Acute Hepatitis B (AHB) in Children: Clinical Guidelines

List of Abbreviations

HBcAg – Hepatitis B virus core antigen

HBeAg – Hepatitis B virus e antigen

HBsAg – Hepatitis B virus surface antigen

HBV – Hepatitis B virus

HBxAg – Hepatitis B virus x antigen

IgM, IgG – Immunoglobulins class M, G

ALT – Alanine aminotransferase

Anti-HBe – Antibodies to HBe antigen

Anti-HBs – Antibodies to hepatitis B surface antigen

Anti-HDV – Antibodies to hepatitis D virus

Anti-HBc – Antibodies to hepatitis B core antigen

AST – Aspartate aminotransferase

WHO – World Health Organization

HB – Hepatitis B

GGT – Gamma-glutamyl transpeptidase

DIC – Disseminated intravascular coagulation

DNA – Deoxyribonucleic acid

ELISA – Enzyme-linked immunosorbent assay

cccDNA – Covalently closed circular DNA

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

ICU – Intensive Care Unit

AHB – Acute hepatitis B

ALF – Acute liver failure

PTI – Prothrombin index

PCR – Polymerase chain reaction

ESR – Erythrocyte sedimentation rate

FL – Federal Law

CHB – Chronic hepatitis B

CLIA – Chemiluminescent immunoassay

ALP – Alkaline phosphatase

Terms and Definitions

Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence (clinical research results) in making decisions about the care and treatment of individual patients.

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

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

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

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 providing medical care, and the degree of achievement of the planned result.

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

Clinical situation refers to a case requiring the regulation of medical care regardless of the specific disease or syndrome.

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

Medical intervention encompasses types of medical examinations and/or medical manipulations performed by a medical professional in relation to a patient, affecting their physical or mental state and having a preventive, exploratory, diagnostic, therapeutic, or rehabilitative purpose, as well as artificial termination of pregnancy.

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.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Acute hepatitis B (AHB) is an anthroponotic infectious disease caused by the hepatitis B virus (HBV), with a predominantly parenteral mechanism of infection and natural and artificial routes of transmission. It is characterized by cyclically progressing hepatitis (with or without jaundice) with pronounced polymorphism of clinical manifestations and the risk of transition to a chronic form [1-10].

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

The causative agent of AHB is the hepatitis B virus (hepatitis B virus - HBV), a DNA-containing virus belonging to the Hepadnaviridae family, Orthohepadnaviridae genus. One of the smallest enveloped human viruses. HBV is characterized by high tissue and species specificity, a unique genome organization, and replication mechanism. It integrates into the host cell. Not only viral particles but also the surface antigen of the virus—HBsAg (Hepatitis B surface Antigen)—persist in blood serum as filamentous and spherical bodies without a core, consisting of lipids and proteins. They are non-infectious [2,8,9,11-15].

The HBV virion (virus outside the host cell) is a particle 42–45 nm in diameter, consisting of a lipoprotein envelope (supercapsid), an inner envelope (capsid), and a nucleoprotein (DNA) [6,8,9,11,12,14,15]. The supercapsid is a lipid membrane into which HBsAg is embedded. In historical sources, HBsAg may be referred to as the "Australia antigen." The antigen was named "Australian" by its discoverer, B.S. Blumberg, as it was first detected in the blood of Australian aborigines. In addition to HBsAg, the supercapsid contains pre-S1 and pre-S2 proteins [6,8,9,11,12,14,15]. The capsid (nucleocapsid) has a polyhedral (icosahedral) shape with a size of 28 nm. The capsid includes HBcoreAg/HBcAg (Hepatitis B core Antigen), its subunit HBeAg (transformed HBcAg), and HBxAg. Inside the capsid are enzymes—DNA polymerase, reverse transcriptase—and a nucleoprotein, the genetic material of the virus. The HBV genome has an atypical structure and is represented by relaxed circular partially double-stranded DNA (rcDNA) [6,8,9,11,12,14,15].

HBV DNA has 4 open reading frames encoding 7 proteins:

gene P (polymerase): Pol/RTHBV - polymerase, reverse transcriptase;

gene S (surface): pre-S1, pre-S2, HBsAg;

gene C (core): HBcAg, HBeAg;

gene X: HBxAg [9,11,12,14,15].

Viral antigens and their corresponding antibodies reflect the stage of the infectious process (for details, see the "Diagnostics" section). Each HBV protein has its own function and plays a role in the viral life cycle. HBsAg, together with pre-S1 and pre-S2 proteins, is responsible for the integration of the virus into hepatocytes. HBcAg has protein kinase activity necessary for protein phosphorylation. It possesses high immunogenicity, which is associated with an adequate immune response of the organism during the cyclic course of AHB. HBcAg can be detected only in hepatocytes; this antigen does not enter the bloodstream. A transformed variant of HBcAg circulates in the peripheral blood—HBeAg, which is a marker of active viral replication and high DNA polymerase activity. HBxAg activates the expression of all viral genes and enhances the synthesis of viral proteins [9,11,12,14,15]. Recent studies demonstrate a special role of HBxAg in the development of epigenetic mutations and oncogenesis (formation of hepatocellular carcinoma) [13,16-18]. Mutations occurring in individual gene regions, especially those responsible for the pre-S, pre-S1, and pre-C zones, lead to the formation of new mutant strains of the virus [12,19]. The most conservative antigenic determinant is the a-determinant (HBsAg), mutations in which lead to vaccine escape [20-24]. In addition, mutations can cause an acyclic course of hepatitis and difficulties in diagnosis, for example, during infection with a mutant strain of the virus in which HBsAg production is preserved.

To date, 10 HBV genotypes (A-J) have been described, with nucleotide sequence differences between them of about 8%. The best-studied variants are A-D. In addition, subgenotypes (A1-A4, B1-B5, C1-C16, etc.) and recombinant viral strains (formed as a result of mutations during co-infection with different genotypes) are distinguished [12]. Genotypes have a phylogenetically established geographical distribution (Table 1). Differences between them are of clinical significance—they affect the effectiveness of therapy, the frequency of chronic infection development, disease severity, etc. [11,13,14,15,19]. To date, the clinical role of HBV genotypes has not been sufficiently studied, and research in this direction is ongoing worldwide.

Table 1. Geographical distribution of various HBV genotypes [12,19].

Pathogenesis. After entering the human body (infection), HBV enters the liver hematogenously. Specific receptors are located on the surface of hepatocytes, through which bile acids normally enter liver cells. HBsAg has a high affinity for these receptors, and their interaction ensures the penetration of the virus into the cell [6,9,25]. Subsequently, the virus is uncoated and enters the nucleus of the hepatocyte in the form of rcDNA. In the nucleoplasm, rcDNA is transformed into covalently closed circular DNA (cccDNA), enveloped by histone and non-histone proteins, forming a "beads-on-a-string" structure [6,12-14,26]. cccDNA is the transcription template for HBV. Inside the hepatocyte nucleus, it exists as a mini-chromosome. The maintenance of cccDNA is necessary for the preservation of the virus. Histone acetylation regulates the transcriptional activity of cccDNA. The synthesized RNAs move to the cytoplasm, where mRNA (messenger RNA) is translated and pregenomic RNA together with polymerase is packaged into a protein envelope; translation of various viral proteins occurs. HBV replication also involves reverse transcriptase; using polymerase on the pregenomic RNA template, new rcDNA is synthesized [9,26-29].

Excess synthesized HBsAg and HBeAg enter the blood, and virus assembly culminates in the presentation of HBcAg and HBeAg on the hepatocyte membrane, resulting in their "recognition" by immunocytes. As a result of the interaction between the virus and the host's immune system, various links of this system are activated (T- and B-lymphocytes, macrophages, cytokines, with the leading role belonging to the T-cell response) [20,23,26,30,31]. T-cells exert both a direct cytolytic effect and an indirect antiviral effect through the expression of antiviral cytokines (interferons) and the activation of B-cells producing neutralizing antibodies that prevent the spread of the virus. As a result of this complex process, the virus is eliminated. Hepatocyte turnover resulting from the death of infected cells leads to the lysis of cccDNA [14,20,23,26,30,31].

The humoral response consists of the accumulation of specific antibodies (anti-HBc, anti-HBe, anti-HBs) and their binding to corresponding antigens, as a result of which the free circulation of antigens in the blood ceases. The resulting immune complexes, consisting of antibodies, antigens, and the C3 complement fragment, are phagocytosed by macrophages and eliminated from the body. Their excess may contribute to the development of an autoimmune component of the pathological process. A self-progressing autoimmune process exacerbates autoimmune cytolysis of hepatocytes, promoting the further spread of liver necrosis, the development of fulminant hepatitis, and chronic progression [9,14,23].

The virus itself is not cytopathogenic. Cell damage occurs via an immune-mediated mechanism. The course and outcome of the disease depend on many factors, including the nature and severity of the immune response, age, genetic predisposition, and characteristics of the virus itself. An adequate immune response results in a severe course of the disease, but ultimately leads to complete elimination of the virus. A hyperimmune response can trigger autoimmune processes. A weak immune response causes low disease activity, and the course of hepatitis will be mild or even subclinical. However, with such subclinical and mild forms, the likelihood of developing chronic hepatitis is significantly higher [8,9,14,20,23,31].

Fulminant course is rare among infants and children [32,33]. Cases of fulminant hepatitis are somewhat more frequently recorded in infants born to HBeAg-negative CHB mothers [54]. HBV vaccination does not always protect against the development of fulminant hepatitis B in newborns or immunocompromised individuals

The frequency of chronic hepatitis development is inversely related to age at the time of infection: CHB develops in approximately 80-90% of infants infected perinatally, in 30-60% of children infected under the age of 6 years, and in less than 5% of cases in older age groups [32,34-36]

The immune response is genetically determined and associated with histocompatibility antigens (HLA). Patients with a hyperimmune response most often show antigens B8, A1-B8 in the blood, while those with a delayed or weakened response show B7, B18, B35 [37]. Recent studies point to a novel antiviral gene INTS10 (chromosomal localization 8p21.3), which suppresses HBV replication in hepatocytes via type 3 interferon-dependent regulatory factor and promotes virus elimination from the body [38].

Extrahepatic replication of the virus in blood cells, bone marrow, spleen, and lymph nodes has been proven. This allows HBV to "escape" immune surveillance. Other pathways of viral persistence and chronicity include the ability of the virus to integrate its genetic apparatus into the hepatocyte genome and its high mutability. The elusiveness of the virus is one of the reasons for the chronic course of the infection. Mutant "vaccine-escape" strains of the virus are one of the main causes of HBV incidence among vaccinated children [6,9,23,26,30].

In the case of complete virus elimination and seroconversion following acute hepatitis, persistent immunity is established [2,5,8,9].

1.3 Epidemiology of the Disease or Condition

Hepatitis B is an anthroponotic infection. The reservoir of infection consists of patients with various forms of hepatitis B. In acute hepatitis B, a person is contagious from the middle of the incubation period until complete clearance of the virus from the body. Patients with asymptomatic forms of HBV pose a particular danger. All patients with chronic infection can pose a lifelong risk as a source of transmission [9,16,39,40]. The transmission mechanism is parenteral (blood-borne). Infection can occur through both natural and artificial routes. Natural routes include sexual, household (blood-borne), and perinatal routes. Transmission occurs through contact with blood, blood products, semen, and vaginal secretions of individuals infected with HBV [1,3,5,6,7,9,41,42].

Among children, the perinatal route is the most common—infection of the fetus and newborn during pregnancy and childbirth [1,9,12,33,35,43]. Studies have shown that newborns of HBsAg- and HBeAg-positive mothers have a higher risk of infection (70-100% according to researchers in Asia and 40% according to African researchers) compared to those children whose mothers are positive only for HBsAg (5-30% in Asia and 5% in Africa) [39]. The highest risk of infection occurs in children born to mothers with high viral replication rates and biochemical activity [44]. A number of authors indicate that cesarean section reduces the risk of perinatal HBV transmission from HBsAg-positive mothers [9]. Breast milk is not a risk factor for transmission [31].

In older children and adults, the main routes of infection are medical and non-medical procedures accompanied by damage to the skin and mucous membranes. HBV transmission via transfusion of infected blood and its components, and instrumental examinations in medical facilities is possible, but is recorded extremely rarely today. The leading routes of transmission are non-medical—infection through damaged skin and mucous membranes via intravenous drug use, tattooing, piercing, cosmetic, manicure, pedicure, and other procedures using contaminated instruments [1,12,31,39,41].

The infectivity of HBV is 500-1000 times higher than that of HIV; 0.0000001 ml of blood is sufficient for infection. The virus is capable of surviving outside the human body for a long time while retaining virulence: at room temperature (in blood spots, on a razor blade, needle tip) – up to several weeks, in blood serum at +30°C – 6 months, at -20°C – 15 years, in dry plasma – 25 years.

According to WHO data, the number of people living with HBV globally is about 300 million; in other words, 3.8% of the world's population is infected with HBV. Approximately 1.2 million new cases of infection are registered annually [68].

The incidence rate varies significantly across different regions. For instance, in the African Region (82 million people) and the Western Pacific Region (116 million people), about 6.7% of the population lives with HBV infection. In Southeast Asia, about 60 million people are infected. At the same time, in the European and Region of the Americas, the rates are significantly lower—15 million and 5 million, respectively [43]. The majority of patients in high HBV prevalence countries were infected perinatally, prior to the implementation of hepatitis B vaccination programs [45]. Thus, a significant decrease in the prevalence of HBV infection can be expected in the future. Great success has already been achieved today—according to recent WHO estimates, the proportion of children under five years of age infected with HBV has dropped to 0.9% (2019), whereas prior to the vaccination era (1980s – early 2000s), this figure was 4.7% [41,45]. In the Russian Federation, the incidence of acute hepatitis B in the pediatric population has decreased enormously since the beginning of the century—from 73.4 per 100,000 population in 2000 to 0.05 per 100,000 population in 2024. Across the entire country, only 16 cases of acute hepatitis B in children were registered in 2024, of which 12 were in children under 14 years of age.

1.4 Features of Coding the Disease or Condition

B16 - Acute hepatitis B

1.5 Classification of the disease or condition

Clinical classification of "Acute Hepatitis B" [1-4,6,8,10]:

By clinical form:

Typical (manifest):

a) icteric cytolytic;

b) icteric cytolytic with cholestatic syndrome;

c) icteric cholestatic

Atypical:

anicteric;

subclinical;

inapparent;

By severity:

Mild;

Moderate;

Severe;

Extremely severe (fulminant).

By duration of the course:

Acute cyclic - up to 3 months;

Acute protracted (progredient) - 3-6 months;

Icteric cytolytic form (typical) is characterized by intoxication, dyspeptic disorders, cytolysis, elevated bilirubin due to the direct fraction, and hepatomegaly. Impairment of the protein-synthetic function of the liver is possible with corresponding dysproteinemia and a decrease in the prothrombin index. The severity of symptoms and laboratory abnormalities is variable and correlates with the severity of the disease.

Icteric cytolytic form with cholestatic syndrome. Against the background of pronounced cytolysis (high activity of liver transaminases), dysproteinemia, and a low prothrombin index at the peak of jaundice, signs of cholestasis progress (skin itching, hyperbilirubinemia due to the direct fraction, elevated ALP, GGT, cholesterol). In children, it is recorded less frequently than in adults and mainly during adolescence.

Icteric cholestatic form is characterized by symptoms of cholestasis and normal or minimally changed transaminase levels.

Anicteric form is characterized by symptoms of intoxication and dyspeptic disorders. Skin rashes of various nature and other symptoms typical of the typical form, except for jaundice, may appear. Liver enlargement may be minimal, but both hepatomegaly and hyperfermentemia are mandatory symptoms of this form. The disease generally runs a mild course, but has a protracted, progredient nature.

Asymptomatic forms are diagnosed during immunobiochemical studies in foci and routine examinations of certain categories (donors, medical personnel, public catering workers, military personnel, and others). Patients with a subclinical form exhibit moderate hyperfermentemia. Hepatomegaly is observed. In the inapparent form , clinical and biochemical symptoms are absent. Serological markers of viral replicative activity serve to confirm the diagnosis.

Criteria for assessing disease severity include both clinical manifestations (severity of intoxication, jaundice, hepatomegaly) and laboratory abnormalities (levels of hepatic transaminases, bilirubin, and impaired protein-synthetic function of the liver). Severity criteria are detailed in Appendix A3.

Examples of diagnosis formulation:

Preliminary diagnosis (newly diagnosed disease - case suspected of acute viral hepatitis B / probable case of acute viral hepatitis B): Acute viral hepatitis B, typical moderately severe icteric form?

Clinical diagnosis (confirmed case of acute viral hepatitis B): B16.9 Acute viral hepatitis B without delta-agent, typical moderately severe icteric form (blood ELISA – HBsAg positive, anti-HBc IgM positive; blood PCR – HBV DNA positive).

1.6 Clinical presentation of the disease or condition

The duration of the incubation period can range from 42 to 180 days, in most cases being 60-120 days [1-4,6,8,10].

Clinically manifest forms of acute viral hepatitis B are characterized by a cyclic course with a gradual onset. The following periods of the disease are distinguished: incubation, pre-icteric (prodromal/initial), icteric (peak period of the disease), and convalescence period (phase of jaundice fading) [1-4,6,8,10].

The duration of the incubation period is from 2 to 6 months. In massive infection (usually via blood transfusions), the incubation period may be shortened to 1.5 - 2 months. In cases of infection resulting from household contact, parenteral procedures (injections), or sexual transmission, the duration of the incubation period is 4-6 months [1-4,6,8,10].

The pre-icteric period lasts from 4 to 7-10 days, less frequently up to 14 days. It is characterized by asthenovegetative and dyspeptic syndromes, as well as hepatomegaly. Arthralgia syndrome, frequently recorded in adults during this period of the disease, is rare in children. The disease begins gradually. Body temperature is generally slightly elevated (except for severe fulminant forms). The first signs are weakness, lethargy, rapid fatigue—manifestations of the asthenovegetative syndrome—and symptoms of dyspepsia (decreased appetite up to complete refusal of food, nausea, sometimes vomiting, bitterness in the mouth, abdominal bloating, constipation (less frequently - diarrhea). Dull pain and a feeling of heaviness in the right upper quadrant are also characteristic, starting from the 2nd-3rd day and progressively worsening toward the end of the pre-icteric period. In some children (10%), exanthema (usually urticarial) and signs of vasculitis are observed. Papular acrodermatitis (Gianotti-Crosti syndrome) may occur during the pre-icteric and icteric periods; dark red (copper-colored) papules appear on the forearms and legs (much less frequently on other parts of the body) due to skin damage by immune complexes. The pre-icteric period ends with a change in the color of excrement—stool acholia (light gray stool color)—and darkening of the urine. Jaundice typically appears 1-2 days after this [1-4,6,8,10]. In 5-7% of patients, the pre-icteric period may be absent. In such cases, darkening of the urine and scleral icterus will serve as the first symptoms of the disease [8]. Laboratory examination of urine reveals an increased urobilinogen level and sometimes bile pigments. Biochemical blood analysis shows elevated ALT and AST. Changes in peripheral blood are not characteristic at the initial stage of the disease. A slight leukocytosis, a tendency toward lymphocytosis, and ESR generally within normal limits may be noted. Virological examination reveals specific markers of HBV infection (HBsAg, HBeAg, anti-HBc IgM), and HBV DNA is detected in blood PCR [1-4,6,8,10].

The icteric period lasts from 2 to 6 weeks, most commonly 3–4 weeks. In isolated cases, jaundice persists for less than 7 days, and a longer persistence of up to several months is rarely observed. Unlike hepatitis A, the transition of the disease into the icteric period is usually not accompanied by an improvement in general condition. Symptoms of intoxication remain pronounced and frequently progress: weakness, irritability, headache, superficial sleep, decreased appetite down to anorexia (in severe forms), nausea, and sometimes vomiting. In some patients, particularly adolescents, euphoria occurs, which may be a harbinger of encephalopathy but creates a deceptive impression of improvement. Jaundice in acute viral hepatitis B (AVHB) develops gradually—usually over 5–6 days, sometimes up to 2 weeks or longer. Initially, the sclerae, the mucous membrane of the hard palate, and the lingual frenulum acquire a icteric tint, followed by the skin. The urine becomes dark, and the stool becomes acholic at the peak of jaundice. Jaundice reaches its maximum by the 2nd to 3rd week, stabilization is noted within 5–10 days, subsequently replaced by decline. The intensity of jaundice generally correlates with the severity of the disease. During the icteric period, liver enlargement increases even further [1-4,6,8,10]. In adolescents, particularly girls, skin pruritus is frequently observed, the intensity of which does not correlate with the degree of jaundice, while the jaundice persists for a long time and has a greenish tint, which is a sign of cholestasis. Epistaxis is frequently noted. Ecchymoses appear (coagulopathy). At the same time, hypotension, bradycardia, muffled heart sounds, and a systolic murmur are frequently detected due to the vagotonic effect of bile acids. Patients are bothered by a sensation of heaviness in the epigastric region and the right upper quadrant, especially after eating, due to the stretching of the liver capsule [6]. The patients' tongue is usually coated with a white or brownish deposit. Palpation reveals hepatomegaly and tenderness, more pronounced in the left lobe (in adolescents, the right lobe may predominantly enlarge), with an elastic or dense-elastic consistency and a smooth surface. The spleen is also enlarged, but somewhat less frequently. A reduction in liver size against the background of progressive jaundice and intoxication is an unfavorable sign indicating a developing malignant form. A dense liver consistency, particularly of the right lobe, with a sharp edge persisting after the disappearance of jaundice, may indicate the transition of the disease to a protracted form and requires active clinical follow-up regarding the development of chronic hepatitis, especially in adolescents [6]. Throughout the entire icteric period, a significant increase in hepatic transaminase activity is recorded (30–50 times above the upper limit of normal). In severe disease courses, the protein-synthetic function of the liver is impaired (decreased albumin levels, prothrombin index). In the peripheral blood, a tendency toward leukopenia and lympho-, monocytosis is detected, and the ESR is decreased or normal. The jaundice fading phase is characterized by a gradual improvement in the patient's condition and the restoration of liver function test parameters [1,2]. As a rule, the fading phase is usually longer than the onset phase. It is characterized by a gradual improvement in the patient's condition and the restoration of liver function tests. However, a number of patients develop exacerbations, which generally have a milder course [6].

Convalescence period - clinical recovery and normalization of biochemical parameters usually occur within 6 months after the onset of the disease. The asthenovegetative syndrome and the feeling of discomfort in the right upper quadrant persist the longest. Clinical and biochemical abnormalities resolve slowly: serum bilirubin normalizes within 2-4 weeks; transaminase elevation persists for 1 to 3 months. Patients may exhibit a wave-like pattern of hyperfermentemia during the convalescence period, and relapses (clinical and/or laboratory-biochemical) with characteristic syndromes are possible, which requires differentiation from chronic hepatitis and/or superinfections with other hepatotropic viruses [1,2,6].

In severe forms of the disease (30-40% of cases), the intoxication syndrome is pronounced, presenting as asthenia, headache, anorexia, nausea and vomiting, insomnia, and euphoria; signs of hemorrhagic syndrome frequently occur in combination with bright ("saffron") jaundice. All liver function tests are severely impaired. In an uncomplicated course, severe forms end in recovery after 10-12 weeks or more [6]. Criteria for the severity of acute viral hepatitis B are presented in Appendix A3.

In newborns and young children, acute viral hepatitis B is predominantly asymptomatic, without classic jaundice, but progresses to a chronic process in 70-90% of cases. This is likely due to the imperfection and immaturity of the immune system. In some cases, the sole manifestation of the disease in this age group may be Gianotti-Crosti syndrome. The course of acute viral hepatitis B is adversely affected by the presence of concomitant chronic diseases [1-4,6,8,10,47].

Malignant (fulminant) hepatitis is an independent form of viral hepatitis B characterized by massive or submassive hepatic necrosis, progressive liver failure, and high mortality. Etiopathogenetic factors in the development of malignant viral hepatitis include both viral characteristics (infection with mutant forms – pre-core HBV mutant, high infectious dose of the pathogen) and host characteristics of the child's body (excessive immune response). Fulminant hepatitis is classified into forms occurring with the development of pre-coma, coma, and without them. Depending on the rate, nature of clinical symptoms, and morphological changes, the following are distinguished:

Hyperacute course (development of hepatic coma and fatal outcome in the pre-icteric period within the first 3-4 days from the onset of the disease).

Acute course (hepatic coma at the height of clinical symptoms, on the 5th-8th day of the icteric period).

Subacute course (gradual wave-like progression of clinical symptoms and development of hepatic coma in the 3rd-5th week of the disease).

Malignant forms of acute viral hepatitis B should be distinguished from liver cirrhosis in chronic hepatitis, where hepatic coma develops as an outcome of decompensated liver cirrhosis. Characteristic features are a short pre-icteric period (3-5 days), an acute onset of the disease with body temperature rising to 38-40°C, lethargy, adynamia, somnolence with bouts of anxiety and motor agitation, and marked dyspeptic disorders (nausea, vomiting, regurgitation, abdominal bloating, loose and/or frequent stools). With the appearance of jaundice, the patients' condition sharply deteriorates, intoxication symptoms rapidly increase, vomiting becomes more frequent with an admixture of blood, hemorrhagic syndrome progresses, liver size decreases, and symptoms of cardiovascular failure develop.

Clinical symptoms of the malignant form can be divided into the following groups:

Neuropsychiatric disorders. In young children, psychomotor agitation, causeless crying, screaming, hand tremor, chin trembling, and tonic-clonic convulsions occur. Bouts last for hours and usually occur at night. Older children exhibit emotional lability, irritability, disorientation in time and space, bouts of melancholy, memory lapses, handwriting disturbances; development of acute psychosis, delirium, delusions, hallucinations, agitation states; tonic-clonic convulsions, impaired consciousness, appearance of pathological reflexes; sleep inversion—somnolence by day and insomnia at night—is characteristic of children of all ages.

Vomiting: nausea, repeated vomiting in the pre-icteric and icteric periods are noted; in young children – frequent regurgitation, blood admixture in vomitus, "coffee-ground" vomiting.

Hemorrhagic syndrome: epistaxis, gastrointestinal bleeding, melena, hemorrhagic rash (skin, mucous membranes). Causes: impaired synthesis of clotting factors, fibrinogenopathy, decreased vitamin K-dependent enzymes.

Jaundice. Rapidly intensifies and reaches maximum severity during the comatose period. In young children, jaundice is less pronounced due to good tissue hydrophilicity.

Hepatic fetor: resembles the smell of raw liver, develops due to impaired methionine metabolism and accumulation of methylmercaptan in the blood.

Fever: can reach 40°C and higher; in the terminal period, it does not respond to antipyretic drugs; in some patients, the disease proceeds with normal temperature, and an increase in temperature indicates secondary intercurrent infections.

Decrease in liver size. One of the most characteristic, but not early (!) signs of the disease. In the early stages of malignant hepatitis, the liver size is generally increased, but its consistency becomes less dense and doughy. Subsequently, a rapid reduction in liver size is observed, reflecting the dynamics of massive necrosis development.

Pain syndrome is an early sign of the developing malignant form. It is associated with necrosis and autolytic breakdown of the parenchyma, and to a lesser extent, with lesions of the biliary tract and liver capsule. It manifests as dull, aching pain in the right upper quadrant, sometimes resembling the sharp pain of cholelithiasis. In young children, it manifests as acute anxiety and crying; attempts to palpate the liver provoke motor agitation and intensified crying.

Cardiovascular system: tachycardia, decreased blood pressure (may be of a collapse type), sometimes extrasystoles, premature appearance of the 2nd heart sound, decreased venous return.

Respiratory system: dyspnea (toxic noisy breathing), pulmonary edema.

Kidney involvement: decreased daily urine output (blood shunting past glomerular capillaries, tubular necrosis).

Simultaneously with and following these symptoms, clouding of consciousness occurs with the development of hepatic coma, accompanied by impaired reflex activity and disorders of vital functions (circulation, respiration, metabolic processes). In the initial stage (precoma), bouts of psychomotor agitation are replaced by periods of adynamia and drowsiness; children cannot fix their gaze on toys, periodically fail to recognize their mother, but respond to painful stimuli with crying. The pupillary light reflex is preserved. Abdominal reflexes are usually absent. Precomatose symptoms are accompanied by repeated coffee-ground vomiting, fever, hemorrhagic rashes on the skin and mucous membranes, tachycardia, dyspnea, and the appearance of peripheral edema. Liver size decreases, the liver edge has a somewhat dense consistency and protrudes 1–2 cm below the costal margin. The duration of precoma in patients with an acute course of hepatodystrophy is 1–1.5 days, and in a subacute course, an average of 8 days. Hepatic coma develops following the precoma. The duration of coma in the acute course averages 17 hours, and in subacute hepatodystrophy, 24 hours. For the timely diagnosis of hepatic coma occurring in patients with malignant forms of viral hepatitis, along with symptoms of central nervous system damage, such symptoms as the intensity of jaundice, severity of the hemorrhagic syndrome, fever unrelated to secondary infections, increased abdominal size, "hepatic" fetor, pulse lability, tachycardia, toxic dyspnea, decreased liver size, its softening, and tenderness upon palpation are of critical importance.

Laboratory findings in the malignant form of hepatitis:

• increase in indirect bilirubin;

• AST:ALT ratio > 1;

• bilirubin-enzyme dissociation;

• bilirubin-protein dissociation;

• decreased prothrombin and fibrinogen levels;

• decreased HBsAg concentration, early appearance of anti-HBs;

• anemia.

Outcomes of acute hepatitis B:

• recovery with complete restoration of liver function;

• recovery with residual effects in the form of fibrosis;

• recovery with residual effects in the form of biliary system damage;

• development of chronic hepatitis;

• fatal outcome.

Fatal outcomes with a high frequency (up to 50% and higher) are observed in the malignant form. Long-term follow-up observations have shown that manifest (icteric) forms of acute hepatitis B in children generally do not result in the development of chronic hepatitis. All cases of so-called "chronization of acute hepatitis B" require the exclusion of superinfection, primarily hepatitis A and hepatitis B in a patient with chronic hepatitis B, as well as other pathologies. Atypical forms of hepatitis B are difficult to distinguish from a primarily chronic course of hepatitis B and require special attention from the physician [6].

Complications may include acute liver failure (ALF in 0.8–1% of cases), massive hemorrhagic syndrome, exacerbations and relapses of the disease (in 1–1.5% of cases), biliary tract damage, and possible secondary bacterial infection (pneumonia, cholangitis, cholecystitis, etc.) [1-4,6,8,10].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

The definitive diagnosis of acute hepatitis B is established based on the detection of HBV DNA in the patient's blood, regardless of the presence or absence of a characteristic symptom complex and/or abnormalities in laboratory test results, since, in addition to clinically manifest forms, a latent course of the disease is also possible. The criterion for differential diagnosis between acute and chronic hepatitis is the duration of the disease course. If the disease duration is less than 6 months, the diagnosis is formulated as acute hepatitis B.

2.1 Complaints and Anamnesis

Comment: when taking complaints and medical history, the patient should be thoroughly questioned about the nature of the onset of the disease, the presence or absence of complaints of fever, weakness, decreased appetite, drowsiness, muscle and joint pain, the appearance of a rash, etc., in order to identify the primary symptoms of the prodromal period. The timing of the appearance of yellowish skin, sclera, and changes in the color of urine and stool (if any) is purposefully clarified.

• During the interview with all patients suspected of having hepatitis B, it is recommended to ascertain epidemiological history data in order to identify children at high risk for HBV infection [1-6,8,10,48].

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

Comment: during the interview, attention should be paid to gathering epidemiological history data. The fact of epidemiological contact (perinatal, sexual, household) with a person infected with HBV, as well as a parenteral history (surgeries, blood transfusions, injections), are cornerstone signs in the diagnosis of HBV. For the epidemiological history of acute hepatitis B, information is needed regarding transfusions, surgical interventions, injections, instrumental examinations, dental treatments, and other medical manipulations 6 months prior to the disease, as well as data on sexual and household contacts with patients having acute and chronic forms of hepatitis B, HBsAg carriers, unprotected sexual contacts, and injection drug use. For infants, information regarding the presence of infection in the mother is of paramount importance. To identify the risk group during the interview, vaccination status data should be ascertained: information on the presence/absence of vaccination against HBV. In the case of diagnosing the disease in infants during their first year of life due to perinatal contact with hepatitis B, the fact of vaccination should not be foundational, as infection could have occurred in the prenatal period (prior to vaccination).

2.2 Physical Examination

Comment: in addition to checking for jaundice, which is typical for the acute course of the disease, the presence of a rash must be ruled out. Petechial rash can be a symptom of a severe course of acute hepatitis B. Furthermore, it must be remembered that in infants and young children, the only manifestation of the disease may be Gianotti-Crosti syndrome, presenting as an acute, symmetrical rash with flat, flesh-colored or pinkish-brown papules or vesicles ranging from 1 to 10 mm in diameter, which can coalesce into plaques [69,70]. The rash may also be maculopapular [71]. Atypical forms may be vesiculobullous [72]. The predominant affected areas are the face, buttocks, extensor surfaces of the forearms and legs, and the feet. Trauma to the skin may result in a hemorrhagic rash [69,70,72-75].

Comments: hepatomegaly may be mild or the sole clinical sign in the anicteric form of acute viral hepatitis B (AVHB). In the typical icteric form, the enlargement and density of the liver peak during the icteric period. The younger the child, the more frequently splenomegaly is registered. The severity of hepatomegaly and splenomegaly correlates with the severity of the disease. A decrease in liver size (compared to normal) can be a prognostically dangerous sign indicating a malignant course of the process.

Comments: in children, urine darkening and "spotted" followed by acholic (light gray) stools appear 2-3 days before the onset of jaundice. In mild cases, the disease may begin directly with dark urine and jaundice. The appearance of "mottled" stools after discolored ones indicates the restoration of bile excretion and corresponds to the crisis of the disease, after which a regression of all symptoms is observed.

Comments: the cardiovascular, nervous, urinary, and other systems are often involved in the process, but these changes are never leading.

Comments: criteria for assessing the degree of impaired consciousness and coma using the Glasgow Coma Scale are presented in Appendix G1.

2.3 Laboratory Diagnostics

Laboratory research methods, including biochemical and hematological parameters, make it possible to diagnose the acute phase of the disease and its severity; the etiological verification of hepatitis is carried out exclusively using serological and molecular genetic methods.

At the diagnosis stage

Comments: the detection of elevated serum ALT and AST levels indicates hepatocyte cytolysis and highly likely confirms the diagnosis of acute hepatitis. The acute phase of the disease is characterized by the predominance of ALT over AST.

Comments: signs of pigment metabolism disorders and intrahepatic cholestasis are an increase in serum total bilirubin levels with the predominance of the direct fraction, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and cholesterol.

Comment: only the detection of specific HBV markers serves as absolute etiological confirmation of the diagnosis of hepatitis B. The most reliable specific marker of AVHB is anti-HBc IgM, which appears at the end of the incubation period and persists throughout the period of clinical manifestations. 4–6 months after the onset of the disease, anti-HBc IgM disappear and anti-HBc IgG appear (they persist for life). In HBV carriers, anti-HBc IgM are absent in the blood.

During the incubation period of HBV, simultaneously with HBsAg, HBe antigen circulates in the blood serum as a marker of active viral replication; it is detected even before the cytolysis syndrome. HBeAg disappears from the blood as early as the icteric period, and anti-HBe appear. The presence of HBeAg always reflects the ongoing replicative phase of acute HBV infection; if it is detected for more than 2-3 months, this indicates the possibility of chronic progression. The indication of HBeAg and anti-HBe is not only of diagnostic but also of epidemiological and prognostic significance. Anti-HBs begin to circulate in the blood during the convalescence period after the cessation of HBs-antigenemia and indicate the clearance of the virus from the body. They are also detected after HBV vaccination. To exclude co-infection with viral hepatitis D, an examination for viral hepatitis D must be performed. It should be taken into account that in some cases HBsAg may be absent, and when infected with a mutant strain, HBeAg is not detected, so it is advisable to determine several markers at once. Criteria for laboratory confirmation of the diagnosis and assessment of the disease stage based on the results of serological diagnostics are presented in Appendix A3.

Comment: HBV DNA is an indicator of viral replication and can be detected in the incubation and icteric periods, as well as at later stages (during exacerbation, progressive, protracted, and chronic courses) of the disease; HBV DNA begins to be detected in the blood on average one month after infection and is the first diagnostic marker of HBV, preceding the appearance of HBsAg by 10-20 days. Testing for HBV DNA allows for early diagnosis of AVHB, detection of occult (latent) forms of HBV and HBeAg-mutant strains of the virus. In protracted hepatitis, it is advisable to determine hepatitis B virus (HBV) DNA in the blood by PCR, quantitative assay, to assess the dynamics of viral activity and predict the outcome of the disease.

Comments: in mild and moderate AVHB, peripheral blood reveals leukopenia or a tendency toward it, lymphocytosis, whereas in severe cases, leukopenia is replaced by leukocytosis with a left shift, slowed ESR, thrombocytopenia, and possible development of anemia.

Comments: an increase in urine levels of urobilin and bile pigments is characteristic of the onset of the icteric period of hepatitis and indicates the first signs of pigment metabolism disorders and intrahepatic cholestasis.

Comments: signs of pigment metabolism disorders and intrahepatic cholestasis are rising levels of total bilirubin with a predominance of the direct fraction in the blood serum, ALP, GGT, and cholesterol.

Comments: protein profile and coagulogram data are essential for assessing the severity of the disease. A decrease in total protein, albumin, fibrinogen, and prothrombin index (PTI) indicates impaired protein-synthetic liver function (signs of hepatocellular insufficiency) and the potential development of disseminated intravascular coagulation (DIC), which is accompanied by phase changes in the blood coagulation system.

Comments: performed in patients with severe and fulminant forms of hepatitis.

At the stage of pathogenetic and symptomatic therapy

Comments: allows for assessing the severity of the inflammatory process (based on leukocyte count, differential, and ESR) and evaluating bleeding risk (based on platelet count). Performed every 7–14 days. If clinically indicated, the frequency is at the discretion of the attending physician.

Comments: performed every 7–14 days. If clinically indicated, the frequency of comprehensive biochemical blood tests is at the discretion of the attending physician.

Comments: performed every 7–14 days. If clinically indicated, the frequency is at the discretion of the attending physician.

2.4 Instrumental Diagnostics

Comment: hepatomegaly without changes in liver structure is characteristic; splenomegaly is possible. If prominent changes are found on the initial examination, repeat imaging may be performed based on clinical indications to assess disease dynamics [1-6,47].

Comments: patients in the acute phase of hepatitis B typically exhibit a tendency toward bradycardia, whereas worsening condition, increasing intoxication, and the risk of pre-coma are characterized by changes in heart rhythm, tachycardia, and muffled heart sounds on auscultation.

2.5 Other Procedures

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

The principles of treatment for patients with acute viral hepatitis B involve simultaneously addressing several objectives [1-6,8,10,47,48]:

• relieving acute symptoms of the disease and preventing the development of complications;

• preventing relapses and the development of chronic hepatitis.

The choice of treatment tactics is influenced by the following factors [1-6,8,10,47,48]:

• variant of the initial period of the disease;

• severity of the disease;

• clinical form of the disease;

• patient's age;

• presence and nature of complications;

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

The volume of drug therapy correlates with the severity of the disease: in mild cases, it is limited to baseline therapy with a sufficient level of patient hydration and nutritional support. As the severity increases, the spectrum of prescribed drugs expands. Unjustified prescription of medications should be avoided due to potential risks of drug-induced liver injury.

3.1 Conservative Treatment

3.1.1 Basic therapy

Comments: bed rest is indicated during the peak of the disease, and strict bed rest for patients with severe, malignant disease courses. During the resolution of jaundice and convalescence, patients transition to a ward-based regimen [50].

3.1.2 Etiotropic therapy

Most patients do not require etiotropic therapy. It is advisable only on vital indications for life-threatening conditions in fulminant acute viral hepatitis B or acute liver failure. There are no studies on antiviral therapy for acute viral hepatitis B in children. In the absence of alternatives, recommendations for treating adult patients with acute viral hepatitis B can be extrapolated [75,76,84]. For etiotropic therapy of acute viral hepatitis B, antiviral drugs used in the treatment of chronic hepatitis B may be used at the same doses. Therapy is carried out until HBsAg disappears and an undetectable HBV DNA level is achieved (qualitative PCR assay for hepatitis B virus DNA in blood), confirmed twice with an interval of 4 weeks [75,76].

3.1.3 Pathogenetic therapy

Comments: mild course — oral detoxification. Moderate severity — infusion therapy using intravenous solutions: electrolyte solutions, electrolytes combined with carbohydrates, carbohydrates (taking into account the children's age, indications, and contraindications). Parenteral fluid administration is calculated based on physiological requirements, ongoing pathological losses, and existing fluid deficits.

Comments: drugs are prescribed taking into account age restrictions in accordance with the drug labeling instructions. Children over 12 years old can start therapy with intravenous forms followed by transition to oral forms. For children aged 3 to 12 years, phospholipids are prescribed only in parenteral form (in accordance with instructions) [49,50,52,85,87].

Comments: administration of glucocorticoids is advisable for patients with any manifestations of the fulminant form of acute viral hepatitis B (precoma, coma, signs of massive hepatic necrosis), with severe forms of hepatitis showing signs of acute liver failure, as well as severe forms without signs of hepatic precoma or coma, but with pronounced manifestations of intoxication and their progression despite ongoing active infusion therapy, with the aim of suppressing immunopathological and inflammatory reactions and preventing brain edema and swelling. Prednisolone** is the drug of choice [6,47,50,51].

Comments: when treating patients with acute viral hepatitis B, it is necessary to monitor regular bowel evacuation in accordance with physiological norms. Laxatives (lactulose**) are used for this purpose.

Comments: therapeutic paracentesis is indicated in cases of tense ascites development.

3.2 Surgical Treatment

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specialized rehabilitation measures have not been developed for patients with acute viral hepatitis B.

Admission of patients with acute viral hepatitis B to health resorts is permitted after clinical recovery [86].

5. Prevention and Dispensary Observation

5.1 Prevention

Prevention of acute viral hepatitis B is carried out in accordance with the Sanitary Rules and Norms SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" (approved by the Decree of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021).

Comments: following clinical recovery, the child is admitted to the educational institution without anti-epidemic restrictions. Quarantine and isolation measures for contacts in the focus are not organized.

Comments: medical examination and monitoring of blood parameters (determination of alanine aminotransferase (ALT) activity, qualitative determination of hepatitis B virus surface antigen (HBsAg), and antibodies to hepatitis B virus surface antigen (anti-HBs) in the blood) are performed once every 2 months. Individuals in whom anti-HBs are detected in a protective titer at the initial examination are not subject to further follow-up (past acute viral hepatitis B infection or vaccinated against hepatitis B).

Specific prevention

Passive and active immunization of the population is the leading measure in hepatitis prevention.

Comments: active immunization of the population against hepatitis B is carried out in accordance with the National Immunization Schedule, the Immunization Schedule for Epidemic Indications, and the instructions for use of medical immunobiological preparations. Both monopreparations for hepatitis B prevention (vaccine for the prevention of viral hepatitis B**) and combinations of antiviral and antibacterial vaccines of domestic and foreign production are registered in the Russian Federation. All vaccines registered in the Russian Federation are interchangeable and can be administered simultaneously with vaccines against other infections. Initiation of vaccination is indicated in the first 12 hours of life. The main immunization schedule is the intramuscular administration of three doses of vaccines at intervals of 0-1-6 months (dose 1 at the start of vaccination [first day of a child's life], dose 2 one month after the first vaccination, dose 3 six months from the start of vaccination). For unvaccinated patients scheduled for surgical interventions, an emergency 0-7-21 day vaccination schedule is indicated, with a booster dose administered 12 months after the start of vaccination. Post-vaccination immunity persists for about 20 years.

For children at risk (born to HBsAg-carrier mothers, mothers with viral hepatitis B or who had viral hepatitis B in the third trimester of pregnancy, those with unknown hepatitis B marker test results, drug or psychoactive substance users, from families with an HBsAg carrier or a patient with acute viral hepatitis B and chronic viral hepatitis), vaccination against viral hepatitis B is performed according to the 0-1-2-12 month schedule (dose 1 at the start of vaccination, dose 2 one month after the first vaccination, dose 2 [sic] two months from the start of vaccination, dose 3 twelve months from the start of vaccination).

Passive immunization using human hepatitis B immunoglobulin is performed in newborns born to HBV-infected mothers. The first 24 hours of life are considered the most desirable time for prophylaxis. Administration of human hepatitis B immunoglobulin is carried out simultaneously with the administration of the vaccine at different injection sites. For the passive immunization of infants born to hepatitis B virus carrier mothers, a single dose of 2 ml (100 IU) of any specific immunoglobulin preparation must be administered.

Comments: emergency prevention of hepatitis B is carried out in the event of injury with medical instruments (as well as instruments used for manicure, piercing, tattooing) used while working with individuals infected with hepatitis B, or after contact of mucous membranes with infected biological fluids: blood, serum, plasma, urine, saliva; unprotected sexual intercourse with an HBV-infected person; intravenous drug use. In individuals not previously vaccinated against hepatitis B, individuals whose vaccination is incomplete, or in cases where the level of HBs antibodies is below the protective level (<10 IU/L), specific immunoglobulin is administered after accidental exposure to infectious material. The most desirable time for prophylaxis is the first 24-48 hours (up to 15 days, although the efficacy of prophylaxis drops sharply during this period) combined with simultaneous administration of the vaccine. Children under 10 years of age exposed to the risk of infection are given 100 IU of the drug. For children over 10 years of age and adults, the drug is administered at a dosage of 6-8 IU per kg of body weight. Vaccination against hepatitis B according to the 0-1-2-12 month schedule should be initiated on the same day, or the previously started course should be continued. Emergency prophylaxis is also indicated for individuals at high risk of hepatitis B virus infection (patients in chronic hemodialysis centers, patients suffering from various diseases who receive frequent blood and blood product transfusions for life-saving reasons, patients prior to organ and tissue transplantation, contacts in hepatitis B focus foci) who have not been vaccinated against hepatitis B; immunoglobulins are administered before the start of the procedure (hemodialysis, blood transfusion, and blood products).

Non-specific prophylaxis

5.2. Dispensary follow-up

Comments: in the absence of patient complaints, dispensary examinations by an infectious disease specialist—or, in their absence, a district pediatrician or general practitioner (family physician)—are indicated at 1, 3, and 6 months after discharge from the hospital/clinical recovery. Dispensary observation of patients who have recovered from acute viral hepatitis B (at their place of residence or treatment) must be established no later than one month after discharge from the hospital. If the patient was discharged with significantly elevated aminotransferase activity, an examination is performed 7–14 days after discharge. Clinical examination, biochemical tests (determination of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase activity in blood, total bilirubin, free and conjugated bilirubin levels in blood), immunological tests (qualitative determination of hepatitis B virus surface antigen [HBsAg] in blood, determination of hepatitis B virus e-antigen [HBeAg] in blood, determination of antibodies to hepatitis B virus surface antigen [anti-HBs] in blood, determination of antibodies to e-antigen [anti-HBe] in hepatitis B virus in blood), and virological tests (qualitative determination of hepatitis B virus DNA in blood by PCR) are performed at 1, 3, 6, and 12 months after hospital discharge. In cases of a non-smooth, protracted course of the disease and persistence of HBV DNA and HBeAg in the patient's blood upon discharge, these markers are monitored (qualitative determination of hepatitis B virus DNA in blood by PCR, determination of hepatitis B virus e-antigen [HBeAg] in blood) on an outpatient basis (at least once every 6 months) until their elimination or the establishment of a diagnosis of chronic hepatitis B. In cases of an acyclic and protracted course, the duration of dispensary observation is determined individually.

Preventive vaccination is permitted no earlier than 1 month from the moment of recovery; clearance for sports and physical education is granted after 3–6 months. The exemption period from heavy physical labor and sports activities should be 6–12 months.

Appendix A3 presents the frequency, duration, and scope of examinations during the dispensary follow-up of patients after acute viral hepatitis B.

6. Organization of Medical Care

Indications for hospital admission:

1) Suspected/confirmed acute hepatitis B.

Treatment of acute hepatitis B must be carried out for all pediatric patients in a hospital setting due to the possibility of severe forms and complications, the high rate of chronicity in childhood, and the complexity of conducting investigations on an outpatient basis [1-6,8,10,47,48]. Hospitalization is carried out in infectious disease hospitals or departments; treatment and monitoring are performed by an infectious disease specialist (or, in their absence, a pediatrician or general practitioner) [1-6,8,10,47,48].

Indications for discharge from the hospital:

1) Reduction of intoxication symptoms.

2) Reduction of jaundice.

3) Reduction in the severity of hepatomegaly.

4) Bilirubin level <40 µmol/L.

5) ALT and AST level <150 IU/L.

6) Prothrombin index (PTI) > 70%.

In mild cases of the disease, these criteria are achieved on average by days 10–15; in moderate cases, by days 15–20; and in severe cases, by days 25–30. The timeframe for complete recovery and clearance for childcare facilities and school is determined by the physician on an individual basis, taking into account the dynamics of clinical and laboratory parameters, the presence/absence of complications, and comorbid somatic diseases [1,2,5,6,48].

7. Additional Information

The outcome of the disease is favorable; in most cases, it has a smooth, cyclic course and ends in recovery. However, in some cases, chronic hepatitis may develop. Discharge from the hospital is generally carried out 25–30 days after the onset of the disease. At the same time, moderate hyperfermentemia, hepatomegaly, and persistence of HBsAg in the blood are acceptable [1,2,5,6,48].

Criteria for recovery are [1,2,5,6,48]:

- absence of intoxication;

- normalization of liver aminotransferases (ALT, AST) and bilirubin levels;

- normalization or reduction of liver and spleen size;

- absence of HBV DNA and antigens in the blood;

- appearance of anti-HBs antibodies in the blood.

Possible outcomes of acute hepatitis B and their characteristics are presented in Appendix A3.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Greshnyakova Vera Aleksandrovna, Candidate of Medical Sciences, Head of the Research Department of Viral Hepatitis and Liver Diseases at the National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the FMBA of Russia. Member of the Euro-Asian Society of Infectious Diseases (EASID), member of the Union of Pediatricians of Russia, member of the Russian Society for the Study of the Liver.

2. Lobzin Yuriy Vladimirovich, Academician of the RAS, Doctor of Medical Sciences, Professor, Honorary President of the National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the FMBA of Russia. Chairman of the Euro-Asian Society of Infectious Diseases (EASID).

3. Zhdanov Konstantin Valerievich, Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Director of the Scientific and Clinical Center for Infectious Diseases of the National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the FMBA of Russia.

4. Goryacheva Larisa Georgievna, Doctor of Medical Sciences, Leading Researcher at the Research Department of Viral Hepatitis and Liver Diseases of the National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the FMBA of Russia. Member of the Euro-Asian Society of Infectious Diseases (EASID).

5. Rychkova Svetlana Vladislavovna, Doctor of Medical Sciences, Associate Professor, Head of the Department of Organization of Medical Care for Children, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the FMBA of Russia. Member of the Euro-Asian Society of Infectious Diseases (EASID).

Conflict of interest:

The developers of the clinical guidelines reported no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Infectious disease specialist;

2. Pediatrician;

3. General practitioner;

4. Gastroenterologist;

5. Medical students, residents, postgraduate students.

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

Table 2. Scale for assessing the levels of reliability of evidence (LRE) for methods of prevention, treatment, medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

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

1. Federal Law No. 157-FZ dated September 17, 1998 (as amended on December 25, 2023) "On Immunoprophylaxis of Infectious Diseases".

2. Federal Law No. 326-FZ dated November 29, 2010 (as amended on October 29, 2024) "On Compulsory Medical Insurance in the Russian Federation".

3. Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 28, 2024) "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 dated August 9, 2005 "On the Procedure for the Use of Medicinal Products in Patients for Vital Indications".

5. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017 (as amended on September 24, 2020, with rev. dated October 26, 2022) "On Approval of the Nomenclature of Medical Services".

6. Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021 "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations for Epidemic Indications, and the Procedure for Conducting Preventive Vaccinations" (with rev. and add. dated December 12, 2023).

7. Order of the Ministry of Health of Russia No. 700n dated October 7, 2015 (as amended on December 9, 2019) "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education" (Registered with the Ministry of Justice of Russia on November 12, 2015, No. 39696).

8. 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" (Registered with the Ministry of Justice of Russia on May 17, 2017, No. 46740).

9. 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 '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).

10. Order of the Ministry of Health and Social Development of Russia No. 521n dated May 5, 2012 (as amended on February 21, 2020) "On 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).

11. Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020 "On Approval of the Procedure for Providing Patients with Therapeutic Nutrition" (Registered with the Ministry of Justice of the Russian Federation on September 30, 2020, No. 60137).

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 Prophylactic Institutions of the Russian Federation" Registered with the Ministry of Justice of the Russian Federation on September 12, 2003, registration No. 5073 (with amendments dated February 19, 2024).

Laboratory signs of acute viral hepatitis B [1-6,8,10,48].

Severity criteria for viral hepatitis [1-6,8,10,48].

Differential diagnosis of viral hepatitis A, B, and C [1-6,8,10,48].

Possible outcomes of acute hepatitis B and their characteristics [1-6,8,10,48].

Frequency, duration, and scope of examinations and therapeutic/preventive measures during clinical follow-up (dispensary observation) of patients recovering from acute viral hepatitis B [1,2,5,6,48].

List and frequency of laboratory, radiological, and other special diagnostic methods:

• Biochemical blood analysis (determination of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase activity in the blood, measurement of total bilirubin, free and conjugated bilirubin levels in the blood) 10 days after discharge from the hospital, then:

  • in smooth course - at 1, 3, 6 months.

  • if clinical and laboratory signs persist, follow-up for up to 12 months.

• Qualitative detection of Hepatitis B virus surface antigen (HBsAg) in blood, and qualitative detection of antibodies to Hepatitis B virus surface antigen (anti-HBs) in blood at 1, 3, and 6 months.

• If HBsAg persists, tests are performed to detect Hepatitis B virus e-antigen (HBeAg) in blood, antibodies to e-antigen (anti-HBe) in blood, and Hepatitis B virus DNA in blood by PCR (qualitative assay).

Therapeutic and preventive measures:

• Medical exemption from vaccination in cases of:

  • mild and moderate severity — 1–3 months.

  • severe condition — 6 months.

• Medical exemption from sports activities — 3–6 months.

• Restriction of insolation for up to 12 months.

Clinical criteria for the effectiveness of clinical examination (dispensary monitoring)

• Absence of disease relapse.

• Absence of a progressive and chronic course of the disease.

Procedure for admitting convalescents to work, educational institutions, boarding schools, health camps, and other closed facilities

• Clinical recovery and complete normalization of biochemical parameters.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Acute hepatitis B (AHB) is an infectious disease caused by the hepatitis B virus (HBV). The virus is stable in the environment and persists at room temperature for 3 months, upon freezing for up to 20 years, upon heating to 60°C for 4 hours, and is resistant to ultraviolet radiation, ether, and low concentrations of chlorine-containing agents.

According to WHO, about 2 billion people worldwide are infected with HBV, more than 400 million have a chronic course of infection, and over 600,000 people die annually from complications of AHB. Clinical manifestations of AHB vary from mild and asymptomatic forms to severe cases, often resulting in the development of chronic hepatitis B, liver cirrhosis, and fatal hepatocellular carcinoma.

The source of infection is a sick person or a carrier of this virus. Most infected individuals, who serve as a permanent reservoir of the virus, do not suspect that they are ill and therefore do not take any precautions.

The route of transmission is parenteral (when virus-infected blood enters the bloodstream of a patient). This can occur in medical facilities during blood or plasma transfusion, or through the use of infected (poorly processed) medical instruments during examinations, dental treatments, and other medical procedures. Currently, the most common non-medical parenteral route is intravenous drug use. However, other household transmission routes are also possible, such as blood contact (via toothbrushes, hairbrushes, razors, and other hairdressing and cosmetic tools, piercing, and tattooing), as well as sexual and perinatal transmission from an infected mother to her child (during childbirth, less commonly during newborn care, and extremely rarely intrauterine).

The incubation period for HBV ranges from several weeks to 6 months. The most prominent symptom of the disease is jaundice — yellow pigmentation of the skin, sclera, and oral mucosa. However, this symptom does not always occur, so attention should be paid to other most common signs of hepatitis: malaise, weakness, decreased appetite, discomfort, nausea, abdominal pain, and sometimes pain in the right upper quadrant. The onset of the disease may be accompanied by fever and various types of rashes. Upon examination, the doctor may reveal enlargement of the liver and spleen. Confirmation of the diagnosis is only possible through laboratory tests. A child with suspected or newly diagnosed AHB in an outpatient setting requires hospitalization. Discharge from the hospital is usually carried out 15–25 days after the onset of the disease. Attendance at preschools and schools is permitted upon complete normalization of biochemical parameters.

The outcome of the disease is favorable; in most cases, it ends in recovery. However, the development of chronic hepatitis is possible, especially in young children with anicteric forms of the disease. Therefore, patients who have suffered from HBV must follow a regimen, diet (Diet No. 5), and dispensary follow-up for 6 months with clinical and laboratory blood tests at 1, 3, and 6 months.

Quarantine and isolation measures for contacts in the focus are not organized, but terminal disinfection is carried out after the patient's hospitalization, along with examination of contacts including ALT, HBsAg, and anti-HBs testing, followed by medical supervision for 6 months. Physician examination and monitoring of ALT, HBsAg, and anti-HBs every 2 months. Individuals in whom protective titers of anti-HBs are detected during the initial examination are not subject to further follow-up (past HBV infection or vaccinated against HBV). Other contacts who have not been previously vaccinated or whose vaccination status is unknown receive specific prophylaxis — HBV vaccination according to the 0–1–2–12 month schedule.

A similar 0–1–2–12 month schedule is used for emergency prophylaxis in cases of occupational exposure risk (skin injury with infected medical instruments).

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

Appendix G1. Glasgow Coma Scale

Glasgow Coma Scale Glasgow Coma Scale (Teasdale G.M., Jennett B., 1974) [66]

Russian title: Glasgow Coma Scale

Original title: Glasgow Coma Scale

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

Type: rating scale

Purpose: A criterion for assessing the level of consciousness, correlating with the severity of cerebral injury and prognosis.

Content: The scale consists of three tests evaluating 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. The level of consciousness is expressed as the sum of points for each parameter

The initial Glasgow score correlates with the severity of cerebral injury and prognosis. Thus, the Glasgow 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.

Key (Interpretation): The lowest score is 3 points, and the highest score is 15 points. A score of 8 points or lower is defined as coma.

Notes: A score of 3–5 points is prognostically extremely unfavorable, especially when combined with wide pupils and the absence of the oculocephalic/oculovestibular reflex.