Hemorrhagic fever with renal syndrome: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

aPTT – activated partial thromboplastin time

WHO – World Health Organization

HFRS – hemorrhagic fever with renal syndrome

DIC – disseminated intravascular coagulation

D.Sc. in Medicine – Doctor of Medical Sciences

DNA – deoxyribonucleic acid

VLE – List of Vital and Essential Drugs

IMV – invasive mechanical ventilation

TBE – tick-borne encephalitis

EIA – enzyme immunoassay

Ph.D. in Medicine – Candidate of Medical Sciences

CT – computed tomography

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

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

INN – International Nonproprietary Name

INR – international normalized ratio

ARF – acute respiratory failure

CHI – compulsory health insurance of citizens

AKI – acute kidney injury

ARDS – acute respiratory distress syndrome

ICU – intensive care unit

PCR – polymerase chain reaction

RB – Republic of Bashkortostan

IIFA – indirect immunofluorescence assay

RF – Russian Federation

SS – septic shock

US – ultrasound examination

FL – Federal Law

HR – heart rate

ECG – electrocardiography

HLA – human leukocyte antigen system

Terms and Definitions

Evidence-based medicine is 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 is a disturbance of the body's activity, working capacity, and ability to adapt to changing environmental and internal conditions, arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Primary disease is a disease that, by itself or due to complications, necessitates primary medical care due to the greatest threat to working capacity, life, and health, or leads to disability, or becomes the cause of death;

Concomitant disease is a disease that has no causal relationship with the primary disease, is inferior to it in terms of the need for medical care, impact on working capacity, danger to life and health, and is not the cause of death;

Severity of a disease or condition is a criterion determining the degree of damage to organs and (or) systems of the human body or impairment of their functions caused by the disease, condition, or their complications;

Disease outcomes are the medical and biological consequences of a disease;

Consequences (results) are disease outcomes, as well as the social and economic results of applying medical technologies;

Disease complication is the addition to a disease of a syndrome of physiological process impairment; - impairment of the integrity of an organ or its wall; - bleeding; - developed acute or chronic insufficiency of an organ or organ system function;

Instrumental diagnostics – diagnostics using various devices, apparatuses, and instruments to examine a patient.

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

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

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

Patient model is a set of clinical, laboratory, and instrumental diagnostic signs that allow identifying a disease (poisoning, trauma, physiological state) and classifying it into a group of conditions with a common etiology and pathogenesis, clinical manifestations, and common approaches to treatment and condition correction;

Medical professional is 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 them.

Nosological form is a set of clinical, laboratory, and instrumental diagnostic signs that allow identifying a disease (poisoning, trauma, physiological state) and classifying it into a group of conditions with a common etiology, pathogenesis, and clinical manifestations.

Syndrome is a condition developing as a consequence of a disease and defined by a set of clinical, laboratory, and instrumental diagnostic signs that allow identifying it and classifying it into a group of conditions with different etiologies but a common pathogenesis and clinical presentation

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

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

Drug formularies – a section of patient treatment protocols containing information on medications, regimens, and specific features of their prescription used for a particular disease (syndrome).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hemorrhagic fever with renal syndrome (HFRS) (synonyms: hemorrhagic nephrosonephritis, Churilov's disease, epidemic nephrosonephritis, Far Eastern hemorrhagic fever, Korean hemorrhagic fever, Manchurian hemorrhagic fever, Scandinavian epidemic nephropathy, Tula fever; hemorrhagic fever with renal syndrome) is an acute viral zoonotic natural focal disease characterized by systemic microvascular damage, hemorrhagic diathesis, hemodynamic disorders, and specific renal damage of the acute interstitial nephritis type with the development of acute kidney injury [1, 4, 5, 12, 18, 34, 40, 78, 79, 81].

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

The causative agent of HFRS belongs to the Bunyaviridae family, Hantavirus genus. To date, more than 30 serologically and genetically distinct hantaviruses are known. Two clinical forms of hantavirus infection in humans have been described:

- hemorrhagic fever with renal syndrome, caused by Puumala (PUUV), Seoul (SEOV), Amur (AMRV), Hantaan (HTNV), and Dobrava (DOBV) viruses [9, 35, 69];

- hantavirus pulmonary syndrome, first described in the USA in 1993, caused by Sin-Nombre, Black Creek, New York, Bayou, Andes, and Laguna Negra hantaviruses [9, 35, 67, 69].

Only the first clinical form of the disease (hemorrhagic fever with renal syndrome) is registered in Russia, with the circulation of 7 hantavirus types established, including 5 pathogenic ones. In European foci, the overwhelming majority of cases are caused by the Puumala type [4, 5, 6, 10, 25, 44]. The possibility of circulation of Hantaan, Seoul, and Dobrava has also been demonstrated. Hantaan, Seoul, and Amur viruses circulate in natural foci of the Russian Far East, South Korea, North Korea, China, and Japan [35, 51, 54, 61, 71].

The generalized nature of the infection involving various organs and systems in the pathological process determines the polymorphism of symptoms regardless of the hantavirus serotype [3, 11, 22, 37, 39, 56, 78, 79, 81]. Hantaviruses are polytropic; they are capable of infecting monocytes, macrophages, endothelial cells, platelets, and cells of the lungs, kidneys, liver, etc.

During the incubation period, the HFRS virus enters the body through the epithelium of the respiratory tract, gastrointestinal tract, and damaged skin. Subsequently, it reproduces in the cells of the macrophage system, activating specific and nonspecific defense factors.

The pathogenetic basis of the initial (febrile) period of HFRS includes viremia, intoxication, activation of the hormonal and immune systems, production of proinflammatory cytokines, massive vasopathy, coagulopathy, microcirculatory disorders, tissue destruction, and the formation of autoantigens with the generation of autoantibodies (in severe HFRS) [3, 8, 11, 14, 22, 28, 37, 41, 56, 57].

In the oliguric period of HFRS (peak of the disease), systemic circulatory disorders, hypovolemia, hemoconcentration, organ hypoperfusion and hypoxia, tissue acidosis, and damage to vital body systems continue. The hypocoagulation phase of disseminated intravascular coagulation (DIC) predominates. Edema, hemorrhages, dystrophic, and necrobiotic changes occur in the pituitary gland, adrenal glands, kidneys, myocardium, and other parenchymal organs.

The greatest changes are observed in the kidneys, accompanied by a decrease in glomerular filtration and impaired tubular reabsorption [4, 6, 22, 36, 57, 64]. Acute kidney injury (AKI) in HFRS is caused by damage to the renal parenchyma and acute interstitial nephritis. On the one hand, microcirculatory disorders and increased vascular wall permeability contribute to plasmorrhea and serous-hemorrhagic edema of the renal interstitium, mainly in the pyramids, followed by compression of the tubules and collecting ducts, leading to dystrophy, desquamation of the tubular epithelium, leakage of protein and fibrin with obstruction of the tubules and collecting ducts by fibrin plugs, and impaired urine reabsorption. On the other hand, an immunopathological factor—the fixation of immune complexes on the glomerular basement membrane—reduces glomerular filtration. Interstitial edema exacerbates renal microcirculatory disorders, up to ischemia and, in some cases, renal tubular necrosis, contributing to a further decrease in glomerular filtration and tubular reabsorption. Tubular cells are particularly sensitive to hypoxia and the lack of energy substrates arising during ischemia. Autoantibodies to damaged tissue structures may also participate in the pathological process. Central hemodynamic disorders (hypovolemia, decreased cardiac output, arterial hypotension) exacerbate renal blood flow disorders [1, 3, 4, 5, 6, 14, 29, 36, 70].

The polyuric period begins between the 9th and 13th days and lasts until the 21st–24th day of the disease. As a result of the development of specific immunity, elimination of the pathogen, and clearance of immune complexes, pathological changes in the kidneys and other organs regress, and trends toward the normalization of their functions are observed. In the polyuria stage, glomerular filtration is the first to increase. Under conditions of a damaged tubular apparatus, even a slight increase in filtration contributes to increased diuresis. Polyuria is caused by osmotic diuresis. Slow restoration of the tubular reabsorption function leads to the loss of potassium, sodium, and chlorine [4, 14, 37, 60, 67, 69].

The recovery period is pathogenetically characterized by the formation of stable post-infection immunity with a high level of specific IgG, restoration of hemostasis, microcirculation, and glomerular filtration, but with prolonged persistence of tubular disorders (tubular insufficiency) [3, 4, 5, 6, 8, 31, 37, 42, 60].

The correspondence of clinical syndromes to pathogenetic mechanisms and morphological substrate [3, 11, 37, 56, 57] is presented in Appendix A3.

1.3 Epidemiology of the Disease or Condition

HFRS is a strictly natural-focal zoonosis. The main reservoir of the pathogen in nature consists of wild murine rodents.

In the European part of Russia, the source of infection is the bank vole (infection rates in rodents in endemic foci reach 40–57%). In the Far East, the main reservoirs of infection are the striped field vole, the grey-red vole, and the Korean field vole. Rodents carry this infection in the form of latent virus carriage. In field mice trapped in natural foci, the viral antigen has been detected in the tissues of the lungs, kidneys, liver, lymph nodes, spleen, and rectum. The pathogen is excreted into the external environment with feces, urine, and saliva. Transmission between rodents occurs mainly via the respiratory tract.

Literature data indicate that the role of other mammals (about 40 species) and birds (about 13 species) in maintaining the hantavirus infection epizootic in the wild cannot be excluded [3, 4, 5, 9, 10, 25, 30, 35, 38, 44, 69, 78, 79, 81].

Human infection occurs predominantly via the airborne dust route (up to 80%), by inhaling dried excreta of infected rodents. Virus transmission is also possible by contact, through damaged skin and mucous membranes upon contact with rodents or infected environmental objects (brushwood, straw, hay, etc.). Alimentarily acquired infection is also considered possible, for example, through consumption of heat-untreated foods (cabbage, carrots, etc.) contaminated by infected rodents. Human-to-human transmission does not occur.

Susceptibility is universal. Males fall ill more frequently (70–90% of patients) of the most active age group (from 16 to 50 years), predominantly industrial workers, drivers, tractor operators, and agricultural workers. The incidence is recorded less frequently in children (3–5%), women, and elderly individuals due to less contact with the natural environment and, likely, immunogenetic features. Urban residents predominate among the sick (up to 70–80%), which is associated with both their larger population size and the level of immune layers.

HFRS incidence is characterized by a pronounced summer-autumn seasonality, which is due to increased human contact with the wild (dacha activities, hiking trips, recreation, harvesting berries and mushrooms). There is a direct correlation between human incidence and rodent population numbers and their infection rates in a given territory [9, 10, 25, 35, 38, 44, 69].

HFRS is distributed worldwide. It is registered in Scandinavian countries (Sweden, Norway, Finland), Bulgaria, Yugoslavia, Czechoslovakia, Belgium, France, the Far East (PRC, DPRK, South Korea), and Russia [24, 30, 35, 51, 54, 61, 71]. About 97% of the total annually registered cases of HFRS occur in the European part of Russia and 3% in the Asian part. The most active foci of the disease are the regions between the Volga and the Urals (Bashkiria, Udmurtia, Tatarstan, Samara and Ulyanovsk Oblasts), and the Far East of the Russian Federation (Primorsky and Khabarovsk Krais, Jewish Autonomous and Amur Oblasts).

The past infection leaves lasting life-long type-specific immunity. Isolated cases of reinfection are known.

1.4 Features of Coding the Disease or Condition

A98.5 – Hemorrhagic fever with renal syndrome.

1.5 Classification of the disease or condition

[4, 5, 7, 18, 34, 39].

• By clinical course:

  1. Typical (manifest);

  2. Atypical (asymptomatic, mild/subclinical).

• By severity (Appendix A3):

  1. Mild;

  2. Moderate;

  3. Severe;

  4. Extremely severe (complicated) degree of severity

• By the nature of the course:

  1. Uncomplicated;

  2. Complicated;

1.6 Clinical presentation of the disease or condition

[3, 4, 5, 7, 8, 16, 20, 21, 28, 31, 39, 41, 53, 56, 57, 60, 65].

The incubation period of HFRS ranges from 1 to 5 weeks, averaging 2–3 weeks. The disease proceeds cyclically; the following periods of the disease are distinguished: febrile (initial, general toxic), lasting on average from 3 to 7 days; oliguric (on average 6–12 days); polyuric (on average 6–14 days); and convalescence period (early – up to 2 months and late – up to 2–3 years).

The clinical picture of the disease features the following main syndromes:

1) asthenovegetative (weakness, malaise, reduced performance, etc.);

2) intoxication (myalgia, high fever, eye pain, headache, decreased appetite, etc.);

3) hemodynamic (central and microcirculatory disorders);

4) renal (lower back pain, oligoanuria, polyuria, etc.);

5) hemorrhagic (petechial rash, scleral hemorrhages, epistaxis, gastrointestinal bleeding, etc.);

6) visual disturbances (decreased vision, appearance of "fog, net" before the eyes);

7) abdominal (vomiting, abdominal pain, diarrhea);

8) respiratory syndrome (nasal congestion, dry cough, sore throat);

9) neuroendocrine.

Various combinations of these syndromes characterize each of the four periods of the disease. Symptoms of dysfunction of various organs involved in the infectious process are observed throughout all periods of the disease.

In the majority of patients, HFRS begins acutely. Chills, headache, muscle and joint pain, dry mouth, thirst, sometimes mild cough, and pronounced general weakness appear. In a small fraction of patients, the appearance of pronounced signs of the disease is preceded by a prodromal period: general malaise, rapid fatigability, low-grade fever.

Fever in most patients reaches high values on the very first day of the illness, lasting from 5–6 to 10–11 days, averaging 6–7 days. The temperature curve has no specific pattern; in most cases, it decreases lytically over two to three days.

Physical examination reveals pronounced hyperemia of the skin of the face, neck, and upper torso. Particularly noticeable are the injection of scleral and conjunctival vessels, hyperemia of the oropharyngeal mucosa, and the appearance of a spotted enanthema on the soft palate. The development of hemorrhagic syndrome is possible in the form of petechial rash on the inner surfaces of both shoulders, lateral surfaces of the torso, on the chest ("whip, lash" symptom), ecchymoses at injection sites, and brief nosebleeds. Positive endothelial symptoms (cuff, pinch, tourniquet tests) are determined. Blood pressure is normal or shows a tendency toward hypotension; relative bradycardia is characteristic. Some patients note a feeling of heaviness in the lower back.

At the end of the initial period, the frequency of urination decreases along with a slight reduction in diuresis. Laboratory shifts are characterized by a slight increase in serum creatinine and urea levels, a decrease in the relative density of urine, and the appearance of isolated fresh red blood cells and proteinuria in the sediment. Blood tests in most patients are characterized by moderate leukopenia and, less frequently, mild leukocytosis and a left shift of band neutrophils, along with signs of hemoconcentration against the background of plasma leakage and hypovolemia in the form of elevated red blood cell and hemoglobin counts. A pathognomonic symptom of HFRS in the early period is thrombocytopenia caused by the damaging effect of the virus, the development of immunopathological reactions, increased platelet adhesive properties, and the formation of cellular aggregates with their retention in microvessels, leading to impaired blood rheological properties [1, 4, 5, 7, 14, 16, 21, 23, 28].

The oliguric period is the most vivid stage, during which the clinical picture inherent to HFRS unfolds. The drop in temperature is not accompanied by an improvement in the patient's condition; as a rule, it worsens. General toxic phenomena reach their maximum, and signs of hemodynamic disorders, renal damage, and hemorrhagic diathesis intensify. The most constant sign of transition into the oliguric period is the onset of lower back pain of varying intensity: from discomfort and heaviness to sharp, agonizing pain, nausea, vomiting unrelated to food intake or medication, and, in severe cases, hiccups. Asthenia and adynamia increase. The face is hyperemic; as acute kidney injury and disseminated intravascular coagulation progress, the flush is replaced by pallor, hemorrhagic manifestations intensify—mainly in severe disease courses: scleral hemorrhages, ecchymoses, epistaxis, gross hematuria, hematomas at injection sites, and less commonly, intestinal bleeding, blood in vomitus, and hemoptysis. Of critical importance in diagnosis is identifying visual impairments (decreased visual acuity, "floaters", sensation of fog before the eyes) caused by microcirculation disorders in the retina, which appear on days 2–7 of the illness and last for 2–4 days [1, 4, 5, 7, 14, 16, 21, 23, 28].

In most patients, blood pressure is within the normal range at the beginning of the oliguric period, whereas arterial hypotension develops in severe cases. In the second half of this period, blood pressure (BP) increases in 1/3 of patients; the duration of hypertension rarely exceeds 5 days. Absolute or relative bradycardia is characteristic. Harsh vesicular breathing, isolated dry rales, and occasionally moist rales can be auscultated over the lungs. Pulmonary changes ("congestive lungs" manifested by plethora and perivascular infiltration, decreased aeration, focal pneumonia, pleural effusion, and alveolar edema), similar to hantavirus pulmonary syndrome, are observed in severe and complicated forms of HFRS [3, 4, 5, 27, 28].

On days 2-5 of the disease, diarrhea occurs in 10-15% of patients. The tongue is dry, coated with gray or brown fur. The abdomen is moderately distended; tenderness on palpation is noted in the epigastric and umbilical regions, particularly in the renal projections and sometimes of a diffuse nature. Signs of peritonism may be present. The liver is enlarged and tender in 20-25% of patients. In severe cases, an "acute abdomen" symptom complex may develop, caused by extensive hemorrhages into the mucosa of the stomach, intestines, and peritoneum (the so-called abdominal form) [1, 4, 5, 20, 39, 58].

Renal syndrome is among the leading manifestations. Pasternatsky's sign is positive or markedly positive. The full-blown picture of AKI is characterized by progressive oligoanuria, escalating uremic intoxication, water-electrolyte balance disorders, and progressive metabolic acidosis [3, 4, 5, 14, 37, 42].

Central nervous system disorders are observed in virtually all patients, both as manifestations of general cerebral symptoms associated with intoxication and as a consequence of focal lesions. Meningism symptoms, encephalitic reactions with the appearance of meningeal signs (nuchal rigidity, Kernig's and Brudzinski's signs), focal neurological deficits (corresponding to the areas of brain damage), as well as psychiatric disorders (ranging from sleep disturbances to various disorders of consciousness) may develop [1, 4, 13, 17, 32, 63].

The hemogram consistently reveals neutrophilic leukocytosis (up to 15-30×10⁹/L of blood), plasmacytosis, and thrombocytopenia [1, 4, 7, 17, 21, 34, 39, 53, 56, 57, 60, 65]. In severe cases, the blood picture is characterized by a leukemoid reaction. Due to hemoconcentration, hemoglobin and erythrocyte levels may increase, but these parameters decrease in the event of bleeding, and the ESR gradually accelerates. Elevated residual nitrogen, urea, and creatinine levels are characteristic, as well as hyperkalemia, hypermagnesemia, hyponatremia, and signs of metabolic acidosis. General urinalysis reveals massive proteinuria (up to 33-66 g/L), the intensity of which fluctuates during the day ("protein shot"), hematuria, cylindruria, and the appearance of renal epithelial cells (so-called Dunaevsky cells). Hyposthenuria develops from the second half of the oliguric period.

Significant changes occur in the blood coagulation system. While hypercoagulation persists in a portion of patients, hypocoagulation develops in severe courses of the disease. It is caused by the consumption of plasma clotting factors due to microthrombus formation in small vessels. It is precisely during the oliguric period of HFRS that hemorrhagic manifestations reach their peak and frequently become the cause of death.

The polyuric period begins on days 9-13 and lasts until days 21-24 of the disease. Vomiting ceases, back and abdominal pain gradually disappear, sleep and appetite normalize, daily urine output increases (up to 3-10 L), and nocturia is characteristic. Against the background of hypokalemia, weakness, muscular hypotonia, intestinal paresis, bladder atonia, tachycardia, and arrhythmia persist; dry mouth and thirst appear. The duration of polyuria and isohyposthenuria, depending on the severity of the clinical course, can range from several days to several weeks.

Laboratory shifts during this period consist of a slight decrease in red blood cells and hemoglobin, and an increase in platelet count. The erythrocyte sedimentation rate (ESR) is somewhat accelerated. Serum urea and creatinine levels gradually decrease, and hypokalemia frequently develops. A low relative urine density, not exceeding 1001-1005, is characteristic. The urine sediment contains a small amount of protein, moderate hematuria and cylindruria, occasionally leukocyturia, and a small number of renal epithelial cells.

During the convalescence period, a marked improvement in general condition occurs, along with the restoration of daily diuresis and the normalization of urea and creatinine levels. Convalescents exhibit asthenovegetative syndrome: general weakness, rapid fatigue, decreased work capacity, emotional lability, shortness of breath upon minor physical exertion, finger tremor, hyperhidrosis, and insomnia. During this period, a feeling of heaviness in the lower back, a positive Pasternatsky's sign, nocturia, and persistent isohyposthenuria (lasting up to 1 year or more) may be noted. A secondary bacterial infection may supervene with the development of pyelonephritis, most commonly observed in patients who have undergone AKI.

A comprehensive assessment of the severity of toxemia, hemorrhagic, and renal syndromes reflects the severity and prognosis of the infection Appendix A3. [1, 4, 5, 7, 14, 17, 20, 29, 34, 39, 86].

Prognostic criteria for severity (on days 2-4 of the disease) [1, 7, 17, 20, 21, 39, 42, 43, 46, 53, 57, 87]:

• Persistent hypotension, dizziness, collapse-like reactions;

• Pronounced hemorrhagic syndrome;

• Repeated vomiting unrelated to food intake; persistent hiccups;

• Sharp decrease in visual acuity;

• Severe pain in the lower back and abdomen, oliguria, massive proteinuria;

• Signs of acute respiratory distress syndrome (ARDS): shortness of breath, cough, bouts of air hunger, asphyxia;

• Early leukocytosis >10.0×10⁹/L, significant increase in blood urea and creatinine levels in the first days of the disease, pronounced proteinuria, erythrocyturia.

• Increased concentration of C-reactive protein (CRP) in the patient's blood upon admission (concentration is determined by immunoturbidimetric assay at a wavelength of 340 nm). The severity of the disease course is predicted based on the CRP level within the following ranges: 10-21 mg/L – moderate HFRS course, 22-27 mg/L – severe HFRS course, 28 g/L and above – severe HFRS course complicated by acute renal failure.

Severe forms of HFRS from the first days of the disease demonstrate the full symptom complex of multiple organ dysfunction syndrome (MODS) in the form of various combinations of hemodynamic disorders with dysfunctions of the kidneys, liver, heart, lungs, and nervous system.

Complications of HFRS are divided into two groups:

a) specific – septic (infectious-toxic) shock, disseminated intravascular coagulation (DIC) syndrome, acute kidney injury (AKI), azotemic uremia, pulmonary edema, cerebral edema, hemorrhages in the brain, pituitary gland, adrenal glands, myocardium, profuse bleeding, eclampsia, acute cardiovascular disease, infectious myocarditis, rupture or tear of the renal capsule;

b) nonspecific – pyelonephritis, pneumonia, purulent otitis media, abscesses, phlegmons, parotitis, sepsis, etc.

A peculiar pathomorphological triad of fatal HFRS cases is characteristic: hemorrhagic necroses in the kidneys (medullary zone) and in the heart (right atrium), and pulmonary edema. In addition, gelatinous edema of the perirenal adipose tissue is frequently noted. In some deceased patients, foci of necrosis in the anterior lobe of the pituitary gland were discovered, which were the direct cause of death [1, 4, 13, 32].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria

Diagnosis of hemorrhagic fever with renal syndrome in adults is made on the basis of epidemiological and clinical history, clinical examination, laboratory and special examination methods, and is aimed at determining the nosology and clinical form, the severity of the condition, and identifying complications and indications for therapy.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

2.3.1. Nonspecific laboratory diagnostics

Comments: in an uncomplicated course of HFRS during the febrile period, normocytosis or leukopenia, neutropenia, relative lympho- and monocytosis, and elevated erythrocyte and hemoglobin levels due to plasma leakage and hemoconcentration are characteristic; during the oliguric period, leukocytosis with a left shift increases, and the erythrocyte sedimentation rate (ESR) rises. From the early period of HFRS, progressive thrombocytopenia, caused by increased platelet adhesiveness and the formation of cellular aggregates with their retention in microcirculatory vessels, is characteristic.

Comments: during the febrile period, there is an increase in urine specific gravity, moderate proteinuria, and the appearance of isolated fresh erythrocytes in the sediment; the oliguric period is characterized by massive proteinuria with rapid positive dynamics, micro- and macrohematuria, cylindruria, and the appearance of degenerated renal epithelium (Dunaevsky cells) in the urine sediment. With the onset of polyuria against the background of slower regeneration of tubular epithelium and their reabsorption function, hyposthenuria and nocturia develop regardless of the severity of the disease.

2.3.2. Specific laboratory diagnostics

Laboratory testing to identify the HFRS pathogen is mandatory upon hospitalization of a patient with an acute febrile illness accompanied by renal involvement (development of acute kidney injury) and hemorrhagic syndrome.

Comments: Serological diagnostic methods (IFA, ELISA) are used to confirm the diagnosis of HFRS, including mild and subclinical forms of the disease, with an informative value of 96–98%. Seronegative forms of the disease are registered in 2–4% of cases. The optimal time for collecting clinical material is an early collection of the first serum sample — before days 4–7 of the disease or on the first day of hospitalization. When serum is collected after the 15th day of the disease, an increase in antibody titer may not be detected. ELISA and IFA are performed using paired sera at intervals of 4–7 days. The following is considered diagnostic:

- detection using serological tests of total antibodies (IgM and IgG) to HFRS pathogens in blood serum and urine, or detection of a 4-fold or greater increase in antibody titer in paired blood sera; after recovering from the disease, specific antibodies at a low titer of 1:64–1:128 persist almost for life, regardless of the severity of the past disease;

- detection of IgM to HFRS pathogens in blood serum during the acute period of the disease in conjunction with the detection of IgG in paired serum;

- detection of a 4-fold or greater increase in IgG titers to HFRS pathogens in paired sera, or seroconversion;

IgM to the HFRS pathogen are detected in the patient's serum from the 6th to the 56th days of the disease, IgG begin to be detected from the 6th day, reach high levels by the 11th day, and persist at these values for up to 5 months from disease onset and at anamnestic titers for life.

- detection of a specific hantavirus RNA fragment of HFRS pathogens in the samples studied;

- isolation of hantaviruses — the causative agents of HFRS [SanPiN 3.3686-21].

2.3.3. Special laboratory diagnostics

Comments: In the diagnosis of HFRS, the dynamics of changes in general clinical and biochemical parameters across periods of the disease are significant; they also serve as criteria for severity, development of complications, and prognosis.

Biochemical blood parameters change depending on the period of the disease. At the end of the initial period, laboratory shifts are characterized by a slight increase in serum creatinine and urea levels, moderate hyperenzymenemia (ALT, AST), and azotemia parameters reach their peak during the oliguric period. In the polyuric period, there is a slow recovery of tubular reabsorptive function.

Comments: The release of blood and tissue thromboplastin in hemorrhagic fever with renal syndrome (HFRS) triggers disseminated intravascular coagulation (DIC), which is accompanied by phase changes in the blood coagulation system. As a rule, the initial period of the disease is dominated by the hypercoagulation phase (shortening of thrombin time to 10-15 s, blood clotting time, fibrinogen concentration to 4.5-8 g/L, prothrombin index to 100-120% [12, 39]); with the onset of oliguria, especially in severe disease, hypocoagulation develops (prolongation of thrombin time to 25-50 s, prolongation of clotting time, decrease in fibrinogen concentration to 1-2 g/L, prothrombin index to 30-60% [12, 39]), which is caused by the pathological consumption of plasma clotting factors due to microthrombus formation in small vessels. In the oliguric period of HFRS, hemorrhagic manifestations reach a maximum and often become the cause of death [1, 3, 12, 39]. By the end of the polyuric period, the blood coagulation system normalizes.

Comments: The synthesis of acute-phase proteins (CRP), increased coagulation processes (D-dimer), and increased vascular permeability are aimed at forming a full-fledged immune response to the HFRS virus. High concentrations of proinflammatory cytokines may play a certain role in the development of severe forms of HFRS by contributing to increased vascular permeability, enhanced coagulation, and activation of cytotoxic lymphocytes and natural killer cells, leading to damage to microcirculatory vessels, the renal parenchyma, lungs, and other organs.

2.4 Instrumental Diagnostics

Comments: microcirculatory disorders and increased vascular wall permeability in the renal glomerular apparatus promote plasma leakage and serous-hemorrhagic edema of the renal interstitium, mainly in the pyramids, followed by compression of the tubules and collecting ducts (akin to "renal glaucoma"), leading to dystrophy and desquamation of the tubular epithelium, leakage of protein and fibrin resulting in tubular and collecting duct obstruction by fibrin clots and impaired reverse urine reabsorption. Ultrasound examination of the kidneys reveals enlarged kidneys, increased cortical echogenicity, and edema of the renal parenchyma ("prominent pyramids sign").

Comments: pulmonary changes ("congestive lungs" in the form of plethora and perivascular infiltration, decreased pneumatization, focal pneumonia, pleural effusion, alveolar edema, bacterial pneumonia) are observed in severe and complicated forms of HFRS, typically during the oliguric period of the disease.

Comments: pulse oximetry is a simple and reliable screening method that allows for the identification of patients with hypoxemia who require respiratory support and for evaluating its effectiveness.

Comments: against the background of microcirculatory disorders, hypoxia, arterial hypertension, and hypokalemia, dystrophic changes in the myocardium and cardiac conduction system develop, which must be diagnosed in a timely manner and managed with corrective therapy in conjunction with a cardiologist. Echocardiographic changes have been identified in convalescents of severe HFRS, requiring further study to assess their prognostic significance.

Comments: abdominal pain appears in the oliguric period of the disease and is caused by erosions and hemorrhages in the mucosa of the stomach, distal esophagus, and intestines resulting from mucosal ischemia, microvessel thrombosis, vessel rupture, and hemorrhages against the background of developing disseminated intravascular coagulation.

2.5 Other Procedures

Comments: Abdominal pain of varying intensity appears in the oliguric period of HFRS, most commonly in severe cases, and is caused by deep focal dystrophy of the gastric and duodenal mucosa, microthrombus formation and stasis in their vessels, multiple hemorrhages, hemorrhagic impregnation of organs, and the formation of acute erosions and ulcers that serve as a source of recurrent bleeding associated with high mortality. The rest of the intestine is also severely affected and can become a source of bleeding and intoxication due to paresis, shedding of villi, and massive autolysis.

2.5.1. Differential diagnosis [1, 4, 5, 17, 27, 31, 36, 88].

Differential diagnosis of HFRS is carried out with infectious diseases characterized by an acute onset and the development of fever-intoxication syndrome, cyclical disease progression, and seasonal incidence. Differential diagnosis of HFRS with other febrile infectious diseases, inflammatory urinary tract diseases, and acute surgical abdominal pathology is presented in Appendix A3.

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

Principles of treatment for HFRS patients involve addressing several tasks:

• preventing the further progression of the pathological process caused by the disease, achieving a complete and stable recovery;

• preventing the development of potential complications of the disease.

The choice of treatment tactics is influenced by the following factors:

• period of the disease;

• severity of the disease;

• leading clinical manifestations and features of the disease course, taking into account signs of immunodeficiency (chronic alcoholism, cachexia, severe comorbidities, old age);

• age of the patient;

• presence and nature of complications;

• availability and feasibility of treatment in accordance with the required type of medical care.

Principles of management of HFRS patients:

• Early hospitalization – by days 3-4 of the disease for patients with manifest manifestations of HFRS of varying severity.

• Gentle transportation for HFRS patients with moderate and severe disease.

• Strict bed rest until the end of the polyuric period for HFRS patients with moderate and severe disease.

• Monitoring of the water balance (in patient charts).

• Gentle diet without salt restriction. During the oligoanuria phase, protein-rich foods (meat, fish, legumes) and potassium-rich foods (vegetables, fruits) are excluded. During the polyuria stage, these foods are necessary. For nutritional support of patients with AKI, enteral and parenteral nutrition formulas in combination can be used.

3.1 Conservative Treatment

3.1.1. Etiotropic (antiviral) therapy.

Goal of therapy:

- suppression of HFRS virus replication;

- reduction of disease severity;

- decrease in the risk of specific complications.

Comments: #ribavirin** is prescribed according to the regimen: 200 mg (one capsule) 5 times a day (1000 mg per day), the treatment course is 5 days [12].

Data on the efficacy of ribavirin treatment are contradictory. In a study of ribavirin treatment in 242 patients with confirmed HFRS in China [55], morbidity and mortality were significantly reduced, supporting efficacy when administered early before clinical signs appeared. In contrast, a clinical trial on the treatment of HFRS caused by PUUV infection conducted in Russia showed that intravenous administration of ribavirin does not alter viral load kinetics [59]. If oral forms of ribavirin cannot be taken, IV ribavirin can be used with an initial dose of 33 mg/kg, followed by 16 mg/kg every 6 hours for 4 days, and 8 hours after the last of these doses, 8 mg/kg every 8 hours for 3 days (7 days in total) [12]. The efficacy of intravenous ribavirin cannot be assessed in either of these trials [52,62,68]. Similar survival curves were observed in patients receiving ribavirin compared to HFRS patients over the same time period or patients receiving placebo [52]. Most completed clinical trials showed anemia, which is reversible after completion of ribavirin therapy [59]. In addition, some patients developed hyperbilirubinemia, sinus bradycardia, and rash.

3.1.2 Pathogenetic and symptomatic therapy for HFRS patients in a hospital setting depending on the period of the disease

Comments: baseline therapy includes bed rest, diet, and oral detoxification in the form of fluid intake up to 2 liters per day (tea, rosehip decoction, drinking water, alkaline mineral waters) taking into account daily diuresis. The diet includes easily digestible foods rich in vitamins (lean meats, fish, dairy products, boiled vegetables, juices, compotes). Alcohol in any form is prohibited.

3.1.2.1 Pathogenetic and symptomatic therapy for patients with HFRS in the initial (febrile) period of the disease

Comments: detoxification therapy aims to relieve the intoxication syndrome; its volume depends on the severity of the patient's condition, blood electrolyte levels, hematocrit, daily diuresis, and the presence or risks of complications. If necessary, provide controlled infusion therapy in case of hypovolemia, but avoid volume overload. Infusion therapy should be carried out under control and monitoring. The total amount of fluid administered parenterally up to the 5th–6th day of the disease may exceed the excreted volume by no more than 750 ml, and later, at the peak of renal failure, by 500 ml, taking into account fever and hematocrit levels.

Comments: timely initiated infusion therapy restores circulatory volume and renal perfusion. Infusion therapy must be carried out under control and monitoring [14, 74], as uncontrolled infusion therapy itself carries risks of AKI due to edema of the renal parenchyma and other organs. Fluid replacement can be performed using various types of infusion solutions (crystalloids, colloids, or combinations thereof). Isotonic crystalloids are the primary solutions used to replenish extracellular fluid deficit. Colloids theoretically promote a faster increase in volemia compared to crystalloids, but this effect depends on vascular wall permeability, which is impaired in HFRS [16, 37]. Human albumin** is preferred for correcting hypo-oncotic hypovolemia. It increases sensitivity to diuretics in patients with hypoalbuminemia [14]. Crystalloids are the primary infusion solutions for replacing circulating blood volume deficit [14, 74].

Comments: in severe disease, high viremia, intoxication, activation of the hormonal and immune systems, production of pro-inflammatory cytokines, massive vasopathy (tropism of hantavirus to microvascular endothelium, release of pro-inflammatory cytokines), hypovolemia, microcirculation disorders, disseminated intravascular coagulation (DIC) with consumption coagulopathy, and tissue destruction cause the development of septic shock, AKI, and DIC syndrome. Treatment in this case will be carried out in accordance with clinical guidelines for emergency conditions in the intensive care unit [74].

Comments: Indications for the use of glucocorticoids: septic shock, cerebral edema, pronounced inflammatory syndrome with multiorgan dysfunction.

Comments: Indications for the use of these drugs are body temperature rise above 38.5°C, muscle and joint pain. It is necessary to avoid prescribing salicylic acid and its derivatives to patients with hyperthermia for antipyretic purposes, considering the risk of adverse events such as hemostasis disorders and exacerbation of gastric and duodenal ulcers (according to the instructions for use).

3.1.2.2 Pathogenetic and symptomatic therapy for patients with HFRS in the oliguric period of the disease

Comments: For this purpose, solutions affecting water-electrolyte balance, plasma substitutes, blood plasma preparations, etc. are used. Treatment in the event of complications will be carried out according to clinical guidelines for emergency conditions in the intensive care unit [74].

Comments: therapy includes solutions affecting water-electrolyte balance, plasma substitutes, blood plasma preparations, etc.

Comments: infusion therapy initiated in a timely manner helps restore circulatory volume and renal perfusion. Infusion therapy should be performed under control and monitoring [14, 74], as uncontrolled infusion therapy inherently carries the risk of acute kidney injury (AKI) due to renal parenchymal edema and edema of other organs. Fluid resuscitation can be carried out using various types of infusion solutions (crystalloids, colloids, or combinations thereof). Isotonic crystalloids are the primary solutions used to replenish extracellular fluid deficits. Compared to crystalloids, colloids theoretically promote a more rapid increase in volemia; however, this effect depends on vascular wall permeability, which is impaired in hemorrhagic fever with renal syndrome (HFRS) [16, 37]. Human albumin** is preferred for correcting hypo-oncotic hypovolemia. It increases diuretic sensitivity in patients with hypoalbuminemia [14]. Crystalloids are the primary infusion solutions for restoring circulating blood volume deficits [14, 74].

Comments: the use of loop diuretics can cause adverse effects in some cases. Considering the mechanism of action of furosemide, its administration under conditions of hypovolemia will promote renal hypoperfusion by reducing left ventricular stroke volume, and will also significantly increase the risk of thromboembolic complications. In AKI, furosemide** does not reduce the need for renal replacement therapy (relative risk 1.02, 95% CI 0.9–1.16, p=0.73) or in-hospital mortality (relative risk 1.12, 95% CI 0.93–1.34, p=0.23) when prescribed for prophylactic or therapeutic purposes in patients with at-risk or established AKI [14, 103]. Therefore, in accordance with KDIGO guidelines, furosemide** should be used only in the presence of hypervolemia [14].

Comments: Indications for glucocorticoid use: septic shock, cerebral edema, pronounced inflammatory syndrome with multiorgan dysfunction. Treatment for acute emergency conditions is carried out in accordance with clinical guidelines [74] in an intensive care unit!

Comments: treatment in the event of complications shall be carried out in accordance with clinical guidelines for emergency conditions in the ICU [74]. To dynamically assess organ failure and impaired consciousness, standardized rating scales should be used (Appendix G1, G2).

Comments: renal replacement therapy is performed in accordance with current clinical guidelines for AKI.

3.1.2.3 Pathogenetic and symptomatic therapy for HFRS patients in the polyuric period of the disease

Comments: to restore water-electrolyte balance, solutions affecting water-electrolyte balance are indicated.

3.2. Surgical treatment

Not performed.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: motor activity is gradually expanded, and patients are transferred to ward-based activity. Medical gymnastics is performed daily, predominantly in the form of breathing exercises and simple arm and leg exercises under the supervision of a physical therapy physician. A standard general diet is prescribed, excluding spicy foods and alcohol.

Comments: the rate and degree of recovery of functional status and occupationally significant functions of convalescents are taken into account (using indirect and direct methods). Extension of the sick leave certificate is determined on an individual basis for each case, taking into account the dynamics of clinical and laboratory parameters, the presence or absence of complications, and comorbid somatic diseases.

For one year following hospital discharge, the convalescent should adhere to a balanced diet rich in macroelements, microelements, and vitamins. Spicy foods, spices, and alcohol are excluded from the diet for 12 months.

During the convalescence period, exemption from heavy physical labor, business trips, and sports activities is also indicated; patients should avoid hypothermia, visiting bathhouses (saunas), and jarring or bumpy rides—for 3 months following a mild form of HFRS, 6 months for a moderate form, and 12 months for a severe form.

5. Prevention and Dispensary Observation

5.1 Specific prevention

Specific vaccine prophylaxis for HFRS is in the registration phase in Russia [15, 23, 66, 68].

5.2 Nonspecific prophylaxis

Falls under the purview of Rospotrebnadzor and executive authorities

Comment: 1) current disinfection of objects and the entire premises using antiseptics, especially upon first visiting country houses (dachas), camps, or tourist bases

2) use of disposable masks during wet cleaning in residential or industrial premises located in natural foci of HFRS, utilizing disinfectants.

3) creation of conditions guaranteeing compliance with sanitary rules and requirements for the procurement, storage, and sale of food products for individuals vacationing, residing, or working in natural wilderness conditions [10, 25, 38, 44, 75].

4) ensuring widespread and continuous compliance with sanitary and hygienic norms and rules, as well as the sanitary and anti-epidemic regime in children's sanatoriums, holiday homes, educational institutions, healthcare organizations, organized military collectives, and other facilities located in natural foci of infection, with provisions for personal hygiene (regular handwashing, consumption of safe drinking water) [10, 25, 38, 44, 75].

5.3 Clinical follow-up (dispensary observation)

Comment: Diagnosing the sequelae of hemorrhagic fever with renal syndrome (HFRS) in some cases requires targeted diagnostic laboratory and instrumental methods, and consultations with specialists. In addition, during the monitoring of this category of patients, various expert issues may arise concerning professional activities, military service, determination of disability groups, etc. Therefore, it is advisable to divide the scope of diagnostic and therapeutic care into two stages.

The first stage is carried out at the outpatient clinic level by an infectious disease specialist or general practitioner/district physician in collaboration with a neurologist, nephrologist, and, if necessary, other outpatient subspecialists.

The second stage is used when pathology is detected that requires a more detailed clinical, laboratory, and instrumental examination, as well as when expert issues need to be resolved. At the second stage, physicians and diagnostic services of specialized hospital departments are involved in the diagnostic and therapeutic process.

In the absence of complaints and internal organ abnormalities upon the expiration of the follow-up period, patients who have suffered from HFRS are discharged from the patient registry.

6. Organization of Medical Care

Comments: given the absence of pathognomonic symptoms in the febrile period of HFRS, and the overlap in the seasonal incidence peak of HFRS and other natural focal febrile diseases (tick-borne encephalitis, Lyme disease, leptospirosis), provisional hospitalization of febrile patients in a hospital is justified.

Comments: 1) in case of symptoms indicating impaired oxygen supply to the body against the background of hemodynamic disorders (development of shock), severe weakness, dizziness, acrocyanosis or total skin cyanosis, shortness of breath, hypotension, tachycardia, oligoanuria, hypoxia detected by pulse oximetry readings;

2) in case of symptoms indicating CNS complications (impaired consciousness ranging from lethargy to cerebral coma, psychomotor agitation, clonic-tonic seizures, focal symptoms);

3) upon the appearance of hemorrhagic syndrome (extensive skin ecchymoses, mucosal hemorrhages [subconjunctival, hemorrhagic enanthema on the soft palate], epistaxis, "coffee ground" vomiting), usually against the background of worsening renal failure (oligoanuria, dry mouth, thirst, anorexia, lower back and abdominal pain).

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 patients with suspected "HFRS" is provided in a hospital setting, ensuring round-the-clock medical monitoring and treatment.

Primary health care is provided to patients in outpatient settings:

• at feldsher-midwifery stations by mid-level medical personnel.

• by a general practitioner/district physician, or a general practitioner (family physician) in an outpatient setting.

Primary specialized health care is provided by an infectious disease specialist of a medical organization providing outpatient care (clinic). When HFRS is suspected or detected in a patient at the outpatient stage, the district physician, general practitioner (family physician), infectious disease specialist, or mid-level medical worker of the medical organization refers the patient for inpatient hospitalization to receive specialized medical care.

Specialized, including high-tech, medical care is provided in an inpatient setting by infectious disease specialists 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, as well as medical rehabilitation.

Treatment of HFRS patients is carried out in a hospital setting, where patients are hospitalized upon referral by a district physician, general practitioner (family physician), infectious disease specialist, or medical workers who identified HFRS, ensuring round-the-clock monitoring and treatment.

7. Additional Information

The earliest possible hospitalization is necessary — at the beginning of the febrile period, i.e., in the first 3 days of the disease. Outpatient monitoring of a patient with suspected HFRS is impractical due to the high risks of complications.

The severity of clinical manifestations of HFRS is associated with:

• the virulence of hantavirus serotypes (Hantaan, Amur, Puumala, Dobrava, Seoul, etc.),

• genetic features of the macroorganism,

• presence of concomitant chronic renal pathology,

• environmental issues,

• infecting dose,

• epidemiological features of infection, and other factors.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Bakhtina Viktoriya Aleksandrovna, Chief Physician, Specialized Clinical Infectious Diseases Hospital of the Ministry of Health of Krasnodar Krai, Candidate of Medical Sciences

2. Valishin Damir Askhatovich, Head of the Department of Infectious Diseases, Bashkir State Medical University of the Russian Ministry of Health, Professor, Doctor of Medical Sciences

3. Gorelov Aleksandr Vasilyevich, Deputy Director for Research, Central Research Institute of Epidemiology of Rospotrebnadzor, 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, Academician of the RAS, Professor, Doctor of Medical Sciences

4. Gorodin Vladimir Nikolayevich, Head of the Department of Infectious Diseases and Epidemiology, Kuban State Medical University of the Ministry of Health of the Russian Federation, Professor, Doctor of Medical Sciences

5. Dmitriev Aleksandr Sergeyevich, Head of the Center for Epidemically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, Infectious Diseases Physician, Candidate of Medical Sciences

6. Ivanis Viktoriya Aleksandrovna, Professor of the Department of Infectious Diseases, Pacific State Medical University of the Russian Ministry of Health, Doctor of Medical Sciences

7. Murzabaeva Rasima Timeryarovna, Professor of the Department of Infectious Diseases, Bashkir State Medical University of the Russian Ministry of Health, Doctor of Medical Sciences

8. Novak Kseniya Egorovna, Associate Professor of the Department of Adult Infectious Diseases and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Candidate of Medical Sciences, Associate Professor

9. Suzdaltsev Aleksey Aleksandrovich, Professor of the Department of Infectious Diseases with a Course of Epidemiology, Samara State Medical University of the Russian Ministry of Health, Doctor of Medical Sciences

10. Fazylov Vildan Khayrullayevich, Professor of the Department of Infectious Diseases, Kazan State Medical University of the Russian Ministry of Health, Professor, Doctor of Medical Sciences

11. Chulanov Vladimir Petrovich, Deputy Director for Research and Innovative Development, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, Doctor of Medical Sciences, Professor

12. Shaikhullina Liana Robertovna, Associate Professor of the Department of Infectious Diseases, Bashkir State Medical University of the Russian Ministry of Health, Specialist at the Center for Clinical Virology, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, Candidate of Medical Sciences

13. Esaulenko Elena Vladimirovna, Head of the Department of Adult Infectious Diseases and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Professor, Doctor of Medical Sciences

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 the clinical guidelines:

1. Infectious disease specialist;

2. General practitioner (internist);

3. General practitioner (family physician);

4. Medical students

5. Residents

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Determination of levels of evidence and grades of recommendation for diagnostic interventions

Table A1 – Levels of evidence certainty for diagnostic interventions

¹ The generally accepted standard for diagnostic intervention clinical trials is a cross-sectional study design, in which the investigational diagnostic method and the reference method—serving as the "gold standard" for diagnosing the studied disease or condition—are applied to each included patient in parallel and under identical conditions. The investigational and reference methods must be applied independently of each other (i.e., the investigational method cannot be part of the reference method) and must be interpreted by the investigator without knowledge of the results obtained from the other method (blinding is recommended)

Table S2 – Levels of clinical usefulness (LCU) grading scale for diagnostic interventions

Table P3. Possible combinations of LCE and GGR for diagnostic interventions

*If a single clinical trial is evaluated, this condition is not taken into account

Determination of the levels of credibility of evidence and grades of recommendation for therapeutic, rehabilitation, and preventive interventions

Table S4 – Levels of evidence (LoE) for therapeutic, rehabilitative, and preventive interventions

Table P5 – Scale for determining the grades of recommendation for therapeutic, rehabilitation, and preventive interventions

Procedure for updating clinical guidelines

Clinical guidelines are updated every 3 years.

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".

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

3. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

4. 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".

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

6. 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".

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

8. 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".

9. Order of the Ministry of Labor of Russia No. 374n of July 26, 2024, "On Approval of Classifications and Criteria Used in Medical and Social Assessment of Citizens by Federal Medical and Social Assessment Institutions".

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

11. Sanitary and Epidemiological Rules SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" (approved by the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021).

12. Order of the Ministry of Health of the Russian Federation No. 330 dated August 5, 2003, "On measures to improve therapeutic nutrition in medical and preventive institutions of the Russian Federation."

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

14. Order of the Ministry of Health of the Russian Federation No. 1008 dated September 23, 2020, "On approval of the procedure for providing patients with medical nutrition".

Criteria for assessing the severity of hemorrhagic fever with renal syndrome

Severity criteria for hemorrhagic fever with renal syndrome (in points)

Severity degrees of HFRS:

mild – up to 3 points

moderate – up to 16 points

severe – 17 points and more.

Differential diagnosis of HFRS

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Hemorrhagic fever with renal syndrome is an acute viral natural focal disease characterized by high fever, general intoxication, hemorrhagic syndrome, and kidney damage. Severe complications can develop in this disease: infectious-toxic shock, acute renal failure, hemorrhages into vital organs, etc.

The Republic of Siberia is one of the largest disease foci in the world. Murine rodents, primarily the bank vole, and less frequently field and forest mice, serve as the natural reservoir and source of the HFRS virus; they excrete the virus in urine and feces, contaminating the environment. Domestic (synanthropic) mice and rats do not fall ill and do not spread the infection among humans. In natural foci of infection, transmission most commonly occurs via the airborne-dust route during harvesting in garden plots, picking berries and mushrooms in the forest or clearing, cleaning and repairing buildings, and preparing hay, firewood, straw, and forage, etc. Transmission via the alimentary route is also possible through the consumption of foods contaminated with the droppings of infected rodents, or through smoking and eating with unwashed hands. Human-to-human transmission does not occur. The peak incidence is observed in spring and especially in autumn, when conditions are most favorable for mass human contact with nature. Following the disease, persistent immunity is formed, and recurrent infections are very rare. Urban residents predominate among the affected individuals (up to 70–80%).

The disease begins acutely with chills, headache, muscle and joint pain, dry mouth, thirst, sometimes mild cough, and pronounced general weakness. Fever reaches high levels on the very first day of the illness and lasts for an average of 6–7 days. Physical examination reveals flushing of the face, neck, and chest, along with scleral and conjunctival injection. Point hemorrhages (petechial rash) may appear on the inner surfaces of both shoulders, the lateral surfaces of the torso, and the chest («whip» sign), along with hemorrhages at injection sites and brief nosebleeds. Starting from days 3–4 of the illness, a sensation of heaviness in the lower back is noted, accompanied by a decrease in urination frequency and a somewhat reduced urine output. From days 5–6 of the illness, body temperature drops, but general well-being continues to deteriorate, and decreased visual acuity («fog, grid before the eyes») may occur. Lower back pain intensifies, abdominal pain joins, appetite disappears, and patients experience nausea, vomiting unrelated to food intake, and hiccups. Weakness and dizziness increase, and hemorrhages appear in the sclera, skin, and nose. During this period, serious complications of the disease may develop (shock, hemorrhages into various organs, etc.).

It is necessary to consult a physician in a timely manner (within the first 2–3 days of illness). If the physician identifies symptoms suspicious of HFRS, the following tests will be ordered on the same day: complete blood count, urinalysis, and chest radiography if necessary, the results of which help clarify the diagnosis. If the diagnosis is confirmed or suspicion of HFRS persists, the patient is referred to an infectious diseases hospital on the same day. Timely hospitalization allows for the initiation of necessary therapy, prevents the development of complications, and promotes a more rapid recovery.

Bed rest is mandatory in the department until polyuria ceases, averaging: 7–10 days for mild forms, 2–3 weeks for moderate forms, and at least 3–4 weeks from the onset of the disease for severe forms.

Rational nutrition for patients plays an important role. Food should be easily digestible, contain an adequate amount of vitamins, and have no restrictions on table salt. In the first days of the illness, when renal excretory function is not yet impaired, abundant fluid intake is indicated (tea, fruit juices, non-carbonated mineral waters). Nevertheless, the amount of fluid consumed and administered orally should not exceed the volume of output (physiological losses, urine, vomit, stool) by more than 500–700 ml. In the oliguric period, the amount of administered protein should be restricted, as well as foods rich in potassium (prunes, raisins, potatoes). Conversely, potassium-rich foods should be included in the diet during the polyuria stage. Starvation must be avoided, as it enhances protein catabolism and increases azotemia.

Patients who have suffered from HFRS are discharged from the hospital upon normalization of daily urine output, complete blood count, blood biochemistry, and urinalysis. The patient is discharged on an open sick leave certificate, which is extended at the outpatient clinic for approximately 10–15 days in mild cases, 15–20 days in moderate cases, and 25–30 days or more in severe cases. During the first year after discharge from the hospital, convalescents are advised to follow a balanced diet rich in macro- and micronutrients and vitamins, while spicy foods, seasonings, and alcohol are excluded from the diet.

During the convalescence period, the patient is advised to avoid heavy physical labor, jarring rides, hypothermia and overheating, visiting baths and saunas, and sports activities for 3–6–12 months, depending on the severity of the past illness. The pronounced changes in internal organs and systems that develop in HFRS dictate a prolonged course of recovery processes—from 6 to 24 months. Therefore, after discharge from the hospital, individuals who have had HFRS require dispensary follow-up for the timely detection and treatment of the consequences of the disease. Following discharge, clinical examinations are conducted in an outpatient setting at 1, 3, 6, 9, 12, 18, and 24 months by an infectious disease specialist (or local general practitioner if unavailable), including a complete blood count, urinalysis, Nechiporenko urine test, blood biochemistry with determination of urea, creatinine, protein fractions, liver function tests, ECG, and renal ultrasound.

If asthenic syndrome persists (weakness, fatigue, decreased appetite), a sparing regimen, fractional nutrition, multivitamins, B-group vitamins, and herbal medicine (rosehip and lingonberry decoctions) are recommended.

If renal manifestations are present (lower back pain, heavy urination, dry mouth, thirst, hyposthenuria, mild proteinuria, and leukocyturia in urinalysis), antibacterial drugs, urinary antiseptics, microcirculation improvers (pentoxifylline, dipyridamole), and herbal therapy (decoctions of lingonberry, nettle, parsley, bearberry) are recommended according to indications. In the event of post-infectious myocardial dystrophy (weakness, shortness of breath, cardiac pain), a potassium-rich diet, regulated work and rest regimen, and cardiocytoprotectors (meldonium, trimetazidine, B and C vitamins) are prescribed.

In the absence of complaints and internal organ abnormalities upon expiration of the dispensary monitoring period, patients who have recovered from HFRS are deregistered.

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

Appendix G1. Glasgow Coma Scale

Russian title: Glasgow Coma Scale

Original name: Glasgow Coma Scale

Source: Teasdale G.M., Jennett B., 1974

Piradov M.A., Suponeva N.A., Ryabinkina Yu.V., Gnedovskaya E.V., Ilyina K.A., Yusupova D.G., et al. Glasgow Coma Scale (GCS): Linguocultural adaptation of the Russian-language version. N.V. Sklifosovsky Journal of Emergency Medical Care. 2021;10(1):91–99. https://doi.org/10.23934/2223-9022-2021-10-1-91-99

Type: rating scale

Contents:

Key:

The initial Glasgow Coma Scale score correlates with the severity of cerebral injury and prognosis.

The scale consists of three tests assessing eye-opening, verbal, and motor responses. A specific number of points is awarded for each test. The eye-opening test ranges from 1 to 4 points, the verbal response test from 1 to 5 points, and the motor response test from 1 to 6 points.

Thus, the Glasgow Coma Scale is an important criterion for assessing the level of consciousness. Each individual response is scored in points, and the level of consciousness is expressed as the sum of points for each parameter. The lowest score is 3 points, and the highest is 15 points. A score of 8 points or lower is defined as coma.

A score of 3–5 points is prognostically extremely unfavorable, especially when combined with fixed dilated pupils and an absent oculocephalic/oculovestibular reflex.

Appendix G2. SOFA score

Original name: Sequential Organ Failure Assessment (SOFA)

Russian name: SOFA scale

Source (official developer website, validation publication): https://pubmed.ncbi.nlm.nih.gov/29443733/

Tee Y.S., Fang H.Y., Kuo I.M., Lin Y.S., Huang S.F., Yu M.C. Serial evaluation of the SOFA score is reliable for predicting mortality in acute severe pancreatitis. Medicine (Baltimore). 2018 Feb; 97(7):e9654. doi: 10.1097/MD.0000000000009654.

Type (underline):

- rating scale

- index

- questionnaire

Purpose: determination of organ failure

Key (interpretation):

PaO2 in mmHg. FiO2 from 0.21 to 1.00.

Adrenergic agents used for at least 1 hour. Dosage in µg/kg/min.

0 – optimal parameter, 4 – most abnormal parameter.

Data must be collected and evaluated once daily throughout the patient's stay in the intensive care unit.

Mean arterial pressure (MAP) is calculated by the formula: MAP = (SBP + 2DBP) / 3.

The SOFA index equals the sum of all six parameters.