata, especially in the region of the floor of the fourth ventricle. Lymphocytic infiltrates (rabies tubercles) appear around areas of affected cells. Eosinophilic round inclusions with basophilic granules – specific Negri bodies, about 10 nm in size, representing sites of production and accumulation of rabies virions – are formed in the cytoplasm of affected brain cells (most often in the neurons of the Ammon's horn). Simultaneously, rabies glial nodules of Babès are formed around nerve cells showing dystrophic and necrotic phenomena. In 20% of patients, Babès-Negri bodies cannot be detected, but their absence does not exclude the diagnosis of rabies [4, 6].

1.3 Epidemiology of the Disease or Condition

Rabies is a zoonotic infection. Reservoir hosts are considered to be bats, and not necessarily vampire bats. Without getting sick themselves, they ensure the prolonged circulation of the virus. The main host of rabies in nature is wild animals. Synanthropic animals become infected from wild ones, creating anthropurgic foci and increasing the threat of disease transmission to humans. Among domestic mammals, the dog is unique as the only representative that is a reservoir, vector, and victim of lyssavirus. Felines are only efficient vectors, not reservoirs, and play an increasingly important role in the epidemiology of the disease [18].

In the modern period, uncontrolled stray dogs in low- and middle-income countries create public health problems associated with rabies.

There are two main epidemic forms of the disease: urban rabies and sylvatic rabies.

In the Russian Federation, the forest type of rabies is predominantly registered, with the largest number of epizootic foci recorded in the Central, Privolzhsky (Volga), Ural, Southern, and Siberian Federal Districts, which account for 77% of all registered cases among animals [7, 8]. Every year, cases of rabies are registered in the country among all categories of animals: wild (foxes, raccoon dogs, wolves, etc.), domestic (dogs, cats), and farm animals (cattle, horses, small ruminants).

Stray animals pose the greatest danger, as their risk of infection with the rabies virus is significantly higher [8-10].

Globally, rabies virus transmission is possible through vampire bat bites (more commonly occurring in Mexico, Argentina, and Central America); cases of rabies following insectivorous bat bites have been reported in the USA, Europe, Australia, Africa, India, as well as in Russia (Belgorod Oblast) and Ukraine [7, 8].

The source of infection for humans is animals in the incubation period of the disease or with the clinical picture of rabies. The main mechanism of human infection is contact. The virus is excreted into the external environment with the saliva of an infected animal. Humans are infected through a bite by a sick animal, or through salivation of the skin (in the presence of microtraumas) and mucous membranes (including undamaged ones) [2-3, 11]. The appearance of the virus in saliva can be detected even before the development of clinical manifestations of the disease in animals. Cases of human illness resulting from bites by outwardly healthy animals that continue to remain so for a long time have been described [12].

The possibility of airborne transmission has been proven, and alimentary and transplacental routes of virus transmission are not excluded. In countries and regions where bats are the main reservoir (primarily the USA, South America), in addition to bites, infection can occur via an aerosol mechanism when visiting caves inhabited by colonies of bats in whose population the rabies virus circulates [13]. Rare cases of aerosol infection mechanisms in laboratory settings have also been documented [14].

Rabies is not transmitted from human to human through direct contact. Although the saliva of a person ill with rabies contains the rabies virus, which theoretically allows for the possibility of its transmission to other people, in practice this variant of the contact mechanism of human infection has not received convincing confirmation [9]. Nevertheless, according to classical concepts [14], caring for and assisting patients with rabies carries a high risk of infection and requires preventive post-exposure vaccination [15].

Cases of rabies transmission from a donor to a recipient via an infected corneal graft, as well as after organ transplantation (lungs, liver, kidneys) and blood vessels, have been described [16-19].

According to WHO data, rabies is reported in more than 150 countries and territories, mainly in Asia and Africa. Tens of thousands of people die from it annually, with 40% of them being children under 15 years of age. In 99% of human rabies cases, infection occurs from dogs as a result of bites and scratches. WHO experts indicate that rabies is fatal in 100% of cases. It is estimated that 59,000 people die from rabies worldwide each year; however, due to underreporting, the number of registered cases often differs from the estimated one. Between 40,000 and 70,000 people die annually, with 95% of human deaths occurring in regions of Asia, Africa, and Latin America. According to WHO, rabies ranks fifth among infectious diseases in terms of economic damage [17].

In Russia, cases of rabies in animals and, albeit rarely, in humans continue to be registered, with a persistent unstable epidemiological situation in certain regions, such as the Central and Privolzhsky Federal Districts. In 2021, 6 cases of human rabies were registered, and an increase in the proportion of dogs and cats in the epizootic process was noted. In 2023, 3,057 people sought medical attention regarding animal bites, which is 14.54% less than in 2022 and 11.65% lower than the long-term average level. The proportion of wild animal bites among all bites was 3.1% for 2023, 4.38% in 2022, and 3.51% in 2021. The proportion of individuals who refused or arbitrarily discontinued the course of anti-rabies care was 24.4% in 2023, 25.3% in 2022, 37.8% in 2021, and 21.7% in 2020.

During the period 2013-2021, 39 cases of human rabies were registered, averaging 4.33 ± 1.8 (p = 0.05) cases of rabies per year. The dynamics of human rabies incidence is subject to non-systemic oscillation, with rates fluctuating from 1 to 7 cases per year. In 2020-2021, a 4.33-fold increase in the incidence of hydrophobia was noted compared to the previous period of 2018-2019 [13]. In 2023, two cases of human rabies were detected on the territory of the Russian Federation – in the Donetsk People's Republic (hereinafter referred to as the DPR) and the Omsk Oblast (Siberian Federal District – SFD) [14]. The relative rate was 0.001 per 100,000 population. Infection of the victims with the virus occurred from domestic animals.

The rate of seeking anti-rabies care averages 300.0 per 100,000 population nationwide. Annually, more than 250,000 people are exposed to the risk of infection and need specific treatment using rabies vaccine**, while about 40,000 people additionally require anti-rabies immunoglobulin** [10, 12, 18-23]. Among those who died from rabies, the vast majority (88-90%) did not seek medical help and, accordingly, did not receive timely anti-rabies treatment. In rare cases, the disease develops against the background of anti-rabies vaccination in the presence of bites of dangerous localization and late presentation for anti-rabies care [10, 15].

In the Russian Federation, it varied from 9.02 thousand rubles in 2015 to 13.34 thousand rubles in 2022 per single case [16].

1.4 Features of Coding the Disease or Condition

Rabies (A82)

A82.0 – Sylvatic rabies

A82.1 – Urban rabies

A82.9 – Rabies, unspecified

1.5 Classification of the disease or condition

Based on clinical manifestations, the following forms of the disease are distinguished:

• bulbar,

• paralytic (Landry's type),

• meningoencephalitic,

• cerebellar.

1.6 Clinical presentation of the disease or condition

Following infection, the incubation period ranges from several days to several months (in rare cases >1 year). The duration of the incubation period is influenced by the bite location. The shortest incubation is observed with bites to the face, head, followed by the upper extremities, and the longest with bites to the lower extremities [1, 2]

There are 3 stages of the disease: I – initial (depression), II – excitation, III – paralysis.

Stage I of rabies. The disease begins gradually over 1-3 days with a prodromal period: fever is possible, usually low-grade, increased sensitivity to auditory and visual stimuli, skin hyperesthesia. In the area of the already scarred wound, local inflammatory phenomena sometimes reappear, the scar becomes red and swells. An increase in emotional activity lasting from several hours to several days is also observed. With bites to the face, olfactory and visual hallucinations occur. The patient is withdrawn, apathetic, refuses to eat, sleeps poorly, and sleep is accompanied by frightening dreams.

Stage II of rabies is characterized by increased reflex excitability and marked sympathicotonia. The most striking clinical symptom is hydrophobia: attempts to drink cause painful spastic contractions of the swallowing muscles and accessory respiratory muscles. These phenomena increase in intensity to such an extent that the mere mention of water or the sound of flowing liquid causes spasms of the pharyngeal and laryngeal muscles. Breathing becomes noisy in the form of short convulsive breaths. At this time, reactions to any stimuli are sharply exacerbated. A convulsive seizure can be triggered by a stream of air blown into the face (aerophobia), bright light (photophobia), or a loud sound (acousticophobia). The patient's pupils are strongly dilated, exophthalmos occurs, and the gaze is fixed on a single point. The pulse is sharply accelerated, profuse painful salivation (sialorrhea) and sweating appear. At the peak of the seizure, stormy psychomotor agitation (fits of rage, fury) occurs with violent and aggressive actions. Patients may strike or bite those around them, spit, and tear their clothes. Consciousness becomes clouded, and frightening auditory and visual hallucinations develop. Cardiac and respiratory arrest is possible. In the interictal interval, consciousness usually clears, patients can correctly assess the situation and answer questions sensibly. After 2-3 days, the agitation, if death has not occurred at the peak of one of the seizures, is replaced by paralysis of the muscles of the limbs, tongue, and face.

Stage III of rabies is the paralytic stage. In 2-3 days, convulsions and agitation cease, and consciousness clears. Against the background of an apparent improvement in condition, paralysis of the muscles of the limbs, tongue, and face develops. Body temperature rises to 40-42°C, tachycardia and hypotension increase. Death occurs in 12-20 hours from paralysis of the heart or respiratory center [1-2, 9, 26-28].

Various disease courses are possible: the absence of a prodromal period or the development of "quiet" rabies—characterized by the development of ascending paralysis resembling Guillain-Barré syndrome. It is precisely "quiet rabies" that has predominated in the clinical picture of rabies over the past two decades in the Russian Federation.

Disease outcome: 100% mortality of the patient. In the absence of intensive care (mechanical ventilation), half of the patients die 4 days after the onset of the first symptoms, and all patients die by 20 days [1-2, 9, 26-28].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

Diagnosis of rabies is carried out based on pathognomonic data¹ [1, 2, 9, 10, 11]:

1) anamnesis data: a history of a bite (salivation) by a wild or domestic mammal, predominantly from the orders Carnivora and Chiroptera.

2) complaints and physical examination data: acute progressive encephalomyelitis including leading to death within 10 calendar days (about 80% of cases) after the onset of clinical symptoms of the disease; in typical cases—hydrophobia (photophobia) against the background of pronounced neurological symptoms.

3) laboratory test results: isolation of the virus, detection of viral antigens or RNA in the brain post-mortem; intravital detection of viral antigens or RNA in scalp skin biopsies, corneal impressions, or saliva, tear fluid, urine; detection of virus-specific antibodies in the cerebrospinal fluid, an increase in the antibody titer in blood serum over time in unvaccinated patients.

¹ Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases.' XXII. Prevention of Rabies."

2.1 Complaints and Anamnesis

Comments: the incubation period of rabies is determined by the localization and severity of the inflicted injuries and ranges from several days to 6 years or more. The shortest incubation is observed when bitten on the face, head, then upper extremities, and the longest when bitten on the lower extremities [1-2].

Comment: various disease courses should be taken into account: the possible absence of a prodromal period and the manifestation of rabies with the development of ascending paralysis resembling Guillain-Barré syndrome

2.2 Physical Examination

At the stages of diagnosis:

Comments: The excitation stage is characterized by increased reflex excitability and marked sympathicotonia. The patient's pupils are significantly dilated, exophthalmos occurs, and the gaze is fixed on a single point. The pulse is markedly accelerated, profuse agonizing salivation (sialorrhea) and sweating appear. Subfebrile fever is characteristic at the onset of the disease and febrile at its peak) [1-2, 9].

2.3 Laboratory Diagnostics

The diagnosis of rabies in typical cases presents no difficulties and can be established clinically. Laboratory diagnostics serve as an aid for the differential diagnosis of rabies with other CNS diseases.

Comments: Characteristics include: leukopenia or lymphocytic leukocytosis, anoxemia, in late stages—elevated hematocrit, thrombocytopenia

Comments: Laboratory studies of material from rabies patients are carried out by institutions licensed to work with microorganisms of pathogenicity groups I-II. The examination confirms the diagnosis of rabies from the first days of the disease; this is the fastest and most accurate method of laboratory diagnosis of rabies. When performing post-mortem DFA, 99-100% agreement with biological testing is obtained [1, 2, 9, 10, 11, 26, 27].

Comment: A positive result is indicated by the presence of Negri bodies—clearly defined oval or oblong granular formations of a ruby-red color with a basophilic internal structure, located in the cytoplasm of neurons or in the pericellular space. The same material is taken for testing as for the DFA test. This is a rapid test, and results can be obtained 1–2 hours after sample delivery. The method is specific for rabies, but less sensitive than DFA and indirect DFA. Negri bodies are found in the brain tissue of dogs in 90–95% of cases, and in humans who died of rabies in 70%. The absence of Negri bodies does not rule out a diagnosis of rabies.

Comment: determination of specific antibodies using the neutralization test (NT) is possible after the 7th–10th day of the illness. However, this method is more commonly used for differential diagnosis purposes, since the lifespan of a patient once clinical rabies develops is limited. In unvaccinated patients, a diagnosis of rabies is confirmed by a fourfold increase in antibody titer when testing paired sera. In vaccinated patients, diagnosis is based on the absolute level of neutralizing antibodies in the serum, as well as the presence of these antibodies in the CSF. Following post-exposure prophylaxis, neutralizing antibodies are typically absent in the CSF or their titer is low (less than 1:64), whereas in rabies, the neutralizing antibody titer in the CSF ranges from 1:200 to 1:160,000.

Comment: viral culture isolation is the most reliable confirmation of a rabies diagnosis. A positive result can only be obtained after 25–30 days. The presence of the rabies virus in infected and deceased mice is confirmed using the direct fluorescent antibody test or by detecting Negri bodies. Identification of the isolated rabies virus is also carried out using the neutralization test in white mice.

A positive result obtained by any single specific method invalidates the negative results of all other tests. Test systems used for laboratory diagnostics of rabies must be duly approved for use².

² Decree of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases.' XXII. Rabies Prevention."

2.4 Instrumental Diagnostics

Comment: Elevated CSF pressure is detected; the CSF shows lymphocytic pleocytosis and a moderate increase in protein content.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1 Etiotropic (antiviral) therapy

Comments: In 2005, following the first successful treatment of a patient with clinical hydrophobia, an experimental treatment protocol for acute human rabies infection was proposed—the Milwaukee protocol. The method involves inducing an artificial coma in the patient to deeply suppress CNS functions, along with administering a combination of systemic antiviral drugs [28]. This treatment protocol has been used in 38 patients worldwide, but only 6 survived, all of whom were infected by bats. The Milwaukee protocol is not universally accepted.

3.1.2 Pathogenetic and symptomatic therapy

Comments: the volume is determined by the degree of dehydration. Electrolytes are used in volumes necessary and sufficient to maintain circulating blood volume at a normal physiological level. Solutions such as Potassium chloride + Sodium acetate + Sodium chloride** are used

Comments: nonspecialized standard formulas for enteral nutrition and restoration of water-electrolyte balance are used, as well as oral rehydration salt formulations in dosages corresponding to the patient's physiological needs.

Comments: prescribed to induce medicinal sleep (for humanitarian reasons) and/or to manage agitation episodes.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not developed

5. Prevention and Dispensary Observation

5.1 Recommendations for identifying patients with rabies and individuals suspected of having this disease3

Identification of patients with rabies is carried out by specialists of medical and preventive institutions during the provision of all types of medical care when the public seeks medical attention regarding animal attacks and bites or saliva contact with damaged skin or external mucous membranes [1, 2].

• Medical workers who identify individuals suspected of being infected with the rabies virus are recommended to collect an epidemiological history, establish (with indication of place and time) all information about the animal that attacked the person, and immediately report this information to the bodies exercising state sanitary and epidemiological supervision and veterinary supervision [1, 2].

GRC CLEL 5Grade of Recommendation C (Level of Evidence - 5

³ Decree of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases.' XXII. Rabies Prevention."

5.2 Measures recommended regarding patients with rabies or those suspected of having rabies. Post-exposure prophylaxis of rabies in humans4

When a person seeks medical attention regarding an animal attack, bite, or salivation, the medical worker should immediately initiate anti-rabies care. The medical worker must inform the victim about the need for prophylactic vaccinations and the potential consequences of violating the vaccination schedule.

• Patients at risk of rabies infection are recommended anti-rabies care, which includes: local treatment of wounds, scratches, abrasions, sites of salivation, and subsequent administration of a rabies vaccine**. When indications are present (dangerous localization and depth of injuries, injuries inflicted by wild and farm animals), a combined treatment course is administered: rabies immunoglobulin** for passive immunization and a rabies vaccine** in accordance with the instructions for use of anti-rabies drugs [1, 2].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: Specific anti-rabies treatment (post-exposure prophylaxis) for individuals who have suffered bites from animals suspected of having rabies is initiated before receiving the results of laboratory tests on the animals.

In cases of severe multiple bites of dangerous localization, along with the vaccine, heterologous equine rabies immunoglobulin or homologous (human) rabies immunoglobulin** is administered to neutralize the rabies virus.

Comments: it is necessary to perform copious irrigation for several minutes (up to 15 minutes) of the wound surface with water and soap or another detergent. In the absence of soap or detergent, rinse the injury site with a stream of water. Afterward, treat the wound edges with 70% ethanol** or iodine+[Potassium iodide+Ethanol].

Comments: Suturing is indicated exclusively in the following cases: for extensive wounds (a few guiding skin sutures after preliminary wound cleansing); for cosmetic reasons (application of skin sutures to facial wounds); ligation of bleeding vessels to stop external hemorrhage. Administration of rabies immunoglobulin** should precede suturing, if indications for its use are present. Following local treatment of wounds (injuries), therapeutic and prophylactic immunization is immediately initiated.

• Therapeutic and prophylactic immunization is recommended for all individuals exposed to the risk of rabies infection. During combined treatment, administration of RIG** is recommended first, and no later than 30 minutes thereafter, administration of the rabies vaccine**. Heterologous equine rabies immunoglobulin is prescribed at a dose of 40 IU per 1 kg of body weight. The volume of administered heterologous equine rabies immunoglobulin should not exceed 20 ml. Homologous (human) rabies immunoglobulin** is prescribed at a dose of 20 IU per 1 kg of body weight. As large a portion of the recommended RIG** dose as possible should be infiltrated into the tissues around the wound and deep within the wound. The unused portion of the drug dose is administered deeply intramuscularly at a site distinct from the administration of the rabies vaccine** [1, 2, 10, 11].

gR CLoE 5Strength of Recommendation Grade C (Level of Evidence - 5)

Comments: Rabies immunoglobulin** is prescribed as early as possible after contact with a rabid animal, an animal suspected of having rabies, a wild animal, or an unknown animal. Before administering heterologous equine rabies immunoglobulin, it is necessary to check the patient's individual sensitivity to horse proteins. Heterologous equine rabies immunoglobulin is administered no later than 3 days after the bite. Individual sensitivity is not tested before administering homologous (human) rabies immunoglobulin**. Homologous rabies immunoglobulin** is administered no later than 7 days after the bite.

Comments: Administration of the vaccine into the gluteal region is not permitted. The vaccinated person must remain under medical supervision for at least 30 minutes after vaccine administration. If neurological symptoms develop following administration, the patient must be urgently hospitalized; symptomatic therapy and systemic antihistamines are prescribed. Vaccination sites must be equipped with anti-shock therapy facilities. Following the immunotherapy course, a certificate is issued indicating the type and batch of drugs, the vaccination course, and post-vaccination reactions.

The most appropriate schedule for therapeutic and prophylactic vaccinations with the rabies vaccine** and rabies immunoglobulin** is presented in the table in Appendix A3.

⁴ Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases.' XXII. Rabies Prevention."

6. Organization of Medical Care

Recommendations on sanitary and anti-epidemic (preventive) measures upon the registration of human rabies cases or suspected cases⁵

The animal associated with a human case suspected of rabies must be isolated for 10 days or euthanized (in case of aggressive behavior). Material from the deceased animal must be delivered to a specialized laboratory by veterinary service specialists

To identify individuals exposed to the risk of infection, house-to-house (apartment-to-apartment) rounds are conducted with the participation of medical personnel and veterinary facility staff

Identified individuals exposed to the risk of infection are referred for an appointment (consultation, examination) with a surgeon, who determines the scope of medical care and treatment, including post-exposure prophylaxis

Personnel caring for a patient with rabies must wear medical protective clothing (medical gown, goggles, medical mask, and medical gloves), especially when performing procedures such as tracheal intubation, fluid aspiration, and other procedures involving contact with the patient's saliva

Instruments used in caring for a rabies patient undergo standard disinfection regimens. The bodies of individuals who died from rabies present a low risk of infection spread. Early burial or cremation of the body of someone who died from rabies is preferred [1, 2].

List of indications for hospitalization of victims of animal bites, scratches, and salivation, and patients with hydrophobia [1]:

surgical indications (multiple lacerated wounds, bites to the face, neck, hands, and fingers);

• infected bite wounds (except the hand);

• infected bite wounds of the hand;

• burdened allergic history, individuals with unusual

• post-vaccination reactions and complications to anti-rabies drugs, and repeatedly vaccinated individuals;

• history of neurological disorders;

• history of neuropsychiatric disorders;

• pregnant women with animal bites;

• neonates with animal bites;

• patients with hydrophobia and those bitten by infected animals.

The regimen is determined by the indication for hospitalization. Patients with hydrophobia must be hospitalized in an infectious disease inpatient unit in the ICU.

The attending physician bears personal responsibility for the interpretation and application of these recommendations.

Medical care is provided in the following forms:

• emergency medical care;

• urgent medical care;

Conditions for the provision of medical services

Medical care is provided in the form of:

• primary health care;

• emergency medical care, including specialized emergency medical care;

• specialized medical care, including high-tech medical care.

Medical care for adult patients with rabies or suspected rabies may be provided under the following conditions:

• outpatient (in settings not providing round-the-clock medical observation and treatment);

• inpatient (in settings providing round-the-clock medical observation and treatment).

Primary health care is provided to patients in outpatient settings at the stages of identifying cases suspected of rabies virus infection and during therapeutic and prophylactic immunization.

Primary health-preventive care in outpatient settings at the stages of identifying cases suspected of rabies virus infection is carried out in all medical and preventive health care institutions, regardless of their organizational and legal form of ownership and departmental affiliation.

Primary general medical care is provided by a general practitioner, family physician, trauma physician, or surgeon in outpatient settings at the stages of identifying cases suspected of rabies virus infection and during therapeutic and prophylactic immunization.

Primary specialized health care is provided by an infectious disease physician, trauma physician, or surgeon of a medical organization providing outpatient medical care at the stage of patient identification.

Specialized medical care, including high-tech care, is provided in an inpatient setting by infectious disease physicians and other medical specialists and includes the prevention, diagnosis, and treatment of diseases and conditions requiring the use of special methods and complex medical technologies.

Treatment of patients is carried out exclusively in an inpatient setting upon referral by a general practitioner, family physician, infectious disease physician, trauma physician, surgeon, or other medical personnel who have identified patients with suspected rabies.

⁵ Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases.' XXII. Rabies Prevention."

7. Additional Information

7.1 Localization of lesions

Dangerous localization of injuries includes any salivation of mucous membranes, bites of the head, face, neck, hand, fingers and toes, and genitals, as this shortens the path of the virus to the neurons of the central nervous system, leading to a shortened incubation period of the disease. In all such cases, an intensive post-exposure rabies prophylaxis regimen is administered, involving immediate administration of rabies immunoglobulin** followed 30 minutes later by rabies vaccine**.

Administration of RIG** + rabies vaccine is also performed for single or multiple deep lacerations inflicted by domestic or agricultural animals, as well as for any salivation and injury inflicted by wild carnivorous animals, bats, and rodents [1-2].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Aleksandr V. Gorelov, Academician of the RAS, Professor, Head of the Department of Infectious Diseases and Epidemiology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health; Deputy Director for Scientific Work, Central Research Institute of Epidemiology of Rospotrebnadzor; Chairman of the Board, Academician V.I. Pokrovsky National Association of Infectious Disease Specialists;

2. Marina G. Avdeeva, D.Sc. in Medicine, Professor, Head of the Department of Infectious Diseases and Phthisiopulmonology, Kuban State Medical University of the Ministry of Health of the Russian Federation.

3. Viktor V. Nikiforov, D.Sc. in Medicine, Professor, Head of the Department of Infectious Diseases and Epidemiology, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation;

4. Ksenia E. Novak, Ph.D. in Medicine, Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation;

3. Denis V. Usenko, D.Sc. in Medicine, Head of the Educational Center, Leading Researcher at the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor; Board Member, Academician V.I. Pokrovsky National Association of Infectious Disease Specialists;

4. Vladimir P. Chulanov, D.Sc. in Medicine, Professor, Deputy Director for Science and Innovative Development, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, Professor at the Department of Infectious Diseases, I.M. Sechenov First Moscow State Medical University, Chief freelance infectious disease specialist of the Russian Ministry of Health;

5. Elena V. Esaulenko, D.Sc. in Medicine, Professor, Head of the Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation;

All working group members are members of the Academician V.I. Pokrovsky National Association of Infectious Disease Specialists

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Infectious disease specialist;

2. General practitioner (internist);

3. General practitioner (family physician);

4. Surgeon;

5. Traumatologist-orthopedist;

6. Medical students, residents, postgraduate students.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 157-FZ of September 17, 1998, "On Immunoprophylaxis of Infectious Diseases".

5. Federal Law of the Russian Federation No. 326-FZ of November 29, 2010, "On Compulsory Medical Insurance in the Russian Federation".

6. Federal Law No. 323-FZ of November 21, 2011, "The Fundamentals of Healthcare Protection in the Russian Federation".

7. Order of the Ministry of Health and Social Development of Russia No. 494 of August 9, 2005, "On the Procedure for the Use of Medicinal Products in Patients for Vital Indications".

8. Order of the Ministry of Health of Russia No. 804n of October 13, 2017, "On Approval of the Nomenclature of Medical Services".

9. Order of the Ministry of Health and Social Development of Russia No. 69n of January 31, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases".

10. Order of the Ministry of Health of Russia No. 205n of May 2, 2023, "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers"

11. Order of the Ministry of Health of Russia No. 700n of October 7, 2015, "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education".

12. Order of the Ministry of Health of Russia No. 1024n of December 17, 2015, "On the Classification and Criteria Used in Carrying out Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise".

13. Order of the Ministry of Health of Russia No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care".

14. Federal Law No. 52-FZ "On the Sanitary and Epidemiological Welfare of the Population" Revision date: 01.01.2021

15. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'. XXII. Prevention of Rabies".

16. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 13 of February 1, 2012, Moscow, "On Strengthening Measures Aimed at the Prevention of Rabies in the Russian Federation" / Rossiyskaya Gazeta - Federal Issue No. 5737, March 23, 2012. Entered into force on April 3, 2012. Registered with the Ministry of Justice of the Russian Federation on March 15, 2012

17. Order of the Ministry of Agriculture of Russia No. 585 "On Amendments to the Veterinary Rules for Carrying out Preventive Diagnostic, Restrictive and Other Measures, Establishment and Lifting of Quarantine and Other Restrictions Aimed at Limiting the Spread and Eliminating Outbreaks of Rabies, Approved by Order of the Ministry of Agriculture of Russia No. 705 of November 25, 2020" approved on August 24, 2021

18. Order of the Ministry of Health of the Russian Federation No. 330 of August 5, 2003, "On Measures to Improve Medical Nutrition in Healthcare Institutions of the Russian Federation".

19. Order of the Ministry of Health of the Russian Federation No. 395n of June 21, 2013, "On Approval of Medical Nutrition Norms".

20. Order of the Ministry of Health of the Russian Federation No. 1008n of September 23, 2020, "On Approval of the Procedure for Providing Patients with Medical Nutrition".

Schedule of prophylactic and therapeutic vaccination for rabies prevention** with rabies vaccine** and rabies immunoglobulin** (RIG**)

Notes on the Schedule of post-exposure and pre-exposure rabies vaccinations with rabies vaccine** and rabies immunoglobulin** (RIG**):

1. Doses and schedules of post-exposure immunization are identical for children and adults.

2. The post-exposure immunization course is prescribed regardless of the time elapsed since exposure when seeking anti-rabies care, even several months after contact with an animal that has rabies, is suspected of having rabies, or is wild or unknown.

3. For individuals who have previously received a full course of post-exposure or pre-exposure vaccinations within the past year, three injections of rabies vaccine** of 1.0 mL each are administered on days 0, 3, and 7; if a year or more has passed, or if an incomplete immunization course was administered, vaccinations are performed in accordance with the specified "Schedule of post-exposure and pre-exposure rabies vaccinations with rabies vaccine** and rabies immunoglobulin** (RIG**)".

4. Upon completion of the post-exposure or pre-exposure immunization course, the vaccinated person is issued a certificate (vaccination certificate) indicating the type and lot numbers of the biologicals, the vaccination course, and the presence of any post-vaccination reactions.

5. The vaccinated person must be informed: consumption of any alcoholic beverages is strictly prohibited throughout the entire vaccination course and for 6 months after its completion. Overwork, hypothermia, and overheating should also be avoided throughout the entire vaccination course.

6. Glucocorticoids and immunosuppressants can lead to the failure of vaccine therapy. Therefore, if vaccination is performed while receiving glucocorticoids and immunosuppressants, determination of the virus-neutralizing antibody titer is mandatory. If virus-neutralizing antibodies are absent, an additional course of rabies vaccine** administration is performed according to the schedule on days 0, 7, and 30.

Differential diagnosis [1-2, 9]

The clinical presentation of rabies must be differentiated from tetanus, encephalitis, hysteroneurosis (lyssophobia), atropine** and strychnine poisoning, and delirium tremens episodes

Differential diagnosis of rabies

Comments. Tetanus is characterized by tetanic spasms, trismus, "risus sardonicus", clear consciousness, and a normal mental state. Spasms are not provoked by the sight of water, and the patient can drink. Muscle hypertonus persists between attacks. Cerebrospinal fluid analysis reveals no inflammatory changes. In encephalitis of other infectious origins, prior to the paralytic phase, there is no excitation stage combined with hydrophobia, aerophobia, and pronounced sympathicotonia. The clinical picture of pseudorabies in hysterical neurosis differs by a confusing medical history (often the biting animals are healthy), an abundance of subjective complaints, a lack of objective signs (no respiratory disorders, tachycardia, mydriasis), and a prolonged course. Poisonings by certain substances are ruled out based on a thoroughly gathered medical history and the absence of characteristic disease cyclicity. Delirium tremens attacks are accompanied by neither hydrophobia nor convulsions.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Rabies is a severe, fatal infectious disease in humans transmitted from infected domestic and wild animals through bites or salivation. The disease is caused by the rabies virus — Rabies virus. The rabies virus affects the nervous system, leading to the development of specific encephalitis (inflammation of the brain) in animals and humans. As a result of inflammation in the brain centers responsible for basic vital functions, severe impairments occur, leading to the death of the organism.

The virus is excreted into the external environment with the saliva of an infected animal. Humans become infected through a bite by an infected animal or when saliva contacts the skin and mucous membranes. The virus penetrates only through damaged skin, including microtrauma. Contact with mucous membranes is particularly dangerous, as the virus can enter through intact mucous membranes. Rabies is not transmitted from human to human through direct contact.

The source of infection for humans is animals in the incubation period of the disease or with the clinical picture of rabies. The appearance of the virus in saliva can be detected even before the onset of clinical manifestations of the disease in animals. The primary host of rabies in nature is wild animals, from which domestic and farm animals become infected, increasing the threat of disease transmission to humans.

In the Russian Federation, the red fox remains the primary natural reservoir of the rabies virus in all natural foci, although a wide range of wild carnivorous animals can serve as a reservoir: raccoon dogs, arctic foxes, wolves, jackals, and corsac foxes. In recent years, cases of rabies have been registered in badgers, ferrets, martens, beavers, moose, lynx, wild cats, brown rats, and house mice. Cases of the disease have been identified in squirrels, hamsters, muskrats, nutria, and bears. The proportion of domestic and farm animals as a source of infection is significantly lower. This may include cattle, horses, and small ruminants. Dogs and cats occupy a dominant position among domestic animals in terms of the risk of rabies spread. Stray animals pose the greatest danger, as the risk of infection with the rabies virus is significantly higher in them.

In countries and regions where bats are the main reservoir of rabies (primarily the USA, South America), in addition to bites—which may go unnoticed due to the sharpness and small size of their teeth—infection can occur via an aerosol mechanism when visiting caves inhabited by colonies of bats in whose population the rabies virus circulates.

Clinical signs of rabies in animals usually appear 3–8 weeks after infection. In dogs and cats, two forms of the disease are clinically distinguished: furious (aggressive) and quiet (paralytic). At the onset of the disease, behavioral changes are noted in dogs and cats: the animal is capricious, wary, and does not obey commands. The dog is agitated, often gnaws at the bite site, its appetite is reduced or perverted, the animal eats inedible objects, and profuse salivation and vomiting are observed. This condition lasts 1–4 days. Wild animals with rabies (foxes, wolves, etc.) lose their sense of caution and fear, come into populated areas, and may attack animals and humans. In the second stage of the disease, the dog becomes sharply agitated, aggressive, chews on the ground and various objects, and tries to run away. Sick dogs often suddenly attack other animals or people. Subsequently, convulsive seizures appear. At the same time, high fever (up to 41°C), vomiting, paralysis of individual muscle groups (pharynx, larynx, limbs), and strabismus develop; the lower jaw drops, saliva flows from the mouth; the bark becomes hoarse and muffled. The duration of this stage is 2–3 days. The final (paralytic) stage is characterized by severe exhaustion of the animal, progressive paralysis of the hind limbs, then the trunk, and the forelimbs; the animal dies. The duration of the third stage is 2–4 days. The total duration of clinical signs in the furious form of the disease is 6–11 days. The quiet form of rabies in dogs and cats is clinically characterized by general depression, without an excitation stage. Paralysis of the limb and trunk muscles rapidly sets in. The disease lasts only 2–4 days, and the animal dies.

The incubation period of rabies in humans usually lasts 1–3 months, but can vary from 1 week to 1 year depending on factors such as the site of virus entry and the amount of virus entering the wound. In the event of acute disease onset with fever and pain, as well as unusual or unexplained sensations of tingling, pricking, or burning (paresthesia) at the wound site, a feeling of causeless anxiety, fear, and sleep disturbances, immediate medical assistance must be sought.

Due to the fact that effective treatment for rabies upon the appearance of clinical symptoms has not been developed, timely measures to prevent the development of the disease in individuals exposed to the risk of infection are of primary importance. Dangerous localizations of injuries include any salivation of mucous membranes, bites to the head, face, neck, hand, fingers, toes, and genitals, as this shortens the path of the virus to the neurons of the central nervous system, leading to a shortened incubation period of the disease and requiring, in addition to the vaccine, the administration of rabies immunoglobulin**.

A person injured by a bite, following contact carrying the risk of rabies infection, must immediately wash the wound and seek medical assistance. Recommended first aid procedures include immediate and thorough washing of the wound with soap, detergent, treatment of the edges with an alcoholic solution of iodine + [potassium iodide + ethanol] or other substances that kill the rabies virus, for at least 15 minutes.

Measures to prevent the virus from entering the central nervous system, which inevitably leads to death, are as follows:

• abundant washing and local treatment of the wound as soon as possible after contact;

• a course of immunization with an effective vaccine for the prevention of rabies**;

• when indicated, administration of rabies immunoglobulin**.

Effective medical care provided shortly after contact involving the risk of rabies infection prevents the onset of symptoms and death.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not used.