Influenza: Clinical Guidelines

List of Abbreviations

BP – Blood pressure

ALT – Alanine aminotransferase

AST – Aspartate aminotransferase

AOS – Antioxidant defense

HIV – Human immunodeficiency virus

WHO – World Health Organization

DIC – Disseminated intravascular coagulation syndrome

RF – Respiratory failure

ELISA – Enzyme-linked immunosorbent assay

IFI – Immunofluorescence

ICA – Immunochromatography

ABDS – Acid-base status

CT – Computed Tomography

CK – Creatine kinase

CK-MB – Cardiac fraction of CK

LDH – Lactate dehydrogenase

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, Tenth Revision (ICD-X)

mL – millilitre

mg/L – milligrams per liter

mmol/L – millimoles per liter

mg/kg – milligrams per kilogram

SRI – Scientific Research Institute

NICEM – National Research Center for Epidemiology and Microbiology

NCI – National Schedule of Preventive Vaccinations

NSAIDs – Non-steroidal anti-inflammatory and antirheumatic drugs

NIC – National Influenza Center

ARF – Acute renal failure

ARVI – Acute respiratory viral infections

ARDS – Acute respiratory distress syndrome

ARI – Acute respiratory infection

OSLT – Acute stenosing laryngotracheitis

PCR – Polymerase chain reaction

RNA – Ribonucleic acid

MAF – Multi-annual average figure

cm – Centimeter

FR – Free radicals

CRP – C-reactive protein

bpm – Beats per minute

LEL – Level of evidence validity

LGR – Level of grading of recommendations

FSI – Federal State Budgetary Institution

FL – Federal Law

A (H1N1) pdm 2009 – Name of the pandemic influenza virus

A(H5N1), A(H7N9), A(H7N7) – Names of avian influenza viruses

CM2 – Transmembrane matrix protein type 2

GISN – Global Influenza Surveillance Network

HA – Hemagglutinin

HEF – Hemagglutinin-esterase protein

NA – Neuraminidase

O₂- – Superoxide anion radical

Terms and Definitions

This document uses terms interpreted in a way that makes them unambiguous for healthcare professionals. For the purposes of this regulatory document, the following terms, definitions, and abbreviations are used.

Viremia is a condition in which a virus enters the bloodstream and spreads throughout the body.

Disease is a condition arising from exposure to pathogenic factors, a disruption of the body's activity, working capacity, and ability to adapt to changing conditions of the external and internal environment, accompanied by simultaneous changes in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

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

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

Quality of medical care is 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 situation – a case requiring the regulation of medical care regardless of the disease or syndrome.

Clinical practice guidelines for the provision of medical care to children are a document of the healthcare standardization system that defines the requirements for performing medical care for a patient with a specific disease, a specific syndrome, or in a specific clinical situation.

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

Medical service is a medical intervention or a complex of medical interventions aimed at the prevention, diagnosis, and treatment of diseases, and medical rehabilitation, having independent completed significance.

Medical intervention is types of medical examinations and/or medical manipulations, as well as artificial termination of pregnancy, performed by a medical worker in relation to a patient, affecting the physical or mental state of a person and having a preventive, investigative, diagnostic, therapeutic, or rehabilitative orientation.

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 and pathogenesis, clinical manifestations, and general approaches to treatment and correction of the condition.

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

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

Pandemic (Greek "all the people") is an unusually strong epidemic that has spread across the territories of countries and continents; the highest degree of development of the epidemic process.

Patient is an individual to whom medical care is provided or who has applied for medical care, regardless of the presence or absence of a disease and their condition.

Consequences (results) are the outcomes of diseases, and the social and economic results of the application of medical technologies.

Symptom is any sign of a disease accessible for determination regardless of the method used for this purpose.

Syndrome is a condition developing as a consequence of a disease and determined 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 common pathogenesis, clinical manifestations, and general approaches to treatment, which, at the same time, also depend on the underlying diseases forming the basis of the syndrome.

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

Condition – bodily changes arising from the impact of pathogenic and/or physiological factors that require medical care.

Severity of a disease or condition is a criterion that determines the degree of damage to organs and/or human body systems or the impairment of their functions caused by the disease or condition or their complication.

Level of evidence validity is a reflection of the degree of confidence that the found effect of a medical intervention is true.

Function of an organ, tissue, cell, or group of cells is a property constituting a physiological process that realizes an action specific to the corresponding structural unit of the organism.

Epidemic threshold is an indicator whose excess signifies the beginning of an epidemic of a certain disease. According to the calculation methodology specially developed by Rospotrebnadzor, statistical data on the total incidence of influenza and acute respiratory viral infections (ARVI) for the calendar weeks of each year over the past 5–10 years are used to calculate epidemic thresholds – this is the number or density of susceptible individuals required for an epidemic to occur.

Epidemic (Greek "epi" – over, "demos" – people) is the progressive spread of an infectious disease among people, significantly exceeding the incidence level usually recorded in a given territory and capable of causing an emergency.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Influenza (from French *grippe* – to seize, catch; Latin *influenza* – to flow in) is an acute respiratory viral disease characterized by fever and symptoms of general intoxication dominating over moderate catarrhal syndrome in the upper respiratory tract [1,2,3].

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

Etiology. Influenza is caused by RNA-containing viruses belonging to the family *Orthomyxoviridae*, genera *Alphainfluenzavirus*, *Betainfluenzavirus*, *Gammainfluenzavirus*, *Deltainfluenzavirus* (until October 2018 – genus *Influenzavirus*). Typical representatives of each genus are influenza viruses types A, B, C, and D (*Influenza A-D*) [1,3,4]. Within the species *Influenza A virus*, several serotypes are distinguished based on the combination of surface proteins hemagglutinin (H) and neuraminidase (N). As of 2016, 18 H-antigen subtypes (H1-H18) and 11 N-antigens (N1-N11) were identified, which theoretically can yield up to 198 combinations. Several serotypes have been isolated in nature: H1N1, H1N2, H2N2, H3N2, H5N1, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, H17N10, H18N11. Three HA subtypes (H1, H2, H3) and two NA subtypes (N1, N2) are of epidemiological significance for humans. Influenza B virus is not subdivided into types, but is subdivided into lineages: B/Yamagata and B/Victoria. The virus envelope contains 4 proteins: HA, NA, NB, and BM2. Influenza C virus, unlike the two aforementioned, contains only two proteins (CM2 protein, hemagglutinin-esterase protein - HEF) combining the functions of HA and NA. The new influenza D virus has been little studied.

The pathogenesis of influenza is due to a complex of processes developing at all stages of pathogen reproduction and their subsequent spread throughout the body, including during the interaction of the virus with the host defense systems [2,5-14].

These phases correspond to the clinical manifestations of the infection characteristic of influenza, the first of which usually appear already after the end of the initial stages of pathogen reproduction, i.e., upon their penetration into the bloodstream (the second phase of the infectious process, which begins even during the incubation period and persists throughout the entire period of pronounced intoxication) [2,5-14].

1.3 Epidemiology of the Disease or Condition

Influenza occurs in the form of epidemics, pandemics, local outbreaks, and sporadic cases.

The transmission route is airborne droplet, and contact transmission via surfaces contaminated with the virus is also possible.

Susceptibility to influenza viruses is universal, which is confirmed by almost 100% morbidity upon the introduction of the infection into long-isolated populations, as well as the rapid spread of infection observed during an influenza pandemic.

The source of infection in influenza is mainly sick people in the acute period of the disease, including those with a mild or asymptomatic form, and more rarely convalescents shedding the virus, on average, within two weeks from the onset of the disease. Sometimes facts of even longer shedding of influenza viruses are observed (up to 22–25 days for influenza A and up to 30 days for influenza B).

Infection of humans with animal or avian influenza viruses is possible.

Currently, the highly pathogenic "avian" influenza A (H5N1) virus has widely spread across the Eastern Hemisphere. In addition to devastating epizootics among wild and domestic birds, it often causes an extremely severe form of disease in humans with a fatality rate of up to 50–60%, but at the same time, the fact of pathogen transmission from human to human is absent, despite its high pathogenicity, which has limited the pandemic spread of the virus.

In 2003, an outbreak of avian influenza A (H7N7) among birds was registered in the Netherlands, followed by the development of infection in 86 poultry farm workers, one of whom died. In three cases, virus transmission through household contact was documented [15]. In subsequent years, no human cases have been reported.

In March 2013, cases of severe influenza with high mortality (36 out of 131 patients died) caused by the avian influenza A (H7N9) virus were recorded in several provinces of China [16].

In the autumn of 2012, cases of influenza caused by a new strain of swine influenza A (H3N2v), first detected in July 2011 and including the M-protein gene of the H1N1pdm2009 influenza virus in its structure, were registered in 13 US states. All patients (307 people, mostly children) were in contact with animals. Symptoms are characteristic of seasonal influenza (fever, cough, pharyngitis, rhinorrhea, myalgia, and headache), however, one fatal outcome was registered. Human-to-human transmission has been confirmed in isolated cases [17].

People can be infected with various zoonotic influenza viruses, such as avian influenza A (H5N1), A (H7N9), and A (H9N2), as well as swine influenza virus subtypes A (H1N1), A (H1N2), and A (H3N2), among others, in sporadic cases upon contact with animals and birds. The likelihood of transmission of these viruses from human to human remains low [18,19].

According to Rospotrebnadzor of the Russian Federation, the incidence of influenza in the Russian Federation in 2022 was 60.8 per 100,000 population, which is 4 times higher than the 2021 figure and 62% higher than the seasonal median level. The incidence of influenza in children was registered at the level of 165.8 per 100,000 population, which is almost 3 times higher than the 2021 figure. The highest incidence in children was noted in the following age groups: 1–2 years — 312.5 per 100,000, and children under 1 year — 291.4 per 100,000. Such an increase in incidence across all age groups can be explained by the lifting of quarantine restrictions for the novel coronavirus infection. In the 2022–2023 epidemic season, influenza viruses were detected starting from September 2022, with the peak of influenza incidence occurring in December 2022; influenza A (H1N1) pdm09 viruses prevailed in circulation, in contrast to the European Region, where both influenza A virus subtypes were encountered in equal proportions (47–48%). In addition to influenza A (H1N1) pdm09 viruses, sporadic cases of influenza A (H3N2) viruses were detected, and since November 2022, influenza B viruses (Victoria lineage) entered circulation, being detected up to the 20th–22nd weeks of 2023. According to laboratory monitoring data from Rospotrebnadzor across Russia as a whole in the 2022–2023 epidemic season, at the peak of the epidemic rise, influenza viruses were detected in 52.5% – 81.3% of samples from patients tested during PCR screening, while the epidemic was driven by the active circulation of the virus [133,134].

In order to identify and promptly detect significant changes, including genetic ones, in the composition of influenza pathogens that could cause a pandemic, and to monitor the provision of adequate treatment and preventive measures, the World Health Organization (WHO) established the Global Influenza Surveillance Network (GISN) in 2009. This network unites the activities of National Influenza Centres (NICs) in a number of countries around the world, which serve as centres for monitoring the global circulation of influenza viruses and studying them. In Russia, influenza surveillance is carried out within the framework of the Federal Centre for Influenza and Acute Respiratory Viral Infections and the WHO National Influenza Centre (NIC), operating on the basis of the Smorodintsev Research Institute of Influenza of the Ministry of Health of the Russian Federation (Russian Ministry of Health) and the Gamaleya National Research Center of Epidemiology and Microbiology of the Ministry of Health of the Russian Federation.

Seasonality: the disease is most frequently observed in winter and spring.

The primary cause of influenza epidemics and pandemics is a change in the nucleotide sequence in the genes encoding the surface antigens of influenza virus types A and B—the glycoproteins hemagglutinin and neuraminidase, which determine their specificity. There are 2 types of virus variability:

- antigenic drift refers to point mutations in a gene associated with evolution and immune selection pressure within a subtype, allowing a new antigenic variant of the virus to evade population immunity and causing annual increases in morbidity;

- antigenic shift (found only in influenza A viruses) is a change in HA and/or NA resulting from gene reassortment (exchange of genome fragments between different viruses during coinfection of a susceptible host). The absence of specific immunity to shifted variants of the influenza A virus leads to the rapid spread of the infection worldwide—a pandemic.

The ability of influenza viruses to undergo antigenic variability determines the high susceptibility of the population and the main epidemiological features of this infection: ubiquitous spread, short intervals between epidemics (1–2 years for influenza A and 2–4 years for influenza B), and involvement of all age groups of adults and children in the epidemic process [1,17,20,21]. Influenza predominantly caused by a new or significantly altered virus (e.g., avian influenza A (H5N1) and A (H7N9), less frequently A (H1N1) pdm 2009) is characterized by an acute, fulminant onset, the development of various variants of toxicosis (neurotoxicosis, infectious-toxic shock combined with hemodynamic disorders and signs of centralized circulation (cold extremities, cyanosis, mottling of the skin against the background of generalized pallor)) and stage III disseminated intravascular coagulation (DIC) syndrome (hemocoagulation shock), frequently against the background of leukopenia and lymphopenia [22].

1.4 Features of Coding the Disease or Condition

J09 – Influenza due to certain identified influenza virus;

J10 – Influenza due to identified seasonal influenza virus;

J10.0 – Influenza with pneumonia, influenza virus identified;

J10.1 – Influenza with other respiratory manifestations, seasonal influenza virus identified;

J10.8 – Influenza with other manifestations, seasonal influenza virus identified;

J11 – Influenza, virus not identified;

J11.0 – Influenza with pneumonia, virus not identified;

J11.1 – Influenza with other respiratory manifestations, virus not identified;

J11.8 – Influenza with other manifestations, virus not identified.

1.5 Classification of the disease or condition

I. By virus type (causative agent):

• Influenza A (A/H1N1), (A/H3N2), etc.;

• Influenza B (Yamagata and Victoria lineages);

• Influenza C.

Clinical classification in children [23]:

II. By form (degree) of severity:

• Mild;

• Moderately severe;

• Severe (toxic);

• Hypertoxic.

III. By course:

• Smooth (uncomplicated);

• Non-smooth (with complications, secondary infection, or exacerbation of chronic diseases).

IV. By presence of symptoms:

• Typical;

• Atypical (mild, asymptomatic).

V. By localization of lesion (topical features):

• Acute rhinitis;

• Acute pharyngitis;

• Acute tracheitis;

• Acute laryngitis;

• Acute bronchitis;

• Combinations of anatomical localizations (e.g., rhinopharyngitis).

1.6 Clinical presentation of the disease or condition

Influenza, including that caused by the novel A (H1N1) pdm2009 virus, in patients of any age typically begins against a background of complete health or after a brief (1–2 hour) prodromal period, with a characteristic predominance of intoxication syndrome over respiratory tract involvement (mainly the nasopharynx, larynx, and trachea). Body temperature reaches its maximum level (38.5–40^◦C) within the first few hours, accompanied by the simultaneous appearance of other intoxication symptoms, the severity of which determines the degree of the disease severity, ranging from mild to extremely severe (Appendix A3).

Intoxication syndrome manifests as chills, headache, muscle and joint aches, pain upon moving or pressing on the eyeballs, photophobia, lacrimation, severe weakness, fatigue, and lethargy. Dizziness, fainting spells, loss of consciousness, delirium, hallucinations, and convulsions may occur. On the first day of the illness, intoxication syndrome dominates over catarrhal syndrome.

Respiratory tract involvement syndrome (catarrhal syndrome) in influenza is usually mild and characterized by nasal congestion, scanty muco-serous rhinitis, mucosal dryness, throat tickling, soreness, or a dry, infrequent, and sometimes (in older children) rough "tracheal" cough with retrosternal pain. Moderate hyperemia with a bluish tinge of the arches, granularity, and vascular injection of the soft palate and posterior pharyngeal wall are characteristic.

Hemorrhagic syndrome manifests as epistaxis; fine-point or petechial rashes on the skin of the face, neck, chest, and upper extremities; hemorrhages on the mucous membranes of the oro- and nasopharynx, posterior pharyngeal wall, and conjunctivae; blood admixture in vomit, sputum; hematuria, etc. DIC syndrome frequently develops. Bleeding and hemorrhages in influenza are primarily associated with severe thrombocytopenia, making it a reliable prognostic factor for this syndrome. The risk of hemorrhages in vital organs arises when the platelet count drops below 105 x 10⁹/mL, presenting a real threat at counts below 50 x 10⁹/mL.

Respiratory complications of influenza may include:

• acute stenosing laryngotracheitis (ASLT);

• acute bronchitis;

• acute pneumonia.

Acute stenosing laryngotracheitis (ASLT) is one of the complications of influenza whose main clinical manifestations (hoarseness, airway obstruction, barking cough, and inspiratory dyspnea)—unlike ASLT in parainfluenza, respiratory syncytial virus, and adenoviral infections—develop in the first hours of the illness against the background of hyperthermia and pronounced intoxication, especially in children with manifestations of respiratory allergosis or a history of laryngitis episodes.

Acute bronchitis involving large and medium bronchi is observed in approximately 20–30% of influenza cases. Obstructive syndrome develops in every fifth child with bronchitis, with a predominant spastic character of obstruction.

Pneumonia holds a leading place among influenza complications; it can develop both at the onset of the disease and during convalescence with approximately equal frequency (in 5–8% of outpatient cases and 12.3–18.5% of hospitalized children).

During the first 4–5 days of the illness, the pulmonary process in influenza most frequently develops in unvaccinated adolescents who have not received antiviral drugs. Diffuse viral pneumonia develops, accompanied by severe hypoxemia, frequently with ARDS and hemorrhagic pulmonary edema, characterized by rapid progression and high mortality.

Pneumonia developing at later stages from the onset of influenza is predominantly of viral-bacterial etiology and is frequently diagnosed only radiologically. Typically, at the end of the first to the beginning of the second week of illness, after a short symptom-free interval, a new rise in body temperature occurs, accompanied by increased intoxication and local pulmonary changes confirmed radiologically [30,31].

Isolated involvement of the myocardium (myocarditis, myocardiopathy) in the infectious process among children and adolescents is infrequently observed. Primarily, at the peak of all the above-listed disease syndromes, disorders leading to hypoxia and acute cardiovascular failure also develop.

Nervous system lesions can also develop as a result of both the toxic (hypoxic) impact of the pathogen and cell breakdown products in the form of toxemia at the onset of the disease, and as a result of pathogen replication in nerve and glial cells with the development of neuritis (predominantly facial and trigeminal nerves).

ENT organ lesions (otitis media, eustachitis, sinusitis, etc.), developing with the participation of bacterial microflora at any stage of the disease, are frequently observed.

In mild influenza, body temperature does not rise above 38.5°C (may even remain normal), while intoxication syndrome (chills, malaise, sweating, decreased appetite) and catarrhal syndrome (acute rhinitis, pharyngitis, tracheitis) are mild to moderate. Hemorrhagic manifestations are absent.

Moderate-to-severe disease, dominating in 86–90% of cases among hospitalized patients, is characterized by a body temperature rise within 38.5–39.5°C, and moderate to severe intoxication syndrome (chills, weakness, headache, dizziness, myalgia, arthralgia, drowsiness or increased excitability, adynamia, vomiting, nausea). In some cases, elevated body temperature, predominantly in the form of hyperthermia, may be the sole manifestation of the disease. Respiratory tract involvement syndrome is moderately expressed, with the development of rhinitis, pharyngitis, tracheitis, and possibly bronchitis. Hemorrhagic syndrome presents as mild and short-lived epistaxis, petechial hemorrhagic rash on the skin and mucous membranes.

Severe disease is characterized by a body temperature rise above 39.5°C, pronounced intoxication syndrome with the development of an encephalitic or meningoencephalitic reaction (delirium, hallucinations, convulsions, confusion or loss of consciousness, vomiting), hemorrhagic syndrome (epistaxis, micropetechial or petechial rash on the skin of the face, neck, chest, and upper extremities, hemorrhages in the oral and nasal mucosa, posterior pharyngeal wall, conjunctiva, blood-tinged vomit, hemoptysis, hematuria, etc.), and DIC syndrome frequently develops. Hemophagocytic syndrome, forming during the course of the disease, should also be considered one of the variants of extremely severe influenza [29].

In approximately 3–5% of cases, predominantly in influenza caused by a shifted virus variant (including A H1N1 pdm2009), on any day from disease onset, even against the background of some clinical improvement, a sudden worsening of the patient's condition may occur. It is not always possible to predict the development of severe disease with statistical significance (one-third to half of all fatal influenza cases occurred among previously healthy individuals without risk factors). Therefore, given the possibility of sudden symptom worsening, one should vigilantly monitor for signs indicating that the disease is taking a more severe course.

These include the appearance of:

• cyanosis and dyspnea upon physical activity or at rest;

• cough with blood-tinged sputum, chest pain, or heaviness in the chest;

• mental status changes, confusion or agitation, convulsions;

• repeated vomiting;

• decreased blood pressure and reduced urine output;

• high body temperature and intoxication symptoms persisting for more than 3 days.

In young children, danger signs include rapid or labored breathing, decreased activity and difficulty waking up, and difficulty sucking during feeding.

The most severe complications are toxemia (septic-like syndrome) with systemic inflammatory response and pantropism (generalization of the process and multi-organ damage):

• infectious-toxic (hypoxic) encephalopathy (neurotoxemia);

• acute respiratory distress syndrome (ARDS);

• Gasser syndrome, acute kidney injury (AKI);

• Reye's syndrome;

• myocarditis and Kissing's syndrome;

• Waterhouse-Friderichsen syndrome;

• DIC syndrome.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Influenza is characterized by an acute onset in a state of complete health, high persistent fever from the first hours of the disease, pronounced intoxication symptoms peaking on days 1–2 in the form of chills (muscle shivering), headache, dizziness, malaise, muscle, abdominal, joint, and eyeball pain, nausea, vomiting, sleep disturbances, moderate or scant catarrhal syndrome (rhinopharyngitis, tracheitis), and sometimes (depending on severity) hallucinations, delirium, convulsions, and hemorrhagic syndrome; DIC syndrome develops in severe cases [6,32,33].

Criteria for establishing the diagnosis/condition of influenza based on:

1) anamnesis data: acute onset; high, persistent temperature rise from the first hours of the disease; chills, headache, dizziness, malaise, muscle, abdominal, joint, and eyeball pain, nausea, vomiting, sleep disturbances, sometimes hallucinations, delirium, convulsions (depending on severity); contact with an influenza patient and/or an acute respiratory viral infection patient, contact with animals or birds infected with the influenza virus;

2) physical examination: respiratory tract involvement syndrome (catarrhal) moderate or scant in the form of rhinopharyngitis, laryngitis, tracheitis, etc.; possible emergence of hemorrhagic syndrome, characteristic febrile response;

3) confirmation by one of the laboratory methods of etiological diagnostics.

In accordance with SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases", a confirmed case of influenza is considered after laboratory confirmation of the diagnosis (by any standardized methods in the Russian Federation recommended for the diagnosis of influenza, or performed using medical devices approved for use in the Russian Federation for the diagnosis of influenza). A laboratory-confirmed case does not necessarily have to meet the clinical case definition.

During periods of epidemic surges in influenza morbidity, a definitive diagnosis of "influenza" can be established both on the basis of laboratory confirmation and on the basis of clinical and epidemiological data.

2.1 Complaints and Anamnesis

Described in the "Clinical Presentation" section.

2.2 Physical Examination

Data are provided in the "Clinical Presentation" section.

2.3 Laboratory Diagnostics

Etiological diagnostics:

Comments: the rapid ICT method is characterized by high sensitivity (73.7–86.8%) and specificity (97.6–100%) and allows for an etiological diagnosis at the patient's bedside (outpatient setting). This is particularly relevant when PCR is unavailable.

Comments: PCR is the gold standard for influenza diagnosis. Isolation of intact virions or their components is advisable in the presence of clinical manifestations of influenza during the epidemic season of increased incidence of influenza or influenza-like ARVI, in severe cases of respiratory diseases, and in outbreaks within closed settings and educational institutions. It is most commonly used when patients are hospitalized.

Comments: the use of serological methods is valid for retrospective diagnosis of a past infection in the presence of a fourfold increase in specific IgG antibody titers. This is relevant for research purposes and epidemiological surveillance of influenza.

Comments: performed in all hospitalized patients for the differential diagnosis of influenza and influenza-like illnesses of non-influenza etiology, as well as for the detection of coinfecting respiratory infections; performed in outpatient settings based on clinical and epidemiological indications (severe course, development of complications, premorbid risk factors) [49].

Differential diagnosis between influenza and novel coronavirus infection is possible using rapid chromatograhic immunoassay (CIA) of a nasopharyngeal swab (for influenza A virus antigens, influenza B virus antigens, and SARS-CoV coronavirus antigens) [136].

Comments: hemogram parameters vary depending on the period and severity of influenza. The blood test reveals normocytosis or mild leukopenia, less frequently a tendency toward leukocytosis with a left shift in complicated moderate influenza. In severe cases, leukocyte counts are elevated above 12 × 10⁹/L or decreased below 3 × 10⁹/L, neutrophils may exceed 60%, with over 10% immature neutrophil forms (metamyelocytes, myelocytes, band cells), and a potential decrease in hemoglobin and platelet count. Leukopenia in influenza patients is a prognostically unfavorable factor indicating a high risk of viral pneumonia; leukocytosis with neutrophilia and a left shift indicates a high risk of viral-bacterial pneumonia or other bacterial complications of influenza. A decrease in hemoglobin and platelet levels requires the exclusion of hemolytic-uremic syndrome (Gasser syndrome), while pancytopenia (leukopenia, anemia, and thrombocytopenia) points to hemophagocytic syndrome.

Comments: in uncomplicated influenza, there are no pathological changes; in pronounced fever and intoxication syndrome, there is an increase in urine specific gravity, mild transient leukocyturia, proteinuria, and cylindruria. A general (clinical) urinalysis is indicated to detect influenza complications.

Comments: blood biochemical parameters vary depending on the severity and complications of influenza. An increase in CRP and procalcitonin by more than 2 standard deviations from the norm is considered diagnostic. The simultaneous increase in CRP and procalcitonin is more effective in determining bacterial complications of influenza, including secondary bacterial pneumonia.

Comments: blood biochemical test results in severe and complicated influenza show an increase in several parameters: aminotransferases (ALT and AST), LDH, bilirubin > 50 mmol/L, CPK, creatinine > 0.2 mg/L, residual nitrogen > 1000 mg/L, urea > 7.0 mmol/L, glucose > 7.7 mmol/L in the absence of diabetes mellitus. These changes allow for the timely diagnosis of influenza complications: an increase in CPK along with myoglobinemia and myoglobinuria indicates rhabdomyolysis; an increase in ALT, AST, hyperammonemia, elevated urea, creatinine, and residual nitrogen along with hypoalbuminemia, hypoprothrombinemia, and hypofibrinogenemia indicates Reye's syndrome; an increase in CPK, CK-MB (cardiac fraction of CPK), LDH, and AST along with changes on the electrocardiogram and echocardiogram indicates cardiac complications.

Comments: used to diagnose DIC syndrome, which develops due to generalized involvement of vascular walls and/or primary effects on platelets resulting from excessive activation of thromboplastin formation with consumption of platelets and plasma clotting factors, and pathological fibrinolysis leading to thrombosis and hemorrhage. Hypercoagulation and excessive thrombus formation are characterized by increased blood clotting. Profound hypocoagulation (activation of fibrinolysis) is characterized by prolonged bleeding time, marked thrombocytopenia, and altered coagulogram parameters.

Comments: indicated for detecting influenza complications: Gasser syndrome — hyponatremia, hypochloremia, and hyperkalemia along with hemolytic anemia and thrombocytopenia, as well as elevated creatinine, urea, micro- and macrohematuria, and proteinuria; it is also used to correct electrolyte disturbances associated with dehydration during hyperthermia in the absence of adequate rehydration.

2.4 Instrumental Diagnostics

Comment: performed at all stages of medical care.

2.5 Other Procedures

Comments: the use of these methods is justified when there are clinical symptoms suggestive of viral pneumonia and/or for the diagnosis of complications, including those resulting from secondary bacterial flora activation. If viral etiology of pneumonia is suspected (bilateral pneumonia within the first four days of the disease inclusively), CT is preferred.

Comments: the use of this method is recommended in patients with underlying cardiac pathology for early detection of decompensation and/or when cardiac rhythm and conduction disorders are suspected to develop against the background of influenza.

Comments: the use of this method is recommended in patients with underlying cardiac pathology for early detection of decompensation and/or when inflammatory changes in the myocardium and cardiac membranes are suspected to develop.

Comments: the use of this method is recommended in patients with decompensation of underlying neurological pathology, development of convulsive syndrome, suspected cerebral edema, meningitis, or encephalitis during the course of influenza.

Comments: consultations with medical specialists are indicated upon the development of complications or decompensation of existing organ pathology.

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

Introduction to the section

Treatment goals:

• stabilization of the patient's condition;

• normalization of body temperature;

• relief of intoxication;

• elimination of catarrhal syndrome;

• prevention and/or relief of complications, exacerbation of comorbid diseases.

3.1 Conservative Treatment

3.1.1. Etiotropic therapy

Comments: treatment should be started based on clinical suspicion of influenza during the seasonal influenza peak or if the patient has a history of epidemiological contact with an influenza patient, without waiting for laboratory confirmation of the diagnosis, regardless of vaccination status against influenza for the current epidemic season and the severity of the disease. If treatment is not initiated early, antiviral therapy may be started at any stage of the peak of the illness in patients with severe disease, or those with risk factors for severe influenza and poor outcomes.

Comments: neuraminidase inhibitors can be used for influenza of any severity, but their frequent use leads to the development of influenza virus resistance. Oseltamivir** is used from 1 year of age. In children older than 14 days and younger than 1 year with laboratory-confirmed severe influenza or with complications, underlying or comorbid conditions, off-label use of #oseltamivir** is possible at a dosage of 3 mg/kg body weight per dose twice daily by decision of a medical board or medical commission and after obtaining informed consent from the legal representative for the off-label use of the medicinal product [72,73]. Zanamivir is used in patients over 5 years of age for severe influenza, administered within the first 36 hours from disease onset. This drug requires cautious use in patients with bronchospasm.

Comments: this recommendation helps prevent the development of influenza virus resistance to neuraminidase inhibitors.

Comments: Baloxavir marboxil is a prodrug that is converted via hydrolysis into the active metabolite baloxavir, which exerts anti-influenza activity. Baloxavir targets the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme within the polymerase acidic subunit of the viral RNA (ribonucleic acid) polymerase complex, which inhibits transcription of the influenza virus genome, leading to the suppression of viral replication. It is active against influenza viruses A, B, C, and D. Baloxavir marboxil can be prescribed to children (with a body weight of 20 kg or more) and is administered orally once [80,81].

Comments: by mechanism of antiviral action, it belongs to fusion inhibitors, interacting with the viral hemagglutinin and preventing the fusion of the viral lipid envelope with cell membranes. It exerts a moderate immunomodulatory effect and increases the body's resistance to viral infections.

It is advisable to use in patients with mild and moderate influenza without premorbid pathology and risk factors for complications. Umifenovir** is used from 2 years of age in accordance with the instructions; the powder for oral suspension and film-coated tablets are used from 3 years of age, and capsules from 6 years of age.

Comments: the main mechanism of action of Kagocel** is the ability to increase interferon production and thereby induce the body's antiviral response to viral exposure. It is advisable to use in patients with mild and moderate influenza without premorbid pathology and risk factors for complications.

Kagocel** is used in accordance with the instructions for use, in children over 3 years of age.

Comments: active against influenza viruses A (A(H1N1) pdm09; A(H3N2); A(H5N1)), B, and other RNA and DNA-containing respiratory viruses; stimulates innate immunity factors. It is used from 3 years of age in accordance with the instructions. It is advisable to start the drug no later than the 2nd day from disease onset. It is appropriate to use in patients with mild to moderate influenza without premorbid pathology and risk factors for complications.

Comments: the mechanism of the antiviral action of inosine pranobex is associated with the inhibition of viral RNA and DNA synthesis, as well as an increase in the production of alpha- and gamma-interferons by lymphocytes; it increases the total number of T-lymphocytes, normal killer cells, and T-helpers, natural killers, enhancing the adaptive mechanism of immunological memory while limiting the systemic inflammatory response. It is used from 3 years of age and older in accordance with the instructions.

Comments: resistance of most influenza virus strains to drugs of this group has been proven.

3.1.2. Pathogenetic and symptomatic therapy

Pathogenetic and symptomatic therapy is selected for the patient individually depending on the existing symptoms (syndromes) in accordance with the instructions for use of the drugs.

Comments: isotonic salt solutions (sodium chloride**, infusion solution) are used alongside dextrose** to relieve intoxication. Parenteral administration of excessive fluid, especially isotonic sodium chloride solution**, carries the risk of pulmonary and cerebral edema. The total amount of fluid administered parenterally should be calculated based on physiological needs and pathological losses.

Comments: in patients with a history of seizure disorders or when seizures develop against the background of the current illness, lowering the temperature, including subfebrile temperature, is indicated.

In children, paracetamol** (oral suspension for children from 3 months, tablets for children from 3 years) and ibuprofen** (oral suspension for children from 3 months, 200 mg tablets for children from 6 years, 400 mg tablets for children from 12 years) are used for antipyretic purposes.

Comments: the action of these drugs is aimed at improving nasal breathing, relieving nasal mucosa edema, and improving the outflow of contents from the paranasal sinuses.

Comments: the action of these drugs is aimed at suppressing cough in patients and has age-related contraindications depending on the dosage form.

Comments: these drugs are aimed at improving sputum clearance from the tracheobronchial tree when lower respiratory tract infection is suspected, and enhancing mucociliary clearance. Concomitant use of expectorants and antitussives is not recommended.

3.2 Other Treatment

For patients with mild influenza without risk factors when mixed viral-viral infection is suspected, as well as in the presence of mild immunodeficiency states, including persistent herpesvirus infections, recurrent respiratory diseases, and age-related immune characteristics, the following drugs may be used [5,11,52,103]:

Comments: interferon alfa-2b** has antiviral, immunomodulatory, and antiproliferative properties; it inhibits the replication of RNA- and DNA-containing viruses. As part of combination therapy, it is used from the first days of life in the form of rectal suppositories, including in premature infants. The dosage form is chosen taking into account the patient's age.

Comments: Meglumine acridone acetate (tablets) is used in the combination therapy of influenza in children aged 4 years and older in accordance with the instructions.

Comments: Anaferon for children is used in children aged 1 month and older, and ergoferon from 6 months. For prophylactic and therapeutic use, the drug exerts immunomodulatory and antiviral effects. Its efficacy against influenza A and B viruses and other viruses has been established experimentally and clinically. The drugs reduce the virus concentration in affected tissues, affect the system of endogenous interferons and associated cytokines, induce the production of endogenous "early" interferons (IFN α/β) and gamma-interferon (IFN γ); and stimulate humoral and cellular immune responses.

Comments: the necessity, feasibility, and indications for prescribing systemic antibacterial drugs in influenza are due to the development of complications of viral-bacterial etiology in the form of sinusitis, tonsillitis, otitis media, pneumonia, urinary tract infections, etc. Treatment of developed complications should be carried out in accordance with clinical guidelines for these nosological entities. Systemic antibacterial drugs should be used taking into account the antibiotic susceptibility of the identified pathogen, as well as in the absence of pathogen isolation in pneumonia patients with influenza that developed from the 5th day of the disease.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation for influenza patients has not been developed.

When complications develop or comorbid conditions exacerbate, rehabilitation measures are prescribed by specialists in the relevant fields.

Acute infectious diseases are a contraindication for sanatorium-resort treatment.

5. Prevention and Dispensary Observation

Dispensary observation for uncomplicated influenza is not indicated.

The patient is isolated at home or in an isolation ward (in closed children's groups), and in a hospital setting - in a separate box or with children having the same nosology for the duration of the peak illness period until complete clinical recovery. Daily routine wet cleaning is carried out. Upon discharging the patient from the room (box), terminal disinfection is performed. After clinical recovery, the child is admitted back to the childcare facility.

It is necessary to:

- provide the patient with separate utensils and care items, and ventilate and perform wet cleaning of the room using available household detergents and disinfectants;

- boil or treat the utensils used by the patient with disinfectants in a special container;

- wash hands thoroughly with soap after each contact with the patient;

- wear disposable masks.

Quarantine and isolation measures for contacts are not carried out.

The child's diet must correspond to the patient's age and somatic characteristics. An adequate drinking regimen must be ensured for detoxification and replenishment of pathological fluid losses.

Comments: specific influenza prophylaxis is carried out in accordance with Order of the Russian Ministry of Health No. 1122n dated December 6, 2021, "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemic Indicators, and the Procedure for Conducting Preventive Vaccinations", as well as Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021 (as amended on May 25, 2022) "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitation and epidemiological requirements for the prevention of infectious diseases'" (registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500).

According to Order of the Russian Ministry of Health No. 1122n dated December 6, 2021 (Order of the Russian Ministry of Health No. 1122n dated December 6, 2021, "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemic Indicators, and the Procedure for Conducting Preventive Vaccinations"), influenza vaccinations are carried out within the framework of the National Schedule for children from 6 months of age, pupils of grades 1-11, students of vocational educational organizations and higher education organizations; persons subject to conscription for military service; persons with chronic diseases, including lung diseases, cardiovascular diseases, metabolic disorders, and obesity.

SanPiN 3.3686-21, paragraphs 2698-2707, defines the goal of influenza vaccination as reducing morbidity and mortality from influenza, its complications, and exacerbations of chronic pathology; therefore, vaccination is primarily administered to individuals at high risk for influenza, which includes children over 6 months old, children attending preschool and school educational institutions, students, children living in permanent residential institutions, and unorganized children, primarily those with chronic diseases of the cardiovascular system, kidneys, liver, respiratory system, neurological diseases, metabolic and endocrine disorders, including immunodeficiency states (primary, secondary, induced).

For specific influenza prophylaxis in children of the first three years of life, children of any age in 24-hour residential care facilities, and children with various chronic conditions, trivalent and quadrivalent inactivated, subunit, split, and recombinant influenza vaccines of domestic and foreign production, registered in the Russian Federation and prepared taking into account epidemiologically relevant virus strains, are used (SanPiN 3.3686-21, para. 2702).

List of vaccines approved for use in childhood:

- Influenza vaccine [inactivated] + azoximer bromide**; suspension for intramuscular and subcutaneous administration - used in children starting from 6 months of age, adolescents; solution for intramuscular and subcutaneous administration - used in children starting from 6 months of age, adolescents.

- Influenza vaccine [inactivated]** (quadrivalent), used in children over 6 months - solution for intramuscular injection (preservative-free).

- Influenza vaccine [inactivated]**, solution for intramuscular injection (preservative-free) intended for use in children from 6 months of age, adolescents.

- Influenza vaccine (live)**, lyophilisate for preparation of nasal spray solution, used in children over 3 years of age.

Basically, for children under 3 years of age, primary immunization is carried out with vaccines from the ATC group J07BB02 Influenza virus purified antigen; most often, vaccination is performed twice at an interval of 1 month, and in subsequent years, vaccination is carried out once annually. If a previously unvaccinated child under 3 years of age has suffered from confirmed influenza, vaccination is carried out once, and in subsequent years also once annually. For children over 3 years of age, including previously unvaccinated ones, vaccination is carried out once annually.

All temporary and permanent contraindications listed in the specific vaccine's product label must be taken into account when screening patients for vaccination.

Immunization of all children begins before the seasonal rise in influenza incidence and may continue until the Rospotrebnadzor authorities declare the end of the epidemic situation and the completion of immunization.

Influenza vaccination is carried out with the written informed consent of the child's legal representatives, or with the consent of children aged 15 years and older.

Home vaccination by mobile immunization teams is permitted for patients with limited mobility.

Seasonal influenza vaccination can be carried out simultaneously (concomitantly) with routine vaccination using other vaccines from the National Schedule of Preventive Vaccinations or the epidemiological indication vaccination schedule.

Vaccination with influenza vaccines (ATC code: J07BB02 Influenza virus, purified antigen) can be administered at any interval before or after other non-live and live vaccines (except for BCG/BCG-M vaccine). Non-live vaccines include all vaccines that do not contain live virus (inactivated, split, subunit, recombinant). Live influenza vaccine** can be administered on the same day or at an interval of 1 month with other live vaccines, but at any interval with non-live vaccines from the National Schedule of Preventive Vaccinations and the epidemiological indication vaccination schedule (the principles of live vaccine administration and intervals are set out in Order of the Russian Ministry of Health No. 1122-n dated December 6, 2021, and the methodological recommendations for preventive vaccinations in accordance with Order of the Russian Ministry of Health No. 1122n issued by the Ministry of Health on January 21, 2022, No. 15-2/I/2-806).

Emergency post-exposure chemoprophylaxis for an immediate antiviral effect with systemic antiviral drugs is indicated for unvaccinated children who have had contact with a patient suffering from influenza or acute respiratory infection during the high influenza incidence season [83,89,91,108,11,112,133].

Post-exposure chemoprophylaxis should be administered to all children with risk factors for an unfavorable outcome of influenza [71–73].

Comments: dosage forms are used in accordance with the instructions for use.

Comments: can be prescribed to children (with a body weight of 20 kg or more), both those with no underlying conditions and those at risk for influenza complications. The drug is administered orally as a single dose.

Comments: used in accordance with the instructions for use.

Comments: prophylaxis of influenza and acute respiratory viral infections (ARVI) with kagocel** in children aged 3 years and older is carried out in accordance with the instructions for use.

Comments: Interferon alfa-2b** dosage forms for intranasal administration are used from the first days of life, including in premature infants, for 5 days, with the exception of the ointment, which is approved for use in children older than 1 year, and the topical spray.

Comments: Meglumine acridoneacetate is used in children over 4 years of age for emergency non-specific prophylaxis of influenza and ARVI (upon direct contact with patients with influenza or acute respiratory infections of other etiology, during an influenza epidemic).

Comments: Anaferon for Children is used in children from 1 month of age in accordance with the instructions.

6. Organization of Medical Care

Medical care for patients with influenza is provided in the following forms:

• primary health care;

• emergency medical care, including specialized emergency medical care;

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

Medical care for patients with influenza may be provided in the following settings:

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

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

Indications for hospitalization in a medical organization:

1) pronounced general intoxication syndrome;

2) hemorrhagic syndrome (epistaxis, blood admixture in sputum, vomitus, and stool, hemorrhagic rash), development of disseminated intravascular coagulation (DIC) syndrome or Hasser syndrome with acute renal failure (ARF);

3) hemodynamic instability with centralization of peripheral circulation (cold extremities, cyanosis, skin mottling against the background of general pallor and hyperthermia, development of collapse and coma);

4) severe respiratory failure against the background of diffuse cyanosis and pallor, as well as symptoms of pneumonia and signs of possible acute respiratory distress syndrome (ARDS): cough with frothy sputum mixed with blood, dullness of the pulmonary percussion sound, abundant moist rales of various calibers and profuse crepitation on auscultation, sharp drop in blood pressure, muffled heart sounds, and arrhythmia;

5) newborns and infants with moderate forms of the disease but a complicated course, with exacerbation of concomitant diseases.

Indications for hospitalization expand as the patient's age decreases and the condition worsens—which often occurs catastrophically with rapid progression and generalization of the process, accompanied by meningoencephalic reactions and hemorrhagic syndrome—and saving the child's life frequently depends on correct medical tactics.

Patients are hospitalized in infectious disease hospitals/departments (beds).

Children are hospitalized in hospitals equipped with intensive care units.

Indications for patient discharge from a medical organization:

1) stabilization of the condition;

2) normalization of body temperature.

7. Additional Information

Risk factors for an unfavorable outcome:

• children under 5 years of age, especially those under 2 years;

• bronchopulmonary diseases: bronchial asthma, bronchopulmonary malformations, chronic obstructive pulmonary disease, cystic fibrosis;

• heart diseases: congenital/acquired heart defects and inflammatory heart diseases;

• endocrine disorders: diabetes mellitus, obesity;

• liver and kidney diseases;

• metabolic disorders: inherited metabolic disorders; mitochondrial disorders;

• immunological disorders: HIV infection, congenital and acquired immunodeficiency states;

• children with neurological disorders.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lobzin, Yuri Vladimirovich – D.Sc. in Medicine, Academician of the Russian Academy of Sciences, President of the Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency (FSBSI DNRC ID FMBA), Chief Freelancer for Pediatric Infectious Diseases of the Russian Ministry of Health and FMBA of Russia, President of the Euro-Asian Society for Infectious Diseases.

2. Zhdanov, Konstantin Valerievich – D.Sc. in Medicine, Corresponding Member of the Russian Academy of Sciences, Professor, Director of the Children's Research and Clinical Center of Infectious Diseases of the FMBA, Chief Freelancer for Infectious Diseases of the St. Petersburg Health Committee, Vice-President of the Euro-Asian Society for Infectious Diseases.

3. Gorelov, Alexander Vasilievich – D.Sc. in Medicine, Academician of the Russian Academy of Sciences, Deputy Director for Research at the Central Research Institute of Epidemiology of Rospotrebnadzor, Chairman of the Board of the Pokrovsky National Association of Infectious Disease Specialists.

4. Usenko, Denis Valerievich – D.Sc. in Medicine, Associate Professor, Leading Researcher at the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor, Executive Director of the Pokrovsky National Association of Infectious Disease Specialists.

5. Babachenko, Irina Vladimirovna – D.Sc. in Medicine, Professor, Head of the Research Department of Droplet Infections, Federal Research and Clinical Center of Children's Infectious Diseases of the FMBA, member of the Euro-Asian Society for Infectious Diseases.

6. Rychkova, Svetlana Vladislavovna – D.Sc. in Medicine, Associate Professor, Head of the Medical Care Organization Department, Federal Research and Clinical Center of Children's Infectious Diseases of the FMBA, pediatrician.

7. Kharit, Susanna Mikhailovna – D.Sc. in Medicine, Head of the Research Department of Vaccine Prophylaxis and Post-Vaccination Pathology, Federal Research and Clinical Center of Children's Infectious Diseases of the FMBA, Chief Freelancer for Vaccine Prophylaxis of the St. Petersburg Health Committee.

8. Ponezheva, Zhanna Betovna – D.Sc. in Medicine, Associate Professor, Head of the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor.

9. Gorodin, Vladimir Nikolaevich – D.Sc. in Medicine, Professor, Head of the Department of Infectious Diseases and Epidemiology at the Faculty of Advanced Training and Professional Retraining of Specialists, Kuban State Medical University of the Russian Ministry of Health, Chief Medical Officer of Infectious Disease Hospital No. 2 of the Ministry of Health of Krasnodar Krai, Chief Freelancer for Infectious Diseases of the Ministry of Health of the Russian Federation in the Southern Federal District.

10. Timchenko, Vladimir Nikolaevich – D.Sc. in Medicine, Professor, Head of the Department of Infectious Diseases, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Chief Freelancer for Pediatric Infectious Diseases of the Northwestern Federal District.

11. Lioznov, Dmitry Anatolievich – D.Sc. in Medicine, Professor, Director of the Smorodintsev Research Institute of Influenza of the Russian Ministry of Health.

12. Afanasyeva, Olga Ivanovna – D.Sc. in Medicine, Head of the Department of Respiratory Viral Infections in Children, Smorodintsev Research Institute of Influenza of dak Russian Ministry of Health, member of the Euro-Asian Society for Infectious Diseases.

13. Zakharenko, Sergei Mikhailovich – Ph.D. in Medicine, Associate Professor, Deputy Director of the Federal Research and Clinical Center of Children's Infectious Diseases of the FMBA, member of the Euro-Asian Society for Infectious Diseases.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• anesthesiologist-intensivist;

• virologist;

• disinfectologist;

• health station physician;

• infectious disease physician;

• clinical laboratory diagnostics physician;

• clinical pharmacologist;

• laboratory physician;

• neurologist;

• general practitioner (family physician);

• pediatrician;

• municipal (district) pediatrician;

• primary care pediatrician;

• medical prevention physician;

• medical rehabilitation physician;

• admitting department physician;

• internist;

• adolescent therapist;

• district general practitioner;

• epidemiologist.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, 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

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

2. Federal Law No. 52-FZ of March 30, 1999, "On the Sanitary and Epidemiological Welfare of the Population". (In Russ.)

3. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021 ("On the Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and epidemiological requirements for the prevention of infectious diseases' (along with 'SanPiN 3.3686-21. Sanitary rules and norms...')") (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500). (In Russ.)

4. Order of the Russian Ministry of Health No. 1122n of December 6, 2021, "On the Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemiological Indications, and the Procedure for Conducting Preventive Vaccinations" (Registered with the Ministry of Justice of Russia on December 20, 2021, No. 66435). (In Russ.)

5. Order of the Ministry of Health and Social Development of Russia No. 521n of May 5, 2012, "On the Approval of the Procedure for Providing Medical Care to Children with Infectious Diseases" (Registered with the Ministry of Justice of Russia on July 10, 2012, No. 24867). (In Russ.)

6. Order of the Russian Ministry of Health No. 804n of October 13, 2017, "On the Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808). (In Russ.)

7. Order of the Russian Ministry of Health No. 302n of May 16, 2019, "On the Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During the Period of Education and Upbringing in Educational Organizations" (Registered with the Ministry of Justice of Russia on June 7, 2019, No. 54887). (In Russ.)

8. Clinical guidelines "Pneumonia (community-acquired)". Union of Pediatrists of Russia, Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. Year of approval: 2022. URL: https://cr.minzdrav.gov.ru/preview-cr/714_1 (In Russ.)

9. https://www.influenza.spb.ru website of the Smorodintsev Research Institute of Influenza of the Russian Ministry of Health. (In Russ.)

10. Temporary guidelines "Prevention, diagnosis and treatment of the new coronavirus infection (COVID-19). Version 18 (October 25, 2023)" (approved by the Russian Ministry of Health) (along with "Recommendations for describing chest X-ray and CT data", "Instructions for diagnosing COVID-19 using nucleic acid amplification methods", "Instructions for diagnosing COVID-19 using immunochemical methods", "Recommended outpatient treatment regimens", "Recommended inpatient treatment regimens", "Instructions for compliance with infection safety measures for mobile emergency medical teams"). (In Russ.)

11. Letter of the Russian Ministry of Health No. 15-2/I/2-806 of January 21, 2022, "On guidelines for immunization in accordance with the Order of the Russian Ministry of Health No. 1122n of December 6, 2021" (along with "Guidelines for conducting preventive vaccinations in accordance with the Order of the Russian Ministry of Health No. 1122n of December 6, 2021, 'On the Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemiological Indications, and the Procedure for Conducting Preventive Vaccinations'"). (In Russ.)

12. Methodological Recommendations MR 3.1.2.0304-22 3.1.2. Respiratory tract infections. "Laboratory diagnostics of acute respiratory infections, including influenza and COVID-19 under conditions of their mixed circulation" (approved by the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing on December 7, 2022).

Criteria for assessing the severity of influenza based on clinical signs [2,11,23,32]

Appendix B. Physician Action Algorithms

Diagram

Appendix C. Patient Information

Influenza is an acute respiratory viral disease characterized by fever and symptoms of general intoxication dominating over moderate catarrhal syndrome in the upper respiratory tract. Influenza is caused by RNA-containing viruses belonging to the family Orthomyxoviridae, genus Influenzavirus, which includes influenza viruses types A, B, and C. Influenza typically begins against a background of complete health or after a short (1-2 hours) prodromal period with a characteristic predominance of the intoxication syndrome over the respiratory tract involvement syndrome (mainly the nasopharynx, larynx, and trachea). Body temperature reaches its maximum level (38.5–40°C) within the first hours, accompanied by the simultaneous appearance of other intoxication symptoms; their severity determines the degree of the disease severity, which can range from mild to extremely severe. The disease manifests with chills, headache, aches in muscles and joints, pain when moving or pressing on the eyeballs, photophobia, lacrimation, severe weakness and fatigue, and lethargy. Dizziness, fainting, loss of consciousness, delirium, hallucinations, and convulsions may occur. On the first day of the disease, the intoxication syndrome dominates over the catarrhal syndrome. The catarrhal syndrome manifests as nasal congestion, scant seromucous rhinitis, dryness of the mucous membranes, tickling in the throat, soreness, or a dry, infrequent, and sometimes (in older children) rough "tracheitic" cough with retrosternal pain. Moderate hyperemia with a cyanotic tint of the arches, granularity, and vascular injection of the soft palate and posterior pharyngeal wall are characteristic. Epistaxis, petechial or punctate rash on the skin of the face, neck, chest, and upper extremities, hemorrhages on the oral and nasopharyngeal mucosa, posterior pharyngeal wall, conjunctivae, admixture of blood in vomit, sputum, hematuria, etc., are possible. Systemic antiviral drugs are used in therapy from the first days of the disease. In the event of bacterial complications, systemic antibacterial drugs are indicated. The most effective method of prevention is annual vaccination.

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

Not applicable.