Tuberculosis in Children: Clinical Guidelines

List of Abbreviations

ALT alanine aminotransferase

AST aspartate aminotransferase

ATR** recombinant tuberculosis allergen in standard dilution**

HIV human immunodeficiency virus

VC medical commission

EPT extrapulmonary tuberculosis

IRIS immune reconstitution inflammatory syndrome

DNA deoxyribonucleic acid

AI artificial pneumothorax

IPMR individual medical rehabilitation plan

CBB valvular bronchoblockade

AFB acid-fast bacilli

FDC fixed-dose combination drugs

DR drug resistance

DS drug susceptibility

LRC treatment and rehabilitation center

MB tuberculosis mycobacteria

MTBC Mycobacterium tuberculosis complex

MGM molecular genetic methods

MDR multidrug resistance

MDR TB tuberculosis caused by an MDR strain

MDT multidisciplinary rehabilitation team

RR TB tuberculosis caused by a rifampicin-resistant strain**

NSAID non-steroidal anti-inflammatory and antirheumatic drugs

NTM nontuberculous mycobacteria

pre-XDR pre-extensively drug-resistant

ATT antituberculosis drug

PTC primary tuberculosis complex

PCR polymerase chain reaction

SCT spiral computed tomography of the lungs

TB tuberculosis

TBLN tuberculosis of intrathoracic lymph nodes

PLNT tuberculosis of peripheral lymph nodes

TSH thyroid-stimulating hormone

UGT urogenital tuberculosis

CNS central nervous system

FRTB Federal Register of Persons with Tuberculosis

XDR extensively drug-resistant

XDR TB tuberculosis caused by an XDR strain

EGD esophagogastroduodenoscopy

EBV endobronchial valve

IGRA Interferon-Gamma Release Assays

H isoniazid**

R rifampicin**

P #rifapentine

Z #pyrazinamide**

E #ethambutol**

S streptomycin**

Km kanamycin**

Am #amikacin**

Cm #capreomycin*

Lfx #levofloxacin**

Mfx #moxifloxacin**

Pto #prothionamide**

Eto #ethionamide**

Bq #bedaquiline**

Lzd #linezolid**

Dlm #delamanid**

Imp #imipenem+[cilastatin]**

Mp #meropenem**

Cs cycloserine**

Trd #terizidone**

Cfz #clofazimine

PAS aminosalicylic acid**

Pa #pretomanid.

Terms and Definitions

Drug-resistant TB patient (DR-TB patient) – a patient whose disease is caused by M. tuberculosis complex with rifampicin resistance** or multidrug resistance, confirmed by any bacteriological or molecular biological method, or established clinically;

Newly diagnosed tuberculosis patient ("new case") – a patient with tuberculosis who has not previously taken anti-tuberculosis drugs as a course of tuberculosis treatment or has taken them for less than 1 month.

Tuberculosis relapse patient – a patient whose previous course of tuberculosis chemotherapy was successfully completed, and a recurrent episode of the disease has subsequently been registered.

Patient with other previously treated case – a patient who has a registered recurrent episode of the disease after treatment interruption or an ineffective treatment course.

Immunodiagnostics – a set of diagnostic tests designed to detect the immune system's reaction to the presence of Mycobacterium tuberculosis (MB) in the human body.

Tuberculosis infection (TB infection) – a state in which MB are present in the human body, causing a positive reaction to an intradermal test with a tuberculosis allergen (tuberculosis allergen for diagnostics**), unrelated to vaccination, in the absence of clinical and radiological signs of tuberculosis disease.

Latent tuberculosis infection (LTBI) – a state in which MB are present in the human body, causing positive reactions to recombinant tuberculosis allergen (RTA) in standard dilution** and/or a positive result of the blood test for interferon-gamma level specific to Mycobacterium tuberculosis complex antigens (IGRA tests), in the absence of clinical and radiological signs of tuberculosis disease.

Drug resistance (DR) – the ability of a pathogen culture to grow on a nutrient medium containing a drug at a critical concentration, which makes it highly probable to assume the lack of clinical effect when using this drug at a standard dosage.

Drug susceptibility (DS) – the ability of a pathogen culture to grow on a nutrient medium containing a drug at a critical concentration, which makes it highly probable to assume the clinical efficacy of using this drug at a standard dosage.

Clinically established drug susceptibility – the drug susceptibility of M. tuberculosis complex to drugs established based on clinical and anamnestical data in the absence of laboratory confirmation.

M. tuberculosis complex (MTC) – a group of microorganisms of the genus Мусоbаctеrium tuberculosis соmрlех that cause specific tuberculous lesions of organs and tissues.

Small form of tuberculosis – characterized by minor hyperplasia of 1–2 groups of intrathoracic lymph nodes (from 0.5 to 1.5 cm) or the presence of single foci up to 10 mm within 1 or 2 segments of one or both lungs.

Monomono-resistance – resistance of Mycobacterium tuberculosis to only one anti-tuberculosis drug (except for rifampicin**).

Isoniazid resistance** – drug resistance of M. tuberculosis complex to isoniazid** confirmed by any bacteriological or molecular genetic method, with confirmed susceptibility to rifampicin**, regardless of drug resistance to other anti-tuberculosis drugs.

Rifampicin resistance** (rifampicin resistance, RR) – drug resistance of M. tuberculosis complex to rifampicin** confirmed by any bacteriological or molecular genetic method, regardless of drug resistance to other anti-tuberculosis drugs.

Multidrug resistance (MDR) – drug resistance of M. tuberculosis complex confirmed by any bacteriological or molecular genetic method to at least isoniazid** and rifampicin**, regardless of resistance to other anti-tuberculosis drugs.

Clinically established multidrug resistance – multidrug resistance of M. tuberculosis complex established based on clinical and anamnestical data in the absence of laboratory confirmation.

Poly-resistance – resistance to more than one first-line anti-tuberculosis drug, excluding the combination of isoniazid** and rifampicin**.

Pre-extensively drug resistance (pre-XDR) – drug resistance of M. tuberculosis complex confirmed by any bacteriological or molecular biological method to rifampicin** with confirmed or unknown resistance to isoniazid** in combination with resistance to #levofloxacin** and/or #moxifloxacin**.

Clinically established pre-extensively drug resistance – pre-extensively drug resistance of M. tuberculosis complex established based on clinical and anamnestical data in the absence of laboratory confirmation.

Chemotherapy regimen (CTR) – a combination of anti-tuberculosis drugs, the duration and frequency of their administration, the timing and content of follow-up examinations, as well as the organizational forms of treatment delivery.

Rifampicin-resistant tuberculosis (RR-TB) – TB caused by rifampicin-resistant** strains of M. tuberculosis. These strains may be susceptible or resistant to isoniazid** (MDR-TB) or resistant to other first- or second-line anti-tuberculosis drugs. Cases of MDR-TB and RR-TB are often combined under the definition MDR/RR-TB when MDR-TB treatment regimens are applied.

Isoniazid resistance** (isoniazid** resistance, IR) – drug resistance of M. tuberculosis complex to isoniazid** confirmed by any bacteriological or molecular biological method, with confirmed susceptibility to rifampicin**, regardless of drug resistance to other anti-tuberculosis drugs;

Risk factors for tuberculosis disease – a combination of signs and anamnestic data that increase the risk of developing localized tuberculosis.

Extensively drug resistance (XDR) – drug resistance of M. tuberculosis complex confirmed by any bacteriological or molecular biological method to rifampicin** with confirmed or unknown resistance to isoniazid** in combination with resistance to #levofloxacin** and/or #moxifloxacin** and at least to #linezolid** or #bedaquiline**.

Clinically established extensively drug resistance – extensively drug resistance of M. tuberculosis complex established based on clinical and anamnestical data in the absence of laboratory confirmation.

MDR TB – tuberculosis caused by strains of M. tuberculosis complex with multidrug resistance, confirmed by any bacteriological, or molecular biological method, or established clinically;

Pre-XDR TB – tuberculosis caused by strains of M. tuberculosis complex with pre-extensively drug resistance, confirmed by any bacteriological, or molecular biological method, or established clinically;

XDR TB – tuberculosis caused by strains of M. tuberculosis complex with extensively drug resistance;

Chemoprophylaxis (preventive treatment) – the use of anti-tuberculosis drugs in individuals without signs of tuberculosis, but with an increased risk of its development, to reduce the likelihood of disease onset.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Tuberculosis – an infectious disease caused by Mycobacterium tuberculosis (Mycobacterium tuberculosis complex – MTC), which can affect any organs and tissues of the human body (except hair and nails).

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

MTC includes Mycobacterium tuberculosis, Mycobacterium bovis and its BCG variant (Bacillus Calmette–Guérin), Mycobacterium africanum, Mycobacterium microti, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii. This group of mycobacteria is characterized by pronounced genetic similarity. Most cases of tuberculosis (up to 95%) are caused by Mycobacterium tuberculosis [1].

The main biochemical components of Mycobacterium tuberculosis (MB) are proteins (tuberculoproteins), which induce a specific tissue inflammatory response with granuloma formation. MB are acid-resistant (acid-fast), alkali-resistant, and alcohol-resistant, which enables mycobacteria to maintain their pathogenic properties in the external environment for a long time.

An important property of M. tuberculosis variability is the development of resistance to anti-tuberculosis drugs, which becomes genetically fixed. This has created a major global public health challenge: the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis.

The natural reservoir of Mycobacterium tuberculosis includes humans, domestic and wild animals, and birds.

The primary mechanism of transmission is airborne. Key factors for infection and the development of tuberculosis include the infectious dose, the duration of contact with the tuberculosis patient, and the state of the susceptible host's immune system.

M. tuberculosis infection is an infectious process characterized by the absence of clinical manifestations in the presence of viable mycobacteria within the body.

When external and internal risk factors leading to a decrease in overall body resistance are present, tuberculosis develops, identified by the appearance of clinical, radiological, laboratory, and microbiological signs of pathology. The disease typically localizes in the intrathoracic lymph nodes and lungs, although other organs can also be involved. Tuberculosis is characterized by a diversity of clinical and pathomorphological manifestations [1, 2].

Two periods are distinguished in the development of the disease: primary and secondary. Primary tuberculosis is characterized by the phenomenon of infection (primary exposure); from a pathogenetic perspective, it involves the generalization of the tuberculous process, involvement of the lymphatic system, frequent occurrence of extrapulmonary forms, and organism hypersensitization.

The secondary process results from endogenous reactivation of foci of tuberculous infection against the background of weakened immunity, or from the re-entry of M. tuberculosis into the body from the external environment (exogenous superinfection).

Pathomorphologically, the inflammatory process is characterized by the formation of a tuberculous granuloma (tubercle): epithelioid-cell tubercles with multinucleated Langhans cells and areas of necrosis (caseation) are specific to tuberculosis [3].

Signs of a primary tuberculous lesion are characteristic of children. The clinical structure of the disease is dominated by intrathoracic lymph node tuberculosis (ITLNT), accounting for about 75–80%, and the primary tuberculous complex (PTC), accounting for about 10–15% [1, 2].

1.3 Epidemiology of the Disease or Condition

The incidence of tuberculosis in children is an important indicator of the overall epidemic situation.

According to WHO estimates for 2024, 10.7 million people fell ill with tuberculosis, which is equivalent to 131 cases per 100,000 population. Of these, 1.177 million were children (aged 0–14 years). In 2024, 172,000 children (aged 0–14 years) died from tuberculosis [4].

Currently, the Russian Federation demonstrates a steady positive trend in the epidemiological situation of tuberculosis in children. Over the past 5 years, the incidence rate has continued to decline both overall in children and adolescents, and across various age groups. The tuberculosis incidence rate among children aged 0–14 years decreased from 7.7 per 100,000 children in 2019 to 6.0 per 100,000 children in 2024; in the 15–17 age group, it decreased from 16.5 per 100,000 children in 2019 to 12.7 per 100,000 children in 2024.

One of the indicators of the effectiveness of active case detection is the identification of fibrous-cavernous pulmonary tuberculosis in children. The last case of fibrous-cavernous tuberculosis in newly diagnosed pediatric patients was recorded in 2020. No cases were detected in 2019 and 2021–2023, whereas prior to 2018, 1–2 cases of fibrous-cavernous tuberculosis were identified annually in children. An indirect sign of effective screening coverage for tuberculosis in children was the decrease in the number and proportion of children aged 0–14 years with tuberculous meningitis and central nervous system tuberculosis to 4 children (0.26%) in 2023 (compared to 4 children (0.25%) in 2019, 7 (0.41%) in 2020, 8 (0.47%) in 2021, and 10 (0.3%) in 2022); in 2014, this figure was 16 individuals (0.52%) [5, 144]. It should also be noted that the number of newly diagnosed pediatric tuberculosis patients aged 0–14 years with bacteriologically confirmed disease decreased, amounting to 86 children (0.34 per 100,000) in 2023 (88 children (0.34 per 100,000) in 2019; 109 children (0.42 per 100,000) in 2020; 117 children (0.46 per 100,000) in 2021; 94 children (0.37 per 100,000) in 2022). Looking at the longer-term trend, in 2014 the number of bacteriologically confirmed tuberculosis cases in children aged 0–14 was 140 (0.57 per 100,000), representing a 38.5% decrease by 2023, despite the improved quality of microbiological tuberculosis diagnostics during this period [144]. The absence of bacteriologically confirmed disease in children necessitates the prescription of empirical chemotherapy regimens, which presents certain challenges for the physician.

1.4 Features of Coding the Disease or Condition

The block "Tuberculosis" (A15–A19) is included in Class I "Certain infectious and parasitic diseases" (A00–B99).

Tuberculosis (A15–A19)

Includes:

• infections caused by Mycobacterium tuberculosis and Mycobacterium bovis

Excludes:

• congenital tuberculosis (P37.0)

• HIV disease resulting in mycobacterial infection (B20.0)

• pneumoconiosis associated with tuberculosis (J65)

• sequelae of tuberculosis (B90.)

• silicotuberculosis (J65)

Respiratory tuberculosis, bacteriologically and histologically confirmed (A15):

A15.0 - Tuberculosis of lung, confirmed by sputum microscopy with or without culture growth;

A15.1 - Tuberculosis of lung, confirmed by culture only;

A15.2 - Tuberculosis of lung, confirmed histologically;

A15.3 - Tuberculosis of lung, confirmed by unspecified methods;

A15.4 - Tuberculosis of intrathoracic lymph nodes, confirmed bacteriologically and histologically;

A15.5 - Tuberculosis of larynx, trachea and bronchus, confirmed bacteriologically and histologically;

A15.6 - Tuberculous pleurisy, confirmed bacteriologically and histologically;

A15.7 - Primary respiratory tuberculosis, confirmed bacteriologically and histologically;

A15.8 - Other respiratory tuberculosis, confirmed bacteriologically and histologically;

A15.9 - Respiratory tuberculosis unspecified, confirmed bacteriologically and histologically;

Respiratory tuberculosis, not bacteriologically or histologically confirmed (A16):

A16.0 - Tuberculosis of lung, bacteriologically and histologically negative;

A16.1 - Tuberculosis of lung, bacteriologically and histologically not done;

A16.2 - Tuberculosis of lung, without mention of bacteriological or histological confirmation;

A16.3 - Tuberculosis of intrathoracic lymph nodes, without mention of bacteriological or histological confirmation;

A16.4 - Tuberculosis of larynx, trachea and bronchus, without mention of bacteriological or histological confirmation;

A16.5 - Tuberculous pleurisy, without mention of bacteriological or histological confirmation;

A16.7 - Primary respiratory tuberculosis, without mention of bacteriological or histological confirmation;

A16.8 - Other respiratory tuberculosis, without mention of bacteriological or histological confirmation;

A16.9 - Respiratory tuberculosis unspecified, without mention of bacteriological or histological confirmation;

A17+ - Tuberculosis of nervous system;

A17.0+ - Tuberculous meningitis (G01*);

A17.1+ - Meningeal tuberculoma (G07*);

A17.8+ - Tuberculosis of nervous system in other sites;

A17.9+ - Tuberculosis of nervous system, unspecified (G99.8*);

A18 - Tuberculosis of other organs;

A18.0+ - Tuberculosis of bones and joints;

A18.1+ - Tuberculosis of genitourinary system;

A18.2 - Tuberculous peripheral lymphadenopathy;

A18.3 - Tuberculosis of intestine, peritoneum and mesenteric glands;

A18.4 - Tuberculosis of skin and subcutaneous tissue;

A18.5+ - Tuberculosis of eye;

A18.6+ - Tuberculosis of ear;

A18.7+ - Tuberculosis of adrenal glands (E35.1*);

A18.8+ - Tuberculosis of other specified organs;

A19 - Miliary tuberculosis;

A19.0 - Acute miliary tuberculosis of a single specified site;

A19.1 - Acute miliary tuberculosis of multiple sites;

A19.2 - Acute miliary tuberculosis, unspecified;

A19.8 - Other forms of miliary tuberculosis;

A19.9 - Miliary tuberculosis, unspecified.

Main codes used for disease coding in children:

A15.7, A16.7 Primary respiratory tuberculosis;

A16.3 - Tuberculosis of intrathoracic lymph nodes, without mention of bacteriological or histological confirmation;

A16.5 - Tuberculous pleurisy, without mention of bacteriological or histological confirmation;

A16.7 - Primary respiratory tuberculosis without mention of bacteriological or histological confirmation.

1.5 Classification of the disease or condition

The classification of tuberculosis generally corresponds to ICD-10. The classification of tuberculosis used in the Russian Federation is based on several principles. These include the clinical-roentgenological and pathomorphological features of the tuberculous process (including localization and extent), its course (phases), and the presence of bacterial excretion [1].

The modern national classification of tuberculosis was adopted at the VII Russian Congress of Phthisiologists and approved by Order of the Ministry of Health of the Russian Federation No. 109 dated March 20, 2003: "On improving anti-tuberculosis measures in the Russian Federation". The classification consists of four main sections: clinical forms of tuberculosis, characteristics of the tuberculous process, complications of tuberculosis, and residual changes after cured tuberculosis [2].

The characteristics of the tuberculous process include data on the localization and phase of the process, as well as the presence or absence of MTB in the diagnostic material obtained from the patient.

Localization and extent of the process: in the lungs by lobes, segments, and in other organs by the site of the lesion.

Phase of the process:

a) infiltration, breakdown, dissemination;

b) resorption, compaction, scarring, calcification.

Bacterial excretion:

a) with detection of Mycobacterium tuberculosis (MTB+);

b) without detection of Mycobacterium tuberculosis (MTB-).

Complications of tuberculosis: haemoptysis and pulmonary haemorrhage, spontaneous pneumothorax, fistulae, cor pulmonale (cardiopulmonary failure). In children, typically – atelectasis, bronchopulmonary lesion.

Residual changes after cured respiratory tuberculosis: fibrous, fibrous-focal, bullous-dystrophic, pleuropneumosclerosis, cirrhosis. In children, more commonly – calcifications in the lungs and lymph nodes.

Main clinical forms of tuberculosis:

- Respiratory tuberculosis:

The following clinical forms of respiratory tuberculosis are distinguished:

• primary tuberculosis complex (a form of primary tuberculosis characterized by the development of inflammatory changes in the lung tissue, involvement of regional intrathoracic lymph nodes, and lymphangitis);

  • tuberculosis of intrathoracic lymph nodes (involvement of various groups of lymph nodes as a result of primary infection with MTB);

  • disseminated pulmonary tuberculosis (various processes developing as a result of the spread of Mycobacterium tuberculosis via hematogenous, lymphogenous, and mixed pathways; proceeds as acute, subacute, and chronic);

  • focal pulmonary tuberculosis (characterized by the presence of focal lesions up to 1.0 cm in diameter of productive, exudative, and caseous-necrotic genesis, localized in one or both lungs and occupying 1–2 segments);

  • infiltrative pulmonary tuberculosis (characterized by the presence of inflammatory foci in the lungs greater than 1.0 cm in diameter, predominantly of an exudative nature with caseous necrosis, with or without destruction of lung tissue and bronchogenic dissemination);

  • caseous pneumonia (development of a specific process with a predominance of caseous-necrotic inflammation localized within a lobe or more, characterized by a severe patient condition, fever, pronounced intoxication, profuse bacterial excretion);

  • pulmonary tuberculoma (a focus of caseous necrosis greater than 1.0 cm in diameter, surrounded by a fibrous capsule);

  • cavernous pulmonary tuberculosis (characterized by the presence of a formed cavity [cavern] in the absence of pronounced fibrous changes in the lung tissue surrounding the cavity);

  • fibro-cavernous pulmonary tuberculosis (characterized by the presence of a fibrous cavity, the development of fibrous changes and other morphological changes in the lungs (pneumosclerosis, emphysema, bronchiectasis), and the presence of foci of bronchogenic dissemination of varying age; the course is frequently complicated);

  • cirrhotic pulmonary tuberculosis (a form of tuberculosis dominated by the proliferation of coarse connective tissue in the lungs and pleura while preserving a fibrous cavity within the thickness of the cirrhotic changes);

  • tuberculous pleurisy (including empyema) (the diagnosis is established based on the presence of an effusion of a serous, serofibrinous, purulent, or less commonly hemorrhagic nature, considering the combination of clinical and radiological signs, and the nature of pleurisy is determined by analyzing material obtained from pleural puncture or pleural biopsy. Pleural tuberculosis accompanied by the accumulation of purulent exudate represents a specific form of exudative pleurisy – empyema, which develops with widespread caseous lesions of the pleura, as well as a result of perforation of a cavity or subpleurally located foci);

  • tuberculosis of the bronchi, trachea, upper respiratory tract (three main forms of bronchial and tracheal tuberculosis are distinguished: infiltrative, ulcerative, and fistulous (lymphobronchial, bronchopleural fistulae));

• miliary tuberculosis, as a variant of a generalized process, is characterized by an acute course with rapid dissemination (generalization) of a predominantly productive nature involving various organs and systems (acute miliary tuberculosis of multiple localizations).

- Tuberculosis of other organs and systems:

In addition to respiratory tuberculosis, children may rarely develop other forms of tuberculosis – of extrapulmonary (extrothoracic) localization. Extrapulmonary tuberculosis is frequently combined with respiratory tuberculosis and develops as a result of predominantly hematogenous dissemination of the tuberculosis infection. Extrapulmonary tuberculosis has no pathognomonic symptoms. The disease should be suspected primarily in cases of standard treatment failure, frequent relapses of a "nonspecific" disease masking a particular form of extrapulmonary tuberculosis, as well as upon the appearance of fistulae of any localization.

In extrapulmonary tuberculosis (EPT), the classification depends on the localization of the process.

Bone and joint tuberculosis:

- most commonly affecting the vertebrae, large single joints, and tubular bones "rich" in cancellous bone.

Stages (phases) of the process:

Phase I – pre-arthritic (pre-spondylitic), formation of the primary focus (ostitis) near the joint;

Phase II – arthritic (spondylitic), transition of inflammation from bone to joint with the development of secondary arthritis;

Phase III – post-arthritic (post-spondylitic), outcome of the disease, stabilization of the process.

It should be noted that bone and joint tuberculosis is practically never diagnosed at the stage of the primary focus, which usually proceeds without clinical manifestations. Inactive tuberculosis is established when residual specific changes (limited small calcified bone foci or soft tissue abscesses) persist in the absence of clinical and laboratory activity. The term "residual changes" is applied to clinically cured patients who have completely finished the main course of specific anti-tuberculosis therapy. The detection of corresponding changes in patients who have not received specific treatment is regarded as a chronic inactive process. The absence of clinical, radiological, and laboratory signs of an active tuberculous process after the main course of combination treatment in the absence of residual changes and sequelae is regarded as a cure.

Practically all clinical forms of bone and joint tuberculosis are classified as surgical diseases, and their detection is considered an indication for surgery.

Surgical treatment is a component of combination therapy, which also includes anti-tuberculosis chemotherapy [Appendix No. 6 to the Order of the Ministry of Health of the Russian Federation No. 109 dated 21.03.2003] and rehabilitation treatment. For primary synovial forms of tuberculous arthritis, indications for surgery are determined individually, taking into account the severity of anatomical and functional impairments and the efficacy of conservative treatment.

Tuberculosis of the central nervous system (CNS)

Factors contributing to the onset of tuberculous meningitis in childhood:

- lack of vaccination with a tuberculosis prevention vaccine** (BCG, BCG-M);

- presence of an immunodeficient state;

- massive infection and late detection of the process.

It is customary to distinguish the following main forms of CNS tuberculosis, which are essentially different stages of a single pathological process:

- Basilar meningitis;

- Meningoencephalitis;

- Spinal form (meningoencephalomyelitis);

- Tuberculoma of the brain (spinal cord);

- Tuberculous brain abscess.

In addition to the typical presentation, variants of atypical disease onset.

1. «Acute serous basilar meningitis» type: acute onset with fever, headache, cranial nerve palsies, and pronounced meningeal syndrome;

2. «Abortive meningitis» type (during specific therapy);

3. «Traumatic brain injury» type;

4. «Lethargic encephalitis» type;

5. «Acute purulent meningitis» type;

6. «Acute cerebrovascular accident» type;

The typical course of tuberculous meningitis comprises three periods:

• prodromal period;

• period of CNS irritation

• period of paresis and paralysis

Outcomes of tuberculous meningitis:

- recovery without residual changes;

- recovery with pronounced residual changes (intellectual decline,

- motor disorder syndrome, hydrocephalus, epilepsy);

- fatal outcome.

(Detailed clinical presentation, diagnostics, and treatment of CNS tuberculosis in children are presented in the Federal clinical guidelines for the diagnosis and treatment of tuberculous meningitis in children: https://docviewer.yandex.ru/view/0/?*=)

Urogenital tuberculosis

The clinical classification of urogenital tuberculosis includes the following forms:

I. Tuberculosis of the urinary system:

1. Renal tuberculosis (nephrotuberculosis)

• Tuberculosis of the renal parenchyma (stage I, non-destructive form).

• Tuberculous papillitis (stage II, limited destructive form).

• Cavernous nephrotuberculosis (stage III, destructive form).

• Polycavernous nephrotuberculosis (stage IV, widespread destructive form).

Complications of nephrotuberculosis: chronic kidney disease (CKD), formation of a lumbar fistula due to rupture of a renal cavity into the paranephric space, arterial hypertension.

2. Tuberculosis of the urinary tract (renal pelvis, ureter, urinary bladder, urethra) is always secondary to renal tuberculosis.

II. Tuberculosis of male genital organs

III. Tuberculosis of female genital organs

IV. Generalized urogenital tuberculosis – simultaneous involvement of the urinary and reproductive systems; typically accompanied by complications.

Abdominal tuberculosis is a specific tuberculous involvement of the digestive organs, lymph nodes of the small intestine mesentery and retroperitoneal space, and the peritoneum.

Classification of abdominal tuberculosis

1. Intestinal tuberculosis:

• Infiltrative

• Infiltrative-ulcerative

• Cicatricial-stenotic

Complications: ulcer perforation with peritonitis or abdominal abscesses, intestinal hemorrhage, cicatricial-ulcerative strictures of the intestine leading to complete or partial intestinal obstruction.

2. Peritoneal tuberculosis (tuberculous peritonitis):

• Exudative

• Adhesive

• Caseous-necrotic

Complications: adhesive intestinal obstruction, fibrinous-purulent peritonitis, abdominal abscess.

3. Tuberculosis of abdominal lymph nodes:

• Active phase (infiltration, caseous necrosis)

• Inactive phase (scarring, petrification)

Complications: abdominal or retroperitoneal abscess, peritonitis.

4. Tuberculosis of other abdominal organs (spleen, liver, stomach, etc.).

5. Combination of tuberculous involvement of various abdominal organs and tissues.

1.6 Clinical presentation of the disease or condition

The clinical presentation of tuberculosis in children differs significantly from that in adults. Children predominantly present with primary forms of tuberculosis, which follow a relatively benign course without prominent clinical symptoms, and are most often asymptomatic. Tuberculosis in children is primarily detected through preventive screening via intradermal testing with a tuberculous allergen [4].

Clinical manifestations of tuberculosis in children are characterized by the absence of pathognomonic symptoms and pronounced polymorphism [2, 7].

Children often lack local symptoms of the disease, and initial manifestations present as intoxication symptoms (functional disorders of various organs and systems):

- general weakness and malaise;

- low-grade intermittent fever over a prolonged period;

- decreased appetite, weight loss, or failure to gain weight;

- autonomic nervous system dysfunction manifested as increased sweating, palpitations, and drastic mood swings.

Primary tuberculosis may present with paraspecific (toxico-allergic) manifestations caused by a specific response of the immunocompetent system to the tuberculosis infection. This leads to organ dysfunction, resulting in a varied clinical picture («masks of tuberculosis»):

- erythema nodosum on the skin, most commonly in the shins;

- enlargement of peripheral lymph nodes (micropolyadenia);

- blepharitis, phlyctenular keratoconjunctivitis;

- synovitis, most commonly of the knee joints.

The most pronounced clinical symptoms appear in disseminated and complicated forms of primary tuberculosis: persistent cough, fever, dyspnea, chest pain, and less commonly hemoptysis. In such cases, tuberculosis must be differentiated from nonspecific inflammatory processes (typically pneumonia).

Symptoms in children:

Primary ostitis (osteomyelitis):

- complaints of pain, decreased play activity, local swelling;

- possible body temperature elevation—from low-grade to febrile;

- appearance of painless or mildly painful space-occupying lesions in soft tissues;

- formation of abscesses with signs of fluctuation, skin hyperemia, often without marked changes in general status;

- moderate joint syndrome (in periarticular ostitis), as a rule, without significant reduction and pain on joint movement.

At this stage of development, the specific process may be complicated by periarticular abscesses and fistulae.

Arthritis (osteoarthritis, synovitis):

- increasing pain syndrome associated with passive and active movements in the joint—from moderate to severe;

- low-grade or febrile temperature reaction;

- joint syndrome: swelling, contracture, and stiffness,

Spondylitis:

- spinal deformity, most commonly single-plane (kyphosis), ranging from button-like to sharp-angled;

- pain syndrome;

- change in general well-being;

- temperature reaction—low-grade or febrile;

- neurological disorders, most commonly in thoracic and cervical spine lesions: paresis, paralysis;

- abscesses in areas remote from the level of spinal lesion, including iliac regions, thigh, etc. (outdated term—cold abscesses)

Chronic destructive osteoarthritis rarely develops, typically in the absence of adequate treatment.

Changes in the joint develop after the acute stage subsides, progress slowly with repeated exacerbations, and are accompanied by joint destruction along with trophic changes in the limb in the form of muscle hypotonia and hypotrophy.

Residual changes: the main inflammatory manifestations of arthritis (spondylitis) subside.

Disturbances in the growth of bones forming the joint and anatomical-functional insufficiency of adjacent skeletal sections, calcified inclusions in the joint and soft tissues, and impaired organ function may develop.

Renal parenchyma tuberculosis is a minimal, initial form of renal tuberculosis without tissue destruction, where both clinical and anatomical cure is possible. Urinalysis in children may show no pathological changes, or changes such as leukocyturia and microhematuria. The hallmark of the disease is generally the detection of MTB in the urine. Complications develop extremely rarely. The prognosis is favorable. The outcome in a favorable course is clinical and anatomical cure; formation of small calcifications in the renal parenchyma; in an unfavorable course—progression of tuberculous inflammation with the formation of a subcortical cavern or tuberculous papillitis.

Tuberculous papillitis in early stages may be asymptomatic. Overall, this disease is quite severe if multiple renal papillae are affected by the infectious process.

The inflammation becomes destructive and involves the entire thickness of the renal pyramids with caseous necrosis and the formation of cavities, which can be either isolated or communicating with the pelvicalyceal system; lumbar pain appears. Bacteriuria (MTB) is not always detected. Breakdown cavities may clear and turn into smooth-walled cysts.

During the healing of cavities, calcification (deposition of calcium salts) of caseous foci occurs, in the depths of which viable mycobacteria often persist.

Cavernous renal tuberculosis pathogenetically develops via two pathways—from parenchymal tuberculosis or from papillitis. In the first case, a subcortical cavity is formed that does not communicate with the pelvicalyceal system; the clinical picture is similar to that of a renal carbuncle. A subcortical cavity is usually diagnosed pathomorphologically after surgery in general healthcare settings. In the second case, cavity formation occurs due to the spread of papillary destruction.

It is extremely rare in children.

As a rule, cavernous renal tuberculosis requires surgical treatment. Complete cure cannot be achieved, although the use of complex etiopathogenetic therapy methods allows in some cases to transform the renal cavity into a sanitized cyst. A favorable outcome is the transformation of the cavity into a sanitized cyst, and the formation of post-tuberculosis deformation of the pelvicalyceal system.

Tuberculosis of the urinary tract (renal pelvis, ureter, bladder, urethra) occurs only against the background of renal tuberculosis and can be considered a complication.

Genital tuberculosis is rare, and may occur in adolescents during the period of hematogenous dissemination from the primary tuberculosis focus.

It develops in adolescent girls:

- salpingitis (90%);

- endometritis;

- salpingo-oophoritis.

In adolescent boys, the following may occur:

- tuberculous epididymitis (unilateral or bilateral).

- tuberculous orchiepididymitis (unilateral or bilateral).

Peripheral lymph node tuberculosis (PLNT) is accompanied by enlargement of mostly cervical and supraclavicular lymph nodes on one side. It can be asymptomatic, with a gradual increase in caseous necrosis within the node stroma.

In this case, intoxication symptoms appear, the skin over the lymph node becomes hyperemic and thinned, fluctuation appears, and an abscess forms. In 10% of cases, melting and rupture of caseous-necrotic masses can occur with the formation of fistulae with thick purulent discharge, usually grayish-white, odorless. After the lymph nodes empty, body temperature decreases, pain diminishes, and the fistulae slowly heal with the formation of characteristic scars in the form of frenula or papillae.

With incomplete emptying of the nodes, the disease acquires a chronic course with periodic exacerbations.

Enlargement of peripheral lymph nodes can be a manifestation of mycobacteriosis (a disease caused by nontuberculous mycobacteria—NTM), especially in individuals with HIV infection.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

Tuberculosis has no specific features, its clinical manifestations are diverse, and the disease can affect various organs and tissues, sometimes localizing simultaneously in several organs.

The diagnosis is formulated in the following sequence: clinical form of tuberculosis, localization, phase of the process, bacillary excretion (MTB + indicating drug susceptibility of MTB), complications.

The diagnosis of tuberculosis is considered verified if in a patient, along with clinical-laboratory and radiological signs of tuberculosis, MTB are identified by any microbiological and molecular-genetic method (etiological verification) and/or results of histological examination indicating the presence of a tuberculous granuloma in the affected organ are obtained (morphological verification).

The diagnosis of tuberculosis is considered established if the patient has clinical and radiological signs of the disease, but there is no bacillary excretion and histological confirmation of the diagnosis (diagnosis verification).

When MTB are detected without clinical, radiological, and laboratory signs of the disease, dynamic follow-up of the patient with repeated examination of biological material for MTB is required.

The diagnosis of "Tuberculosis" is confirmed by a medical commission of a anti-tuberculosis medical organization, which makes a decision on the need for follow-up care and treatment of the tuberculosis patient.

Diagnostic criteria:

The diagnosis of tuberculosis is established based on a set of data:

- anamestic: duration of intoxication symptoms and respiratory complaints, episodes of hemoptysis, lack of effect from nonspecific treatment, contact with a tuberculosis patient;

- immunodiagnostic tests (positive skin tests and/or in vitro – IGRA);

- laboratory: moderate inflammatory changes in the blood count, lymphocytosis;

- radiological: enlargement of intrathoracic lymph nodes, presence of focal, infiltrative, cavitary lesions in the lung tissue;

presence of signs of extrapulmonary organ and system involvement;

- microbiological (etiological diagnostics);

- other (instrumental research methods, morphological).

The main condition for diagnosing tuberculosis is a comprehensive examination of the patient, including all available research methods.

2.1 Complaints and Anamnesis

Comments: In latent tuberculosis infection (LTBI), symptoms are usually absent.

Comments: A thorough medical history allows, firstly, to more accurately assess the risk of tuberculosis and, secondly, to decide on the need for preventive treatment.

• In children with suspected respiratory tuberculosis, it is recommended to thoroughly clarify all existing complaints in order to perform a minimum diagnostic examination to rule out or establish the diagnosis of tuberculosis [2, 112, 115].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: clinical manifestations of respiratory tuberculosis are most often observed as respiratory complaints and intoxication symptoms of varying severity.

Complaints (symptoms) suspicious of tuberculosis include:

1. Presence of intoxication syndrome: prolonged (more than 3 weeks) fever, usually low-grade, worsening in the evening, relatively well tolerated by the patient, sometimes intermittent; generalized unmotivated weakness; sweating, predominantly at night; loss of appetite and weight loss.

2. Presence of respiratory symptoms: cough (lasting more than 2 weeks), dry or with a small amount of odorless mucous sputum; rarely hemoptysis; chest pain; shortness of breath (in widespread and complicated cases).

All of these symptoms can be associated with other diseases. If these complaints are present, a thorough personal and medical history must be taken.

• When taking a history from children with complaints suspicious of tuberculosis, it is recommended that the physician determine whether there has been contact with a tuberculosis patient (relatives, neighbors, friends, etc.); clarify the social status of the family, thereby identifying the source of infection or suggesting the possibility of contact and infection of the child with Mtb [2, 9, 12].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

Comments: Children, especially of early and young age, usually contract tuberculosis while in contact with an adult or adolescent tuberculosis patient. The incidence of tuberculosis in children from infection foci is several times higher than in the general population.

Comments: Considering that chemotherapy regimens are based on the drug susceptibility and resistance of the pathogen, it is very important to perform a drug susceptibility test (DST) for Mtb before prescribing treatment. However, the proportion of children with bacteriodussemination accounts for 5-6% of tuberculosis patients aged 0-14 years [114]. At the same time, the drug resistance profile of Mtb in the suspected source matches the drug susceptibility profile in the infected child from the focus in more than 75%-80% of cases [116, 117, 130, 131], which must be ascertained and taken into account when prescribing a chemotherapy regimen (CTR).

2.2 Physical Examination

• At the stage of diagnosis establishment, it is recommended to perform a physical examination in children with suspected tuberculosis to identify signs of tuberculosis intoxication [1, 2, 9].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: In general, the condition of children with tuberculosis remains satisfactory. In respiratory tuberculosis, physical manifestations of lung lesions are often scanty: percussion and auscultatory pathological signs may be completely absent. However, in widespread and complicated processes, a decrease in skin turgor and subcutaneous tissue, and paraspecific reactions are possible; skin pallor and dark circles under the eyes are noted; dull percussion lung sound, dry or moist rales upon auscultation (in case of lung tissue destruction, bronchial involvement).

In extrapulmonary tuberculosis, symptoms appear from the affected organ (section 1.5).

2.3 Laboratory Diagnostics

Laboratory diagnosis of tuberculosis, regardless of the localization of the process, is carried out according to a single algorithm.

For the laboratory diagnosis of respiratory tuberculosis, any diagnostic material available for examination is used in accordance with the localization of the process: sputum, pleural fluid, bronchoalveolar lavage fluid, bronchopulmonary tissue biopsy, etc. Patients with suspected extrapulmonary tuberculosis, depending on the localization, undergo examination of synovial fluid, ascitic fluid, urine sediment, ear discharge, fistula discharge, punctates, biopsies, cerebrospinal fluid, and other biological materials.

Comments: most often, the complete blood count and urinalysis show no changes. If intoxication symptoms are present, the complete blood count may show moderate inflammatory manifestations in the form of a decreased hemoglobin level, increased leukocyte count, and decreased lymphocyte level. Urinalysis may show an elevated total protein level, elevated leukocyte and erythrocyte counts, which is the basis for additional examination to rule out genitourinary tuberculosis.

• Patients with suspected respiratory tuberculosis are recommended to undergo at least twice microscopic examination of sputum for mycobacteria (Mycobacterium spp.) or other diagnostic material (microscopic examination of bronchial washings or bronchoalveolar lavage for Mycobacterium tuberculosis, microscopic examination of pleural fluid for Mycobacterium tuberculosis) to confirm the diagnosis of tuberculosis [13].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: This method is routine, inexpensive, and can be performed in any medical facility. If M. tuberculosis is detected, the method allows for rapid (within 1-2 days) differential diagnosis of tuberculosis and non-specific inflammatory disease, even in a primary care setting, and identifies patients with TB who pose the greatest epidemiological risk. In pharyngopulmonary/anti-tuberculosis facilities, microscopy is mandatory in all patient evaluation protocols due to the need for diagnosis verification. In addition, this method makes it possible to assess the bacterial load and the dynamics of cessation of bacterial excretion, since microscopic examinations are performed at all stages of tuberculosis diagnosis and chemotherapy efficacy monitoring [17].

• If sputum (or other diagnostic material) is available, it is recommended to include the following in the complex of laboratory tests for children with suspected tuberculosis to detect M. tuberculosis and confirm the etiology of the disease (at least two tests from different portions): microbiological (culture) examination of sputum for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of bronchial washings or bronchoalveolar lavage fluid for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of urine for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of pleural fluid for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of feces for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of purulent discharge for Mycobacterium tuberculosis complex, microbiological (culture) examination of wound discharge for Mycobacterium tuberculosis complex, microbiological (culture) examination of synovial fluid for Mycobacterium tuberculosis complex, microbiological (culture) examination of pericardial fluid for Mycobacterium tuberculosis complex, microbiological (culture) examination of female genital discharge for Mycobacterium tuberculosis, microbiological (culture) examination of cerebrospinal fluid for Mycobacterium tuberculosis complex [1, 8, 84, 85].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments:

Etiological diagnosis is the basis of diagnostic measures for tuberculosis. The priority is to confirm or exclude the presence of mycobacteria in the diagnostic material using methods with the maximum available sensitivity and specificity.

To minimize the likelihood of discrepancy in results obtained by different methods, the comprehensive study should be performed from a single sample of diagnostic material.

In children with respiratory tuberculosis, sputum is an accessible diagnostic material. In the absence of sputum or if sputum collection is impossible (due to the child's age), other types of diagnostic material can be examined (bronchial washings, aspiration material, brush biopsy, biopsy specimen, exudate; in younger children, gastric washings, oropharyngeal washings/swabs).

One of the safe and effective ways to obtain biological material in children of all age groups is sputum induction (irritant inhalation). This procedure requires special equipment and trained personnel [8].

In younger children (under 3 years of age), due to the inability to collect sputum by coughing and induction, gastric washings are examined. Since this technique is associated with significant discomfort for the patient, and the rate of positive results in microscopy and culture is low, this procedure should be used only in the presence of a complicated course of tuberculosis and suspected drug-resistant TB [8].

Examination of stool for M. tuberculosis was included by the WHO in the list of recommended specimen types for the diagnosis of respiratory tuberculosis in children using molecular biological methods [84, 85]. This method can be used as an alternative sample, especially when there are difficulties in obtaining sufficient volumes of respiratory tract samples, or in complicated forms of pulmonary tuberculosis (atelectasis, destruction, dissemination) for the diagnosis of respiratory tuberculosis in young children. In some settings, stool analysis may be more acceptable and practical, as the collection method is less invasive than obtaining gastric aspirate. Children with respiratory tuberculosis swallow sputum containing mycobacteria originating from the lungs; the latter pass through the gastrointestinal tract and can be detected in stool samples.

Patients with suspected extrapulmonary tuberculosis, depending on the localization, undergo examination of feces, urine sediment, menstrual blood, ear discharge, fistula discharge, punctates, biopsy specimens, cerebrospinal fluid, and other potential biological material.

Comments: the main advantage of molecular genetic methods (MGM) is that they are "rapid" and highly sensitive, allowing results to be obtained in a short time (1-2 days), unlike culture methods (up to 90 days), and they also have high diagnostic accuracy (sensitivity of 75%, compared to 50% for microscopy) [21]. The conclusion regarding the presence of M. tuberculosis in diagnostic material is made based on the detection of M. tuberculosis DNA (deoxyribonucleic acid); however, DNA does not indicate the status of active bacterial excretion. An important advantage of MGM is the rapid and reliable detection of patients with multidrug-resistant (MDR) tuberculosis, especially in settings with a high prevalence of tuberculosis and HIV infection [22].

The use of MGM to determine drug resistance is the initial stage of patient evaluation and does not exclude the need for traditional culture methods to test drug susceptibility and resistance of M. tuberculosis.

Comments: The main advantage of culture tests on liquid media using automated systems is a 2-to-3-fold reduction in tuberculosis diagnostic turnaround time compared to traditional cultivation on solid media. The sensitivity of tests on liquid media is approximately 10% higher than that on solid media. Test quality is ensured by the high efficiency of standardized manufacturing of reagents and media certified under ISO 9001, as well as the maintenance of standard testing protocols [29, 30, 87-90].

• As a priority component of the diagnostic workup in tuberculosis patients, it is recommended to determine mutations associated with drug resistance in the DNA of Mycobacterium tuberculosis (Mycobacterium tuberculosis complex) using real-time PCR or PCR followed by hybridization to first-line drugs—isoniazid** and rifampicin**, or at least rifampicin**. The test is performed twice if the first result is negative, as well as in the case of a positive result in the absence of clinical and radiological signs of active tuberculosis, in order to determine treatment tactics [18-22].

GCR BLOC 1Grade of Recommendation B (Level of Evidence 1)

Comments: The main advantage of molecular genetic methods is that they are fast and highly sensitive, yielding results in a short time (1–2 days) compared to culture methods (10–90 days), while also having high sensitivity and specificity. The conclusion regarding the presence of MTB in diagnostic material is made based on the detection of MTB DNA. Positive results from molecular genetic methods do not determine the bacterial excretion status, unlike microscopy and culture methods.

Conclusions regarding drug resistance (DR) using MGM are based on the detection of mutations in genes associated with DR. An important advantage of MGM is the rapid and reliable detection of patients with multidrug-resistant tuberculosis (MDR-TB), which allows for patient triage and the timely prescription of a chemotherapy regimen for MDR-TB treatment. The use of MGM to determine DR is the initial stage of patient evaluation and does not preclude the need for traditional culture-based drug susceptibility testing (DST) of MTB [23–26, 91–92].

Comments: Fluoroquinolones have been used in the treatment of tuberculosis for several decades, which has led to the emergence and spread of drug-resistant MTB strains to this group of drugs [96, 97]. The presence of drug resistance to fluoroquinolones is associated with low treatment efficacy [98]. Determining the drug susceptibility of MTB to fluoroquinolones allows for the timely prescription of MDR, pre-XDR, and XDR chemotherapy regimens when the pathogen is simultaneously resistant to rifampicin**, or allows for the intensification of the treatment regimen for isoniazid-resistant tuberculosis. The detection of mutations associated with fluoroquinolone resistance in MTB DNA does not allow for the differentiation of resistance to individual drugs within the group. To prescribe a chemotherapy regimen, a proportion method drug susceptibility test must be performed for each clinically used drug. Critical concentrations for modern fluoroquinolones have not been established for the absolute concentration method.

Comments: The culture method for determining MTB drug susceptibility allows for assessing susceptibility (DS) to a broad spectrum of anti-TB drugs and prescribing an individualized treatment regimen based on the results obtained. According to WHO recommendations, several culture methods are recommended for determining MTB DS:

- modified proportion method in liquid culture media using an automated system for monitoring MTB growth for first-line drugs (streptomycin**, isoniazid**, rifampicin**, #ethambutol**, #pyrazinamide**) and second-line drugs (#levofloxacin**, #moxifloxacin**, #ethionamide**, #prothionamide**, #capreomycin**, #amikacin**, kanamycin**, #linezolid**, #delamanid**, #bedaquiline**, #clofazimine, #pretomanid**);

- proportion method on Middlebrook 7N10 and 7N11 solid media for first-line drugs (streptomycin**, isoniazid**, rifampicin**, #ethambutol**) and second-line drugs (#ethionamide**, #capreomycin**, kanamycin**, #amikacin**, #moxifloxacin**, #levofloxacin**, #bedaquiline**, #delamanid**);

- proportion method on Löwenstein-Jensen solid medium for first-line drugs (streptomycin**, isoniazid**, rifampicin**, #ethambutol**) and second-line drugs (#ethionamide**, #prothionamide**, #capreomycin**, kanamycin**, #amikacin**, #levofloxacin**, #moxifloxacin**);

For second-line drugs, the absolute concentration method is not validated. Detection of MTB in at least one specimen can be considered sufficient grounds for the etiological confirmation of the diagnosis. Nevertheless, a single detection of MTB DNA without confirmation by microscopy or culture methods requires cautious interpretation of a positive result and correlation with clinical and anamnestical data [15, 24, 27–33, 15, 27, 28, 29, 30, 31, 32, 33].

2.4 Instrumental Diagnostics

Etiological diagnosis of tuberculosis (verification of the diagnosis) is possible in a limited number of children due to the specific clinical forms of tuberculosis and the lack of bacterial excretion.

• All children with suspected tuberculosis based on clinical signs or immunodiagnostic tests (positive tests with recombinant tuberculosis allergen in standard dilution** (CFP-10/ESAT-6 or similar skin test) or alternative tests (see below)) are recommended to undergo chest computed tomography (CT) to establish or rule out the disease [8, 13].

GCR CLOE 5Grade of Recommendation C (Level of Evidence 5)

Comments:

For extrapulmonary tuberculosis (EPTB), computed tomography of the abdominopelvic cavity and retroperitoneum, kidneys and upper urinary tract, spine, joints, and other anatomical regions (depending on the localization of the process), including intravenous bolus contrast-enhanced CT, magnetic resonance imaging of the abdominopelvic cavity and retroperitoneum, kidneys and upper urinary tract, and other anatomical regions (depending on the localization of the process), and ultrasound examination of the abdominopelvic cavity (comprehensive) and retroperitoneum and other anatomical regions, including peripheral lymph nodes (depending on the localization of the process), are used. In bone and joint tuberculosis, magnetic resonance imaging of bone tissue and joints is used for the early detection of abscesses, inflammatory, and necrotic changes [1, 156]. In patients with EPTB, pulmonary tuberculosis must be ruled out using diagnostic imaging methods.

Spiral chest computed tomography (SCT) is the preferred method for confirming or ruling out pulmonary tuberculosis in children, as it has greater diagnostic utility compared to chest radiography [9, 34].

Chest computed tomography is performed for all patients with positive results from the test with recombinant tuberculosis allergen in standard dilution** or alternative tests (in vitro), with symptoms suggestive of tuberculosis regardless of the results of immunological tests; changes on digital chest fluorography or chest radiography, and in febrile patients with HIV infection and immunosuppression.

Chest computed tomography with intravenous bolus contrast enhancement has high diagnostic utility in detecting "small" forms of intrathoracic lymph node tuberculosis. The decision to perform intravenous contrast enhancement is made by the radiologist, who justifies this decision in the research protocol.

Targeted chest radiography (CXR) can be used to diagnose pulmonary tuberculosis in children when CT is not feasible. The overview radiograph may reveal the following signs of tuberculosis: enlargement of the root lymph nodes (wide, poorly structured root without clear contours), foci and infiltration areas in lung tissue, cavities (typically occurring in older children), and pleural or pericardial effusion shadows;

• Children with pulmonary tuberculosis and suspected bronchial involvement are recommended to undergo bronchoscopy (tracheobronchoscopy, videotracheobronchoscopy) with collection of bronchial washings or bronchoalveolar lavage fluid for microbiological (culture) and molecular biological testing for tuberculosis mycobacteria (Mycobacterium tuberculosis complex) to verify the diagnosis [10, 11].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: bronchoscopy (tracheobronchoscopy, videotracheobronchoscopy) is performed in children in cases of:

- presence of clinical symptoms of tracheal and bronchial involvement (obsessive dry cough, bitonal cough);

- presence of radiological signs of bronchial involvement and impaired bronchial patency (hypoventilation or atelectasis of the lung tissue, bronchopulmonary lesion, foci of bronchogenic origin);

- unclear source of bacterial excretion;

- differential diagnosis with other conditions.

Bronchoscopy provides visual information on the condition of the examined target and allows obtaining biopsy material for microbiological, cytological, and histological studies. The most frequently used methods are video-assisted endoscopic techniques (bronchoscopy, thoracoscopy, mediastinoscopy). Currently, video bronchoscopy—an endoscopic examination of the bronchi—is performed more often. During diagnostic bronchoscopy, physicians examine the trachea and major bronchi (up to and including segmental and subsegmental bronchi), and perform various biopsies (tissue and liquid) of the bronchi at various levels, lung tissue, and mediastinal lymph nodes. Endoscopic examination of the trachea and bronchi in young and middle-aged patients is performed under sedation, which requires a preliminary consultation and support from an anesthesiologist-intensivist. In older children and adolescents with a non-severe general condition, tracheobronchoscopy is recommended to be performed using local anesthesia.

For diagnostic purposes, endoscopic methods can be supplemented with a biopsy. Endosonography with puncture biopsy of mediastinal formations, performed using ultrasound-guided bronchoscopes, can be performed. The least complex and safest types of biopsies are bronchial aspirate, brush biopsy, and bronchoalveolar lavage. Material from these biopsy procedures is used for microbiological, molecular-biological, and cytologic studies. Transbronchial needle aspiration biopsies of lymph nodes, including under endosonographic guidance, make it possible to obtain cytologic/histologic material and examine it, including for *M. tuberculosis*. Transbronchial lung biopsy, especially performed under X-ray guidance, can provide material for morphological and microbiological examination. If these methods are ineffective, video-assisted thoracoscopic biopsy of the lymph nodes, lung, and pleura can be used. In case of total obliteration of the pleural cavity, an open biopsy of the lung, lymph nodes, and pleura is justified [99-101].

Comments: the external appearance of the affected organ, the presence of abscesses, fistulas, etc., are clinically evaluated. The standard radiography of the affected area is the baseline method of radiation assessment. To clarify the diagnosis, special techniques are used—radiotomography, CT, MRI. Each of these methods is used according to indications depending on the localization of the process and the diagnostic tasks set. In the presence of abscesses, fistulas, material from previously performed operations or biopsies, bacteriological, cytologic, and/or histologic examination is performed [1,2].

2.5 Other Procedures

2.5.1 Immunodiagnostics

Immunodiagnostics (specific diagnostic tests using Mycobacterium tuberculosis antigens) is performed to detect body sensitization (infection) to Mycobacterium tuberculosis and is the priority method for detecting tuberculosis infection in children.

Main immunodiagnostic preparations: bacterial allergens** (tuberculin purified protein derivative in standard dilution**, whose biological activity is measured in tuberculin units (Mantoux test with 2 TU) [2]; recombinant tuberculosis allergen in standard dilution** (CFP-10-ESAT-6 protein 0.2 µg).

Currently, the intradermal test with tuberculosis allergen (Mantoux test with 2 TU of tuberculin purified protein derivative in standard dilution**) is used to detect infection in children aged up to 7 years inclusive and to select individuals for revaccination with tuberculosis prevention vaccine** (BCG).

In children aged 8 to 17 years (inclusive), an intradermal test with tuberculosis allergen with recombinant tuberculosis allergen in standard dilution** (RTA) is performed to detect tuberculosis (screening).

To detect tuberculosis in children, the results of in vitro tests based on the evaluation of gamma-interferon release by T-lymphocytes (IGRA tests) can be taken into account¹

To form high-risk groups for the development of tuberculosis and diagnose the disease, RTA** [119, 120, 121] or alternative tests are used — testing the blood level of interferon-gamma in response to Mycobacterium tuberculosis complex antigens (IGRA tests) [122].

The use of immunodiagnostic methods can also be used in a comprehensive examination for the diagnosis of tuberculosis [2].

Comments: the action of bacterial allergens** (tuberculin purified protein derivative in standard dilution**) is based on detecting a cellular immune response to Mycobacterium tuberculosis-specific antigens. Upon intradermal administration, bacterial allergens** cause a specific skin reaction, which is a manifestation of delayed-type hypersensitivity. Under conditions of mandatory vaccination with the tuberculosis prevention vaccine**, intradermal tests with tuberculosis allergen to determine the infection rate have relative value. Positive reactions to the intradermal test with tuberculosis allergen may be due to prior vaccination with the tuberculosis prevention vaccine**. Due to the complexity, and sometimes impossibility in the initial stages of observation, of differential diagnosis between infectious and post-vaccination allergy, tuberculosis infection in children is established retrospectively by comparing reactions to the intradermal test with tuberculosis allergen over a number of years, taking into account revaccination with the tuberculosis prevention vaccine**.

Comments: in case of a positive reaction to the intradermal test with tuberculosis allergen with bacterial allergens**, not associated with vaccination, it is necessary to perform an intradermal test with tuberculosis allergen with RTA** or an IGRA test to rule out active tuberculosis infection and determine further examination and management tactics.

Comments: Due to the lack of need for selecting children with an established fact of infectious allergy for tuberculosis revaccination, performing an intradermal test with a tuberculosis allergen using bacterial allergen** in children aged 0 to 7 years is considered inexpedient; for further screening of tuberculosis infection, an intradermal test with a tuberculosis allergen using recombinant tuberculosis allergen (RTA)** may be performed; results of in vitro tests based on the assessment of T-lymphocyte interferon-gamma release (IGRA tests) performed for the purpose of screening (establishing) tuberculosis infection may be taken into account.

Comments: The lack of need to select children over 7 years of age for tuberculosis revaccination and the high frequency of positive reactions to the intradermal test with a tuberculosis allergen using bacterial allergen** in children make its performance in this age group inexpedient. RTA in standard dilution** is a recombinant pCFP-ESAT protein diluted in a sterile isotonic phosphate buffer solution with a preservative (phenol). It contains two components present in virulent strains of Mycobacterium tuberculosis and absent in the vaccine strain of the tuberculosis prevention vaccine** (Registration number: LSR-006435-08). The action of RTA** is based on detecting an immune response to Mycobacterium tuberculosis-specific antigens. Upon intradermal administration, RTA** causes a specific skin reaction in individuals with tuberculosis infection, which is a manifestation of delayed-type hypersensitivity. The technique of performing the intradermal test with RTA** is identical to that of the intradermal test with a tuberculosis allergen using bacterial allergen**. The interpretation of the results of the reaction to the RTA test** is carried out in accordance with the drug instructions leaflet.

• An intradermal test with a tuberculosis allergen with RTA** is recommended as the main method for detecting children in the early stages of an active tuberculosis process and children at high risk of developing the disease [78, 115, 126, 141, 142, 143].

GCR CLEL 5Grade of Recommendations C (Level of Evidence 5).

Comments: an intradermal test with a tuberculosis allergen with RTA** has: 1) maximum high sensitivity (98-100%) – the frequency of positive reactions in individuals with active tuberculosis; 2) maximum high specificity (90-100%) – the frequency of negative reactions in individuals not infected with M. tuberculosis or cured of tuberculosis; 3) absence of a positive reaction associated with vaccination with the tuberculosis prevention vaccine**; 4) minimal frequency of nonspecific allergy manifestations; 5) minimal frequency of excessively strong reactions.

Comments: In vitro diagnostic tests or IGRA tests (Interferon Gamma Release Assay) have been developed, based on the release of IFN-gamma under the influence of specific tuberculosis antigens CFP-10/ESAT-6, etc. These include: a reagent kit for in vitro diagnosis of tuberculosis infection by ELISPOT and ELISA; IFN-gamma release assays have a high prognostic value: individuals with positive results fall ill over the next two years much more often than tuberculin-positive individuals. This is an argument for prioritizing preventive chemotherapy in individuals with positive results of these tests [21-24]. Carrying out these in vitro tests does not involve the administration of drugs into the child's body, which completely excludes, firstly, the possibility of adverse events in the form of allergic reactions in individuals with a burdened allergic history, and secondly, difficulties in interpreting test results in individuals with skin manifestations of allergic diseases and conditions.

A positive result of the intradermal test with a tuberculosis allergen with RTA** and/or in vitro indicates an actively metabolizing population of MBT (multiplying), which requires a more thorough examination to exclude a local form of tuberculosis, in particular, performing chest SCT [36].

It must be taken into account that immunological diagnostic tests in children with HIV infection with a CD4 lymphocyte count of less than 350-200 cells/µl cannot be an informative method for diagnosing tuberculosis, since in almost 90-95% of cases they give a negative result with an established diagnosis of tuberculosis [38, 39].

Comments: Intradermal tests for the diagnosis of tuberculosis infection against the background of immunodeficiency states with impairment of the cellular branch of immunity have no clinical significance in accordance with the pathogenesis of delayed-type allergy in tuberculosis infection. The study of the level of interferon-gamma to Mycobacterium tuberculosis complex antigens in the blood by the ELISPOT method does not depend on immunosuppression, and therefore has proven advantages over other tests in individuals with immunodeficiency diseases and conditions.

¹ Order of the Ministry of Health of the Russian Federation dated April 11, 2025 No. 190n "On Approval of the Procedure and Timeframes for Preventive Medical Examinations of Citizens for the Purpose of Tuberculosis Detection"

2.5.2. Additional studies

• In rare cases, in children with negative immunodiagnostic tests, absence of bacterioexcretion, and radiological pathological formations of the thoracic cavity that cannot be diagnosed by a comprehensive patient examination, it is recommended to perform a biopsy (biopsy of the trachea, bronchi, lungs during bronchoscopy, transthoracic lung biopsy, open lung biopsy, pleural biopsy, lymph node biopsy using video-endoscopic technologies) and subsequent pathomorphological examination of the biopsy (surgical) material of the trachea and bronchi, lung tissues (including using immunohistochemical methods) to verify the diagnosis [69].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Morphological verification of the diagnosis is recommended in cases of differential diagnosis of tuberculosis and proliferative processes in mediastinal lymph nodes or pulmonary tissue.

• For children with complaints of hearing loss and a history of otitis media, before including injectable drugs in the chemotherapy regimen, it is recommended to have an appointment (examination, consultation) with anotorhinolaryngologist with pure-tone and/or speech audiometry to determine the possibility or impossibility of their prescription [84].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Speech audiometry is indicated for all patients with hearing impairment and hearing organ diseases to resolve the issue of the possibility of including aminoglycosides (#amikacin**, kanamycin**) and polypeptides (#capreomycin**) in the chemotherapy (CT) regimen, as these drugs can cause hearing loss (drug instructions). If pathological conditions are identified, injectable drugs are not included in the CT regimen.

• Before including #ethambutol** (up to 13 years old, (see Table 9, Appendix A3)), ethambutol** (13 years and older) in the CT regimen, children are recommended to have an appointment (examination, consultation) with an ophthalmologist to rule out eye pathology and the absence of contraindications for its prescription [84].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Eye diseases with decreased visual acuity are a contraindication for prescribing the anti-tuberculosis drug #ethambutol** (drug instructions).

• During the treatment of children with respiratory tuberculosis, it is recommended to perform follow-up tests in order to monitor the efficacy and tolerability of anti-tuberculosis drugs and systemic antibacterials [84].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: During chemotherapy, to prevent adverse reactions, clinical, laboratory, and instrumental monitoring is carried out: complete blood count, urinalysis, general clinical blood biochemistry; electrocardiography, chest radiography, and computed tomography of the thoracic cavity [13,44,83]. Frequency of examinations: Appendix B, Table 11.

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

3.1. Chemotherapy

Chemotherapy is the main treatment method for tuberculosis, consisting of the long-term administration of medications regardless of the localization of the process, aimed at suppressing the reproduction of Mycobacterium tuberculosis (bacteriostatic effect) or destroying M. tuberculosis in the patient's body (bactericidal effect).

Treatment of intrathoracic lymph node tuberculosis is carried out according to the same principles as respiratory tuberculosis.

A chemotherapy regimen is a combination of anti-tuberculosis drugs and systemic antibacterials, the duration and frequency of their administration, the timing and content of follow-up tests, as well as the organizational forms of treatment delivery.

The chemotherapy regimen (CTR) is determined based on the drug susceptibility testing results of Mycobacterium tuberculosis isolated from pathological material, or on anamnesis data if such results are absent [13, 19, 44, 25, 40, 83].

Anti-tuberculosis drugs and systemic antibacterials are prescribed in therapeutic doses appropriate for the child's age and body weight (Appendix A3, Table 8).

Chemotherapy (CT) is carried out in 2 phases:

1. intensive phase of therapy – CT is aimed at eliminating the clinical manifestations of the disease, maximizing the effect on the MTB population in order to stop the reproduction of mycobacteria and prevent the development of drug resistance, and reducing infiltrative and destructive changes;

2. continuation phase – CT aimed at suppressing the persisting mycobacterial population, ensuring further reduction of inflammatory changes and involution of the tuberculous process, as well as restoring the body's functional capabilities.

Drugs used in tuberculosis chemotherapy are subdivided into:

1. first-line anti-tuberculosis drugs (primary, drugs of choice for treating tuberculosis caused by drug-susceptible mycobacteria):

   - isoniazid** (in accordance with the drug's prescribing information),

   - rifampicin** (in accordance with the drug's prescribing information), rifapentine is used from 12 years of age in capsules at 10 mg/kg of body weight 2-3 times/week (see Table 9, Appendix A3);

   - pyrazinamide** – used in tablets from 3 years of age in accordance with the drug's prescribing information, 15-20 mg/kg;

   - ethambutol** – used from 13 years of age at 15-25 mg/kg/day in accordance with the instructions (see Table 9, Appendix A3),

   (for the route of administration of rifapentine**, pyrazinamide**, ethambutol**, drug dose, and duration of use in children, see Appendix A3, Table 9);

2. second-line anti-tuberculosis drugs (reserve drugs, drugs of choice for treating multidrug-resistant tuberculosis): kanamycin**, #amikacin**, #capreomycin**, #levofloxacin**, #moxifloxacin**, #linezolid**, #bedaquiline** #delamanid**, #prothionamide**, #ethionamide**, #cycloserine** #terizidone**, aminosalicylic acid**; #clofazimine, #pretomanid (for the route of administration of #bedaquiline**, #delamanid**, #terizidone**, #clofazimine, and #pretomanid, drug doses, and duration of use in children, see Appendix A3, Table 9);

   other anti-tuberculosis drugs and systemic antibacterials recommended for the treatment of MDR/XDR-TB in cases where a chemotherapy regimen cannot be formed from a minimum of four effective drugs: #imipenem+[cilastatin]**, #meropenem**, #amoxicillin+clavulanic acid** (for the route of administration, drug dose, and duration of use in children, see Appendix A3, Table 9);

In consolidated WHO guidelines for the treatment of drug-resistant tuberculosis, drugs for MDR-TB treatment are divided into three groups (A, B, C) according to their probable efficacy and safety [47, 84]:

• Group A: #levofloxacin**/#moxifloxacin**, #bedaquiline**, #linezolid**;

• Group B: #cycloserine**/#terizidone**; #clofazimine (#clofazimine is an antileprosy drug, poorly studied in children for tuberculosis treatment);

• Group C: #ethambutol**, #pyraminamide**, #delamanid**, #imipenem+[cilastatin]**, #meropenem**, #amikacin** #ethionamide**/#prothionamide**, aminosalicylic acid**. Group A: Drugs are recognized as highly effective, safe, and strongly recommended for inclusion in all CT regimens for MDR-TB treatment unless contraindicated;

Group B: conditionally recommended as second-choice drugs to build a complete CT regimen;

Group C: all other drugs that may be used when the CT regimen cannot be composed of Group A and B drugs.

Chemotherapy for tuberculosis is prescribed according to the following regimens (Appendix A3, Table 9).

• treatment regimen for drug-susceptible tuberculosis;

• treatment regimen for isoniazid-resistant tuberculosis;

• treatment regimen for MDR-TB;

• treatment regimen for pre-XDR-TB;

• treatment regimen for XDR-TB;

CT regimens:

Comments: The following patient groups are eligible for treatment with the drug-susceptible tuberculosis CTR:

- patients with newly diagnosed tuberculosis with bacterial excretion detected by microscopy or culture prior to obtaining pathogen drug susceptibility testing (DST) results, without clinically established MDR-TB;

- patients with a tuberculosis relapse with bacterial excretion prior to obtaining drug susceptibility test results, if during the previous course of treatment M. tuberculosis susceptibility to isoniazid** and rifampicin** was preserved or not determined;

- patients with established M. tuberculosis susceptibility to isoniazid** and rifampicin** (according to drug susceptibility testing data from the start of the current course of chemotherapy or molecular-genetic testing data prior to obtaining pathogen drug susceptibility results by the culture method on liquid or solid media);

- patients without bacterial excretion and without clinically established MDR-TB (from contact with an index case whose M. tuberculosis was susceptible to isoniazid** and rifampicin**, or whose drug susceptibility was not determined);

Comments: if drug resistance of the pathogen to isoniazid** is established while susceptibility to rifampicin** is preserved, a chemotherapy regimen for isoniazid-resistant tuberculosis is prescribed; if pathogen resistance to rifampicin** and isoniazid**, or to rifampicin** alone, is established while drug susceptibility to any fluoroquinolone is preserved, a chemotherapy regimen for multidrug-resistant tuberculosis (MDR-TB) is prescribed; if drug resistance of the pathogen to isoniazid**, rifampicin**, and any fluoroquinolone is established, a treatment course according to the pre-XDR-TB chemotherapy regimen is prescribed; if $M.$ tuberculosis drug resistance to rifampicin** and isoniazid**, or to rifampicin** alone, is combined with resistance to fluoroquinolones and any other Group A drug (#bedaquiline**, #linezolid**), a treatment course according to the XDR-TB chemotherapy regimen is prescribed (see the section on treatment of drug-resistant TB).

Comments: The criteria for clinically established MDR-TB in children are considered to be:

- patients with a reliable contact history with a patient suffering from MDR-TB (MDR $M.$ tuberculosis in the probable source of infection must be documented);

- the presumed source of infection has a chronic destructive pulmonary process (fibrocavernous tuberculosis), or has previously undergone 2 or more ineffective courses of chemotherapy with no $M.$ tuberculosis drug resistance data available;

- tuberculosis relapse;

- other cases of retreatment;

- appearance of negative clinical and radiological dynamics in a patient undergoing chemotherapy for drug-susceptible tuberculosis in the absence of bacteriological excretion and the inability to determine $M.$ tuberculosis drug susceptibility.

(drug dosages are presented in Table 8, Appendix A3).

3.1.1 Chemotherapy regimen for drug-susceptible tuberculosis

Comments: During the intensive phase of chemotherapy, patients with newly diagnosed tuberculosis must take at least 60 daily doses (2 months) of a combination of 4 first-line antituberculosis drugs (at least 3 if #ethambutol** cannot be prescribed);

patients from the groups "After interruption of a chemotherapy course", "Tuberculosis relapse", and "Other retreatment cases" must take at least 90 daily doses (3 months).

During the continuation phase of therapy, patients with newly diagnosed tuberculosis must take at least 120 doses (4 months), and patients from the groups "After interruption of a chemotherapy course", "Tuberculosis relapse", and "Other retreatment cases" must take at least 150 doses (5 months) [13, 44, 83].

By decision of the medical panel (central medical panel), the intensive phase of therapy may be extended up to 120 or 150 daily doses in cases of disseminated and complicated tuberculosis, with confirmed or suspected $M.$ tuberculosis susceptibility to isoniazid** and rifampicin**.

The duration of treatment with the drug-susceptible tuberculosis chemotherapy regimen may be extended to 9-12 months (in severe, disseminated, and generalized cases, including meningitis, with preserved $M.$ tuberculosis susceptibility to isoniazid** and rifampicin** or in the absence of MDR-TB risk).

Comments: Children and adolescents with limited drug-susceptible TB are prescribed 4 ATDs (at least 3 ATDs) in the intensive phase (2 months) and 2 ATDs in the continuation phase (2 months).

Criteria for limited forms of TB:

- TB of intrathoracic lymph nodes (ITLN) stages 1-2;

- ITLN TB at the stage of regression (formation of small residual changes);

- foci within 1-2 lung segments;

- uncomplicated TB.

Combinations of antituberculosis drugs (chemotherapy regimens):

Comments: if it is impossible to prescribe ethambutol**/#ethambutol**, the intensive-phase chemotherapy regimen may consist of three drugs: isoniazid**, rifampicin**, pyrazinamide**/#pyrazinamide** [84].

Comments: Administration of medications in both the intensive and continuation phases must be daily. By decision of the medical commission (VK), ethambutol**/#ethambutol** may be used in both 6-month and 4-month chemotherapy regimens during the intensive phase.

Comments: The 4-month treatment regimen (2 months of isoniazid**, rifampicin**, pyrazinamide**, and (optionally) #ethambutol**, followed by 2 months of isoniazid** and rifampicin**) is not inferior in efficacy to the standard 6-month regimen [84, 157]

Comments: The use of FDCs is possible in children; they are prescribed in accordance with the product instructions: two-component combination drugs with pediatric dosages. Taking combination drugs implies a reduction in the number of tablets and does not require tablet splitting (breaking).

Comments: If drug resistance of MBTs is detected during treatment, the patient is transferred to an appropriate chemotherapy regimen depending on the spectrum of pathogen resistance to specific drugs.

Table 1 shows treatment regimens for drug-susceptible TB depending on the severity and extent of the process (combination of anti-tuberculosis drugs, duration)

Table 1. Treatment regimens for drug-susceptible TB

* the following standard abbreviations are used for drugs: H – isoniazid**, R – rifampicin**, Z – pyrazinamide**, E – #ethambutol**, S – streptomycin**; Mfx – #moxifloxacin**. The number preceding the designation of the coded components of each phase corresponds to the duration of this phase in months (e.g., the 2HRZE regimen implies treatment with isoniazid**, rifampicin**, pyrazinamide**, and #ethambutol** for 2 months).

¹ – for newly diagnosed patients with respiratory tuberculosis;

² – for patients with respiratory tuberculosis from the groups "after interruption of a chemotherapy course", "tuberculosis relapse", or other cases of re-treatment;

³ – for tuberculous meningitis, osteoarticular tuberculosis, and disseminated tuberculosis.

Table 2. Doses of anti-tuberculosis drugs for the treatment of drug-susceptible TB (product instructions)

* higher values from the isoniazid dose range** apply to young children with meningitis.

3.1.2 Chemotherapy regimen for isoniazid-resistant tuberculosis

Isoniazid-resistant tuberculosis (Hr-TB), caused by isoniazid-resistant** and rifampicin-susceptible** strains of Mycobacterium tuberculosis complex

Comments: The duration of chemotherapy treatment can be extended beyond 6 months (by decision of the medical commission) in the following cases:

- with positive results of microscopy and/or culture studies after taking 60-90 doses of medications;

- MTB polyresistance (with preserved susceptibility to rifampicin);

- in the absence of positive radiological dynamics after taking 60-90 doses, regardless of MTB sputum test results;

- in case of extensive and/or destructive process [13, 44, 83].

The duration of treatment for patients in these cases can be increased to 9-12 months.

• Transfer of patients with extensive and/or destructive respiratory tuberculosis to the continuation phase is recommended to be carried out after completing 90-120 doses of the intensive phase drug combination, upon obtaining negative microscopy and culture results and positive clinical and radiological dynamics of the process, for the purpose of cure [13, 44, 83].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Combinations of anti-tuberculosis drugs (CT regimens)

Comments: in cases where resistance to isoniazid** is combined with resistance to other drugs (polyresistance, but not MDR) and the process is extensive, the CT regimen in the intensive phase may consist of 5 anti-tuberculosis drugs (at least 4 effective ones) for 3-4 months, followed by a continuation phase of 3 anti-tuberculosis drugs for up to 9-12 months [13, 44, 83, 84].

If rifampicin** resistance is detected in a patient, one should switch to the MDR-TB treatment regimen (see the following sections).

Comments:

Chemotherapy regimen: the duration of the REZ regimen with #levofloxacin** is usually 6 months (6REZLfx), i.e., completion of the chemotherapy course) [44, 139].

Comments: ideally, resistance to fluoroquinolones (and, if possible, to pyrazinamide**) should be similarly ruled out before starting treatment.

Comments: if subsequent DST results indicate susceptibility to isoniazid**, #levofloxacin** is discontinued, and the patient undergoes treatment with the HREZ/HR regimen. Patients in whom Hr-TB is detected after the start of the HREZ regimen must continue taking the drugs included in the REZ regimen, while #levofloxacin** should be added after ruling out rifampicin resistance.

3.1.3 Chemotherapy regimen for MDR tuberculosis

Treatment of MDR-TB can be carried out using short and long chemotherapy regimens: for 6 months, 9 months, and 18–20 months. The regimen is determined by a medical commission decision and depends not only on *M. tuberculosis* drug resistance and susceptibility, but also on the extent of the specific process, the presence of complications and comorbidities, and treatment tolerability.

Comments: long MDR-TB treatment regimens refer to treatment courses lasting 18–20 months, which may be standardized or individualized [44, 84, 139].

Comments: A short treatment regimen for MDR/RR-TB is basically a standardized, all-oral (without an injectable drug) course of MDR-TB treatment lasting 6 or 9 months, including #bedaquiline** [48–50, 139].

Comments: A short MDR-TB treatment regimen is basically a standardized, all-oral (without an injectable drug) course of MDR-TB treatment lasting 6–9 months, including #bedaquiline** [48–50, 139]. Long MDR-TB treatment regimens refer to treatment courses lasting more than 9 months [44, 84, 139].

Comments: Group A drugs are prioritized, followed by Group B and, if necessary, a drug from Group C with proven or suspected drug susceptibility of the pathogen.

Short 9-month MDR-TB chemotherapy regimen in children

Comments: the short 9-month chemotherapy regimen is administered to tuberculosis patients with multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB) provided that [44, 84, 139]:

- resistance of M. tuberculosis to fluoroquinolones has been ruled out or susceptibility to fluoroquinolones is suspected;

- they have not received treatment with the second-line antituberculosis drugs used in this regimen for more than 1 month or M. tuberculosis susceptibility to these drugs is preserved;

By decision of the medical panel, the intensive phase may be extended up to 5 months, and the total course of chemotherapy up to 12 months.

Comments: #Bedaquiline** (for the route of administration, dose of #bedaquiline**, and duration of use in children, see Appendix A3, Table 9) is a core drug (in the absence of contraindications) in the short-course chemotherapy regimen. #Bedaquiline** is prescribed for a duration of 6 months, or for more than 6 months by decision of the medical panel; #bedaquiline** may be used in children of any age [44, 84, 139].

Comments: the treatment regimen in children is usually supplemented with #levofloxacin** due to the slightly higher risk of cardiotoxicity with #moxifloxacin**; regardless of the chosen fluoroquinolone, active safety monitoring of fluoroquinolone use together with #bedaquiline** must be performed

Short 6-month chemotherapy regimen

Comments:

Chemotherapy regimen: Bq-Pa-Lzd-Mfx

If clinical dynamics are delayed, treatment can be extended up to 9 months.

Comments:

Chemotherapy regimen: Bq-Pa-Lzd

If clinical dynamics are delayed, treatment can be extended up to 9 months.

Comments:

CT regimen: Bdq Lzd Lfx Dlm (alternative to the BPaL(M) regimen).

If clinical dynamics are delayed, treatment can be extended up to 9 months.

Long-term MDR-TB chemotherapy regimen

Comments: When designing the treatment regimen, priority should be given to Group A and B drugs.

Comments: Long-term MDR-TB treatment regimens with a sufficient number of effective drugs increase the likelihood of clinical cure and reduce the risk of tuberculosis relapse [44, 59].

By decision of the medical panel, the intensive phase and the overall course of chemotherapy can be shortened (to 15-17 months) in cases of favorable positive clinical and radiological dynamics of the process and negative sputum test results for M. tuberculosis.

• If it is impossible to construct a chemotherapy regimen from the aforementioned drugs or if certain drugs cannot be used, it is recommended to use the following drugs to form a complete regimen: ethambutol**/#ethambutol** (15-25 mg/kg/day), pyrazinamide**/#pyrazinamide** (30-40 mg/kg/day), aminosalicylic acid** (200-300 mg/kg/day), #delamanid** (25 mg twice daily (weight >10 kg and <16 kg); 50 mg in the morning and 25 mg in the evening (weight ≥16 kg, <30 kg); 50 mg twice daily (weight <35 kg); 100 mg twice daily (weight ≥35 kg)) (for the route of administration, dosage of #ethambutol**, #pyrazinamide**, and #delamanid**, and duration of use in children, see Appendix A3, Table 9) (Group C drugs) [84].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• The drug #amikacin** (15-25 mg/kg/day) (for the route of administration and dosage of #amikacin** and #capreomycin**, and duration of use in children, see Appendix A3, Table 9), provided that $M.$ $$ tuberculosis$ susceptibility to them is preserved, is recommended to be prescribed in individual cases, when it is impossible to form a complete chemotherapy regimen from other drugs, by decision of the medical panel (VKK) for the purpose of achieving a cure [83, 84].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments:

An injectable drug is prescribed in the intensive phase by decision of the medical panel (VKK) for a period of not more than 3 months. Injectable drugs are prescribed with caution in children, especially of early age, due to frequent adverse events associated with these drugs [44].

Comments: It is undesirable to add #bedaquiline** to an ineffective chemotherapy regimen (persistence of bacteriological excretion, negative clinical and radiological dynamics of the process) or when susceptibility to two or fewer anti-TB drugs is preserved; by decision of the medical panel (VKK) based on vital indications, the duration of treatment with #bedaquiline** may be increased; simultaneous administration with #levofloxacin** is possible [66] (for the route of administration, dosage of #levofloxacin**, #moxifloxacin**, #bedaquiline**, #linezolid, #terizidone**, #ethambutol**, and #capreomycin**, and duration of use in children, see Appendix A3, Table 9).

Comments: #Delamanid** can be included in the chemotherapy regimen for children of any age for 6 months by decision of the medical panel (VKK) (for the route of administration, dosage of #delamanid**, and duration of use in children, see Appendix A3, Table 9) [84].

Comments: Transition to the continuation phase is made after the successful completion of the intensive phase, manifested by positive clinical and radiological dynamics and the absence of bacteriological excretion. If the duration of the intensive therapy phase is 4 months, administration of #bedaquiline** (for the route of administration, dosage of #bedaquiline, and duration of use in children, see Appendix A3, Table 9) should be continued up to six months.

Comments: Tuberculous meningitis is a severe form of extrapulmonary MDR/RR-TB and requires prolonged treatment. Treatment of meningitis should take into account the ability of drugs to cross the blood-brain barrier and the resulting concentrations in the cerebrospinal fluid (CSF) (Table 3). It is desirable that the treatment regimen includes at least 3 TB drugs with good CSF penetration. The addition of #bedaquiline** is possible in the presence of pulmonary disease combined with CNS involvement (for the route of administration, dosage of #levofloxacin**, #moxifloxacin**, #bedaquiline**, #linezolid, #terizidone**, and duration of use in children, see Appendix A3, Table 9).

3.1.4 Chemotherapy regimen for pre-XDR tuberculosis

Pre-XDR-TB – Multidrug-resistant tuberculosis (MDR/RR-TB) with additional resistance to fluoroquinolones.

Comments: The duration of the chemotherapy regimen for pre-XDR-TB can be extended by decision of the medical commission up to 15–18 months, depending on the severity of the process and clinical-radiological dynamics.

Drug Combinations (Chemotherapy Regimens)

Comments: #Bedaquiline** and #delamanid** (for the route of administration, dosage of #bedaquiline** and #delamanid**, and duration of use in children, see Appendix A3, Table 9) have demonstrated efficacy and safety in combination when treating multidrug-resistant tuberculosis in children, including those with additional resistance to fluoroquinolones [50].

By the decision of the medical commission, the administration of bedaquiline** by patients after six months may be continued (taking into account the resistance of MBT to fluoroquinolones or intolerance to linezolid** (for the route of administration, dose of linezolid**, and duration of use in children, see Appendix A3, Table 9)) [84].

The duration of therapy with delamanid** (for the route of administration, dose of delamanid**, and duration of use in children, see Appendix A3, Table 9) is 6 months.

Comments: Linezolid** is a Group A medication; in MDR/RR-TB with additional resistance to fluoroquinolones, the duration of linezolid** use can be increased to 6–9 months or more, if the absence or intensity of adverse reactions permits [84].

Comments: The use of fluoroquinolones is possible if drug susceptibility of the pathogen to one of them is preserved.

In the continuation phase of the pre-XDR tuberculosis chemotherapy regimen, it is necessary to prescribe a combination simultaneously including at least 3-4 effective antituberculosis drugs and antibiotics with preserved or suspected drug susceptibility of the pathogen to increase treatment efficacy.

CT regimens:

Bdq* is prescribed for 6 months; by the decision of the medical commission, it can be extended for more than 6 months.

Dlm** is prescribed for 6 months

Short 6-month chemotherapy regimen

Comments:

- chemotherapy regimen for 6 months: #Bdq**-#Pa-Lzd**-#Mfx** – standardized treatment regimen

- chemotherapy regimen for 6 months: #Bdq**-#Pa-#Lzd** (can be extended up to 9 months)

Comments:

Chemotherapy regimen: #Bdq** #Lzd** #Cfz #Dlm** (alternative to the BPaL(M) regimen).

In case of drug resistance of M. tuberculosis to fluoroquinolones, #clofazimine is included in the chemotherapy regimen. If the response is delayed, treatment can be extended up to 9 months.

3.1.5 Chemotherapy regimen for XDR tuberculosis

XDR-TB – tuberculosis caused by M. tuberculosis complex strains with extensively drug resistance

Comments: Chemotherapy according to the XDR-TB regimen is prescribed to children when the patient has confirmed XDR M. tuberculosis, or from contact with a tuberculosis patient with proven extensively drug-resistant M. tuberculosis.

The total duration of treatment can be modified in accordance with the patient's response to therapy: the duration of treatment for patients with limited uncomplicated processes and good positive dynamics can be reduced to 15–17 months [44].

Drug Combinations (Chemotherapy Regimens)

• To the core drugs for the treatment of XDR-TB, it is recommended to add, taking into account drug susceptibility: #delamanid** (25 mg 2 times/day for weight >10 kg and <16 kg; 50 mg in the morning and 25 mg in the evening for weight ≥16 kg, <30 kg; 50 mg 2 times/day for weight <35 kg; 100 mg 2 times/day for weight ≥35 kg), cycloserine** for children over 3 years old according to instructions / #cycloserine** (15-20 mg/kg/day for weight from 7 to 30 kg, 10-15 mg/kg/day for weight of 30 kg and more) or #terizidone** (15-20 mg/kg/day for weight from 7 to 30 kg, 10-15 mg/kg/day for weight of 30 kg and more), #amikacin** (15-25 mg/kg/day) (if susceptibility is preserved), pyrazinamide**/#pyrazinamide** (under 3 years old) (30-40 mg/kg), ethambutol**/#ethambutol** under 13 years old (15-25 mg/kg/day), prothionamide**/#prothionamide** under 3 years old (15-20 mg/kg/day) / ethionamide**/#ethionamide** under 3 years old (15-20 mg/kg/day) (for the route of administration, dosage of #delamanid**, #terizidone**, #amikacin**, #ethambutol**, and duration of use in children, see Appendix A3, Table 9) [44, 84].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• If it is impossible to assemble a regimen from the 5 aforementioned drugs, it is recommended to include the following drugs in the treatment regimen: aminosalicylic acid**; #meropenem** (20-40 mg/kg every 8 hours) / #imipenem+[cilastatin]** (15 mg/kg/day) in combination with #amoxicillin+clavulanic acid** (20-45 mg/kg (calculated as amoxicillin**)) (for the route of administration, dosage of #meropenem**, #imipenem+[cilastatin]**, #amoxicillin+clavulanic acid**, #capreomycin**, and duration of use in children, see Appendix A3, Table 9) to increase treatment efficacy [41, 67, 68, 84].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments:

The use of #bedaquiline** is not permitted in ineffective chemotherapy regimens (persistence of bacterial excretion, negative clinical and radiological dynamics of the process) or when *M. tuberculosis* susceptibility is preserved to only two or fewer antituberculosis drugs; it is used for 6 months, and by decision of the medical commission for health reasons, the duration of treatment with #bedaquiline** (for the route of administration, dosage of #bedaquiline**, and duration of use in children, see Appendix A3, Table 9) may be extended (Table 4 shows treatment regimen options for XDR-TB).

• When prescribing chemotherapy to tuberculosis patients under any chemotherapy regimen, it is recommended to monitor adverse reactions to antituberculosis drugs and manage them in order to control the development of adverse events and correct them. Adverse drug reactions of the applied chemotherapeutic agents are one of the most frequent causes of treatment interruption, switching to individualized regimens, and/or patient refusal of treatment [44, 84].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

3.2. Surgical treatment

Comments: The issue of the feasibility and timing of surgical intervention is decided by the medical commission with the participation of a phthisiatrician, a surgeon, and an anesthesiologist-resuscitologist (with the consent of the parents/legal representative) before the start of chemotherapy and during the chemotherapy period.

Basic principles of the optimal combination of chemotherapy and surgical treatment:

In active respiratory tuberculosis, chemotherapy prior to elective surgery must continue for at least 6 months (in isolated cases, 4 months), and in the case of tuberculoma, for at least 2 months.

The chemotherapy regimen must remain uninterrupted, except for the first one or two days of the early postoperative period.

In the postoperative period, the intensive phase of therapy is continued or resumed, the duration of which is determined by the medical commission.

The duration of postoperative chemotherapy must be at least 3 months for tuberculosis with preserved pathogen drug susceptibility, 6 months in the presence of mono- or poly-resistance of *M. tuberculosis*, and at least 6-12 months for MDR/pre-XDR/XDR-TB. If the pathogen's drug susceptibility is unknown, the duration of postoperative chemotherapy must be at least 6 months.

The total duration of chemotherapy for a patient suffering from tuberculosis is determined by the chemotherapy regimen in accordance with the pathogen's drug susceptibility test results, including results from surgical material.

3.3. Other treatment

3.3.1 Collapsotherapy

Controlled collapse involves creating protective conditions for the affected organ or part of it by reducing the elastic tension of the lung and partially bringing the cavity walls closer together, and also promotes visceral-visceral reflexes leading to a decrease in the tone of the elastic and smooth muscle elements of the lung, which facilitates the healing of destruction cavities and makes the patient sputum-negative.

Comments: methods of collapse therapy include:

Artificial pneumothorax (AP) is a method of treating pulmonary tuberculosis consisting of the introduction of air through a needle into the chest cavity between the parietal and visceral pleura.

Pneumoperitoneum (PP) is a method of treating pulmonary tuberculosis consisting of the introduction of air through a needle into the abdominal cavity.

Endobronchial valve placement (EBP) is a method of creating therapeutic hypoventilation in the affected area of the lung while preserving the drainage function of the bronchus by placing an endobronchial valve (EBV) into its lumen.

Comments: AP is prescribed strictly according to indications with mandatory consultation by a thoracic surgeon. Contraindications to AP are:

1. Clinical forms of tuberculosis: caseous pneumonia, cirrhotizing pulmonary tuberculosis, exudative and adhesive pleurisy on the side of AP administration.

2. Cavities: larger than 6 cm, located in cirrhotic areas of the lung adjacent to the pleura.

3. General contraindications: active bronchial tuberculosis on the affected side; active bronchial inflammation of any etiology; grade 2-3 bronchial stenosis; pulmonary emphysema; grade II-III respiratory failure; broncho-obstructive syndrome;

Comments: during pneumoperitoneum, the gas introduced into the abdominal cavity causes a viscero-visceral reflex, lung collapse, elevation of the diaphragm, enhancement of costodiaphragmatic respiration, increased lymph flow, improved blood circulation, and intensification of oxidative processes.

Contraindications to pneumoperitoneum:

1. obliteration of the draining bronchus during cavity healing and formation of a "blocked" cavity;

2. miliary tuberculosis;

3. grade II-III respiratory failure;

4. inflammatory changes in the abdominal cavity, umbilical hernias, inguinal hernias, overstretched abdominal wall muscles;

5. active tuberculosis of the pelvic organs;

6. early postoperative period following abdominal surgery.

Comment: the valve bronchoblockade technology is used to treat thin-walled cavities and decay cavities without prominent perifocal infiltration in disseminated, cavitary, and fibro-cavitary tuberculosis. The method is based on creating therapeutic hypoventilation in the affected area of the lung (local lung collapse) while preserving drainage function, which is achieved by placing an endobronchial valve (EBV) into the lumen of the draining bronchus (segmental and larger).

Contraindications to valve bronchoblockade: inflammatory bronchial diseases, cicatricial bronchial stenosis [1, 41, 70].

3.4. Preventive treatment (chemoprophylaxis)

Comments: Preventive treatment is the use of antituberculosis drugs in individuals without signs of tuberculosis, but with a high risk of its development, to reduce the likelihood of developing the disease.

Tuberculosis infection (TI) is a state of persistent immune response caused by

the presence of Mycobacterium tuberculosis in the human body, resulting in a positive reaction to bacterial allergens**, unrelated to vaccination, in the absence of clinical and radiological signs of tuberculosis disease.

There is no "gold standard" of diagnostics that allows direct detection of Mycobacterium tuberculosis infection in humans. The vast majority of infected individuals have no signs or symptoms of tuberculosis, but are at risk of developing its active form [84, 130]. The state of Mycobacterium tuberculosis infection (without signs of activity) can be determined if the immune response is confirmed solely by immunodiagnostics using an intradermal test with a tuberculosis allergen (with bacterial allergens** (Mantoux test with 2 TU)), with negative results for more modern tests: laboratory interferon-gamma release assays (IGRA tests), intradermal test with a tuberculosis allergen (recombinant tuberculosis allergen at standard dilution**). Conversely, a positive response to the blood test for interferon-gamma levels against Mycobacterium tuberculosis complex antigens (IGRA tests) and the intradermal test with a tuberculosis allergen (with recombinant tuberculosis allergen**), along with a response to the intradermal test with a tuberculosis allergen with bacterial allergens**, may indicate the activity of tuberculosis infection (latent tuberculosis infection) and thus determine the indications for prescribing preventive antituberculosis treatment [153, 154].

• Before prescribing preventive treatment, it is recommended to test for tuberculosis infection to determine the indications for its implementation [84, 130].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: to detect tuberculosis infection and latent tuberculosis infection, an intradermal test with a tuberculosis allergen (with bacterial allergens**, with recombinant tuberculosis allergen** and/or blood interferon-gamma assay in response to specific tuberculosis antigens (IGRA test) is used.

Children with HIV infection; children receiving immunosuppressive therapy; and malnourished children with severe illness may have a negative result on any test, which does not rule out the presence of tuberculosis infection or tuberculosis disease in such children.

Preventive treatment is indicated for (provided tuberculosis is ruled out – see section 2 – diagnostics):

- children and adolescents with positive reactions to recombinant tuberculosis allergen** or alternative in vitro tests (IGRA) (children with latent tuberculosis infection);

- children and adolescents who are contacts of tuberculosis patients;

- children and adolescents with HIV infection in the presence of immunodeficiency, regardless of the results of immunodiagnostic tests;

- children and adolescents initiating immunosuppressant therapy (selective immunosuppressants, genetically engineered biologic drugs (tumor necrosis factor-alpha (TNF-alpha) inhibitors, interleukin inhibitors, etc.)), undergoing dialysis, preparing for organ or bone marrow transplantation, regardless of the results of immunodiagnostic tests;

Indications for preventive chemotherapy in patients receiving genetically engineered biologic drugs:

• tuberculosis infection (positive intradermal test with a tuberculosis allergen with bacterial allergens** (Mantoux) provided that preventive chemotherapy has not been administered previously or was administered 2 or more years ago;

• latent tuberculosis infection with a positive intradermal test with a tuberculosis allergen with recombinant tuberculosis allergen** or a positive blood interferon-gamma assay result in response to specific tuberculosis antigens, regardless of previously administered preventive chemotherapy;

• presence of post-tuberculosis changes in individuals who have had tuberculosis and have been clinically cured during comprehensive treatment, or a history of past active tuberculosis of any localization, regardless of prior antituberculosis treatment;

• history of contact with a tuberculosis patient.

Preventive antituberculosis chemotherapy is not a contraindication for treatment with genetically engineered biologic drugs.

Preventive antituberculosis chemotherapy is performed once, and subsequently as indicated by the decision of the medical commission.

Comments: The efficacy of currently available tuberculosis preventive treatment regimens is 60-90% [84]. Repeated courses of preventive treatment are prescribed as indicated (depending on the situation, e.g., in HIV infection) by the decision of the medical commission.

Comments: Treatment of tuberculosis infection can be arbitrarily divided into two categories: 1) isoniazid** monotherapy for 6 or 9 months; 2) a shortened preventive treatment regimen based on #rifampicin**, provided that the specific Mycobacterium tuberculosis strain is susceptible to these drugs.

Treatment for 3 months with isoniazid** (5–15 mg/kg/day) and #rifampicin** (10–20 mg/kg/day) (for the route of administration, drug dose of #rifampicin**, and duration of use in children, see Table 6) (3HR) is the preferred option for preventive treatment. For children living with HIV, isoniazid** for 6 months (6H) remains the primary option (taking into account the compatibility of antiretroviral and antituberculosis drugs) [84].

Preventive treatment regimens and drug dosages are presented in Table 5 and Table 6, respectively.

Comments: In newly diagnosed post-tuberculosis residual changes (dispensary observation group VIb), dispersible FDC can be prescribed by decision of the medical commission (VK).

Comments: A side effect of long-term treatment with isoniazid** is peripheral neuropathy, which develops due to vitamin B6 (pyridoxine) deficiency during treatment. If there is a risk of developing peripheral neuropathy (in individuals with malnutrition, HIV infection, renal failure, diabetes mellitus, etc.), it is necessary to additionally prescribe #pyridoxine (vitamin B6) for the duration of the course of therapy (5–10 mg daily for children under five years of age; 25 mg daily for children over five years of age) [84, 130].

Comments: Preventive treatment for children exposed to patients with MDR-TB is prescribed based on the drug susceptibility and resistance profile of Mycobacterium tuberculosis (M.tb) in the presumed source case [84, 139].

By decision of the medical commission, under strict supervision by a medical worker (in sanatoriums, rehabilitation centers, or via video-assisted directly observed therapy), preventive treatment in children exposed to patients with MDR-, pre-XDR-, and XDR-TB may be carried out using antituberculosis drugs to which M.tb from the presumed source has proven drug susceptibility, taking tolerability into account.

In cases of subtotal (total) drug resistance of M.tb in the source of infection, children are subject to isolation from the focus of infection and follow-up observation.

Comments: Possible adverse reactions to antituberculosis drugs and their management are presented in Appendix A, Tables 7 and 8. The effectiveness of preventive treatment is assessed by chest computed tomography (CT) every 6 months for 2 years.

Table 5. Options for tuberculosis preventive treatment (TPT) regimens

Note: 1HP – one month of daily isoniazid** and #rifapentine; 3HP – three months of weekly isoniazid** and #rifapentine; 3HR – three months of daily isoniazid** and #rifampicin**; 6H – six months of daily isoniazid**; FDC – fixed-dose combination drug.

Table 6. Drug dosages for recommended preventive treatment regimens [84].

¹ In children > 13 years old with the 1HP regimen: 600 mg/day

² In children > 14 years old with the 3P regimen: 13–30 mg/kg/day

3.5. Pathogenetic and symptomatic therapy

Comments: Pathogenetic and symptomatic therapy is a component of the comprehensive treatment of patients with tuberculosis and aims to increase its effectiveness. A mandatory condition for prescribing any method of pathogenetic therapy is its administration against the background of ongoing chemotherapy. The choice of pathogenetic therapy agent (method) must be justified, taking into account the child's age, the phase of the process, and existing functional impairments.

Comments: the main adverse reactions, as well as algorithms for their prevention and management, are described in Appendix A3.

Diet therapy

By Order of the Ministry of Health and Social Development of the Russian Federation No. 316 dated April 26, 2006, "On amendments to the order of the Ministry of Health of the Russian Federation dated August 5, 2003, 'On measures to improve therapeutic nutrition in medical and preventive institutions of the Russian Federation'," a high-protein diet (HPDt) is used for patients with tuberculosis.

Pain management

In cases where medical procedures associated with the provision of medical care to children may cause pain, such procedures must be performed with pain relief.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. Sanatorium-resort treatment

Sanatorium-resort treatment includes medical care provided by medical organizations for preventive, therapeutic, and rehabilitation purposes based on the use of natural therapeutic resources, including staying in health-improving localities and resorts.

Sanatorium-resort treatment is indicated for children with tuberculosis or those at risk for tuberculosis.

Comment: Sanatorium-resort treatment in anti-tuberculosis sanatoria can be carried out as one of the stages of medical rehabilitation in children with tuberculosis by suppressing the viability of the tuberculosis pathogen based on the use of natural therapeutic resources, including staying in health-improving localities and resorts, and the use of antibacterial and anti-tuberculosis drugs.

The duration of sanatorium-resort treatment in the specialty "phthisiology" is determined individually by a medical commission.

Comments: the duration of the child's stay in the sanatorium is determined by the medical commission taking into account the duration of the preventive anti-tuberculosis treatment course (Section 5, Table 5, Appendix A3, Table 10).

Comments: the duration of the child's stay in the sanatorium is determined by the medical commission taking into account the duration of the preventive anti-tuberculosis treatment course, as well as the period of temporary isolation from the tuberculosis focus (Section 5, Table 5, Appendix A3, Table 10).

Comments: the duration of the child's stay inেল the sanatorium is determined by the medical commission taking into account the time required for functional rehabilitation (Appendix A3, Table 10).

Comments: the duration of the child's stay in the sanatorium is determined by the medical commission taking into account the time required to complete the main course of treatment depending on the treatment regimen (Appendix A3, Table 10).

Comments: the duration is determined by the medical commission taking into account the duration of the postoperative treatment period (Appendix A3, Table 10).

Contraindications for referring children and adolescents to sanatoria:

1. Tuberculosis of any localization in the intensive phase of treatment in the presence of bacterial excretion confirmed by bacterioscopic, bacteriological, or molecular-genetic methods.

2. Diseases in the acute and subacute stages, including acute infectious diseases until the end of the isolation period.

3. Chronic diseases in the acute stage.

4. Contagious eye and skin diseases.

5. Parasitic diseases.

6. Malignant neoplasms requiring antitumor treatment, including chemotherapy.

7. Epilepsy.

8. Mental and behavioral disorders in a state of acute exacerbation or unstable remission.

9. Incurable progressive diseases and conditions requiring palliative care.

4.2. Medical rehabilitation

Medical rehabilitation is a complex of medical and psychological measures aimed at the complete or partial restoration of impaired functions and/or compensation for lost functions of an affected organ or body system, maintaining body functions during the completion of an acute pathological process or an exacerbation of a chronic pathological process in the body, as well as the prevention, early diagnosis, and correction of potential functional disorders of damaged organs or body systems, prevention and reduction of the degree of potential disability, improvement of the quality of life, preservation of the patient's working capacity, and their social integration into society [Article 40 of Federal Law No. 323-FZ of November 21, 2011 (as amended on July 23, 2025) "On the Fundamentals of Public Health Protection in the Russian Federation" (with amendments and additions, effective September 1, 2025)].

Medical rehabilitation of children with tuberculosis or those at risk for tuberculosis is carried out through the combined use of natural therapeutic factors, pharmacotherapy, non-pharmacological therapy, and other methods targeting the underlying disease, taking into account the age, anatomical, and physiological characteristics of children, the severity of the underlying disease, rehabilitation potential, presence of comorbid conditions, and mnestic-intellectual impairments.

Early rehabilitation measures include physical and physiotherapeutic interventions that can be administered during the acute stage of the disease.

Comment: Early rehabilitation is conducted in daily group sessions throughout the entire hospital stay. The duration and intensity of the sessions are determined according to the child's age, baseline fitness level, and existing functional impairments.

Early rehabilitation is prescribed based on indications with mandatory evaluation of functional tests.

Contraindications to early rehabilitation:

- rapidly progressive forms of TB;

- forms of TB with pulmonary tissue destruction;

- detection of Mycobacterium tuberculosis in pathological specimens obtained from the patient;

- presence of severe symptoms of intoxication, respiratory failure, and other complications requiring an individual treatment regimen and intensive care;

- hemoptysis and pulmonary hemorrhage;

- presence of chronic diseases requiring special treatment, including those with manifestations of organ function decompensation;

- presence of infectious diseases (acute and chronic);

- presence of malignant neoplasms;

- epilepsy, psychomotor development disorders, and other central nervous system diseases requiring individualized care and regimen.

Medical rehabilitation of children with tuberculosis or those at risk for tuberculosis can be provided in the following settings: out-patient settings (not providing round-the-clock medical observation and treatment), including home-based care; day-patient settings, providing medical observation and treatment during the day without requiring round-the-clock medical observation and treatment; and inpatient settings (providing round-the-clock medical observation and treatment).

Comment: Rehabilitation in a treatment and rehabilitation center (TRC) is carried out by specialists from various fields, educators, and psychologists as part of a multidisciplinary rehabilitation team (hereinafter referred to as the MRT), with the development of an individual medical rehabilitation plan (hereinafter referred to as the IMRP), dynamic monitoring throughout the treatment period, and evaluation of the effectiveness of therapeutic and rehabilitation measures upon completion of treatment.

5. Prevention and Dispensary Observation

5.1. Dispensary follow-up

Comments: The formation of dispensary registration groups for children, their examination, treatment, and follow-up periods are carried out in accordance with Order of the Ministry of Health of the Russian Federation No. 127n dated March 13, 2019²

Subjects of dispensary monitoring:

a) individuals with suspected tuberculosis (Group 0 dispensary registration, ICD-10 code: Z03.0);

б) tuberculosis patients receiving treatment under any tuberculosis chemotherapy regimen (Group I dispensary registration, ICD-10 codes: A15–A19);

в) tuberculosis patients who are not undergoing a course of chemotherapy and whose cure cannot be achieved (Group II dispensary registration, ICD-10 codes: A15–A19);

г) individuals cured of tuberculosis (Group III dispensary registration, ICD-10 code: B90.9);

д) individuals currently or formerly in contact with a source of tuberculosis—individuals who, at their place of residence, place of stay (location), place of work or study, place of serving a sentence, or place of detention, workers of medical anti-tuberculosis organizations currently or formerly in professional contact with a source of tuberculosis, and individuals currently or formerly in contact with a farm animal sick with tuberculosis (Group IV dispensary registration, ICD-10 code: Z20.1);

е) dildren with tuberculosis caused by infection with mycobacteria of the vaccine strain used for tuberculosis prevention, with generalized lesions, and children with tuberculosis caused by infection with mycobacteria of the vaccine strain used for tuberculosis prevention, with localized lesions (Group V dispensary registration, ICD-10 code: Y58.0);

ж) children with suspected tuberculosis established on the basis of immunodiagnosis (children with altered sensitivity of immunological tests to tuberculosis allergens) (Group VIA dispensary registration, ICD-10 codes: R76.1 for tuberculosis infection, Z22.7 for latent tuberculosis infection);

з) children who have had tuberculosis, with newly diagnosed residual post-tuberculosis changes (Group VIB dispensary registration, ICD-10 code: B90.9).

Dispensary registration groups are formed by a phthisiatrician (district phthisiatrician) based on the examination performed in accordance with the Procedure³ for providing medical care to patients with tuberculosis and the professional standard⁴.

The duration of follow-up is determined depending on the severity of residual post-tuberculosis changes and risk factors for disease reactivation.

Residual post-tuberculosis changes include: dense calcified foci and foci of various sizes, fibrous-scar and cirrhotic changes (including those with residual sanitized cavities), pleural layers, postoperative changes in the lungs, pleura, and other organs and tissues, and functional deviations after clinical cure.

Minor residual changes: single (up to 3 cm), small (up to 1 cm), dense and calcified foci (including lymph nodes), limited fibrosis (within 1–2 segments).

Aggravating factors (risk factors): factors contributing to a decrease in the body's resistance to tuberculosis infection: HIV infection, comorbid conditions, prolonged treatment with immunosuppressive drugs [1, 4, 9, 12].

Comments: If there is a suspicion of disease exacerbation/relapse, the examination is carried out in accordance with Section 2 of the clinical guidelines.

Comments: preventive anti-tuberculosis treatment is carried out in accordance with established medical care safety requirements.

² Order of the Ministry of Health of the Russian Federation No. 127n dated March 13, 2019, "On the Procedure for Dispensary Observation of Tuberculosis Patients, Persons in Contact or Previously in Contact with a Source of Tuberculosis, as Well as Persons Suspected of Having Tuberculosis and Cured of Tuberculosis."

³ Order of the Ministry of Health of the Russian Federation No. 932n dated November 15, 2012 (https://normativ.kontur.ru/document?moduleId=1&documentId=211554#l0) "On Approval of the Procedure for Providing Medical Care to Tuberculosis Patients" (registered by the Ministry of Justice of the Russian Federation on March 7, 2013, registration No. 27557).

⁴ Order of the Ministry of Labor and Social Protection of the Russian Federation No. 684n dated October 31, 2018, "On Approval of the Professional Standard 'Phthisiatrician'"

5.2. Prevention, medical indications, and contraindications for the use of preventive methods

Medical preventive measures are carried out to reduce the risk of Mycobacterium infection in healthy individuals, limit the spread of tuberculosis infection, prevent disease in infected persons, and achieve early detection of tuberculosis in sick individuals.

Social, sanitary, and specific prevention of tuberculosis are distinguished [1, 8, 34, 43].

Currently, tuberculosis prevention consists of a set of measures and is based on the requirements set forth in the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21" in the section "Tuberculosis Prevention"⁵.

Measures of social prevention include: improving working and living conditions;

promoting a healthy lifestyle; regulatory control of migration; combating alcoholism and drug addiction; and providing social support to low-income individuals, the homeless, and those released from correctional facilities;

Sanitary prevention is understood as the systematic organization and implementation of a system of sanitary-hygienic and preventive measures aimed at protecting healthy people from infection and developing tuberculosis. Sanitary prevention includes measures to shield the most vulnerable population groups from patients with contagious forms of tuberculosis and restrict individuals with tuberculosis from working in certain professions. The second component of sanitary prevention includes social, anti-epidemic, and treatment measures in foci of tuberculosis infection. Individuals with tuberculosis must be isolated from the focus of tuberculosis infection. After isolation of the source, terminal disinfection is carried out in the focus. Contacts are placed under dispensary observation.

The third component of sanitary prevention is health education work among the population.

Specific prevention of tuberculosis includes:

a) immunization with tuberculosis vaccine** (BCG, BCG-M);

b) chemoprophylaxis (preventive treatment).

Specific prevention of tuberculosis can only be carried out with drugs registered in Russia—tuberculosis vaccine** (BCG, BCG-M). Tuberculosis vaccination is carried out using BCG or BCG-M vaccine, and revaccination is carried out using tuberculosis vaccine** (BCG) in accordance with the schedule of preventive vaccinations. The timing of vaccination is determined by the National Schedule of Preventive Vaccinations.

In accordance with current regulatory legal documents, medical workers performing vaccine prophylaxis of infectious diseases must undergo training on the organization and implementation of preventive vaccinations at least once every 2 years. Training is conducted within the framework of additional professional advanced training programs (Part 4 of Article 82 of Federal Law No. 273-FZ dated December 29, 2012, "On Education in the Russian Federation" [Law on Education]) and is carried out simultaneously and continuously through practical training in the manner established by the educational program and/or education agreement at medical organizations housing structural divisions of educational and scientific organizations (clinical base), and is conducted in accordance with the internship agreement concluded for the implementation of additional professional programs of medical education (Regulations on Licensing Educational Activities, approved by Government Resolution of the Russian Federation No. 966 dated October 28, 2013). Completion of training serves as the basis for issuing a certificate authorizing work after receiving briefing (training) at anti-tuberculosis organizations in the established manner.

 On the day of vaccination (revaccination), the physician must make a detailed entry in the child's medical record regarding their health status, including thermometry results and the prescription for BCG (BCG-M) vaccine administration. The nurse records the administration method (i/d), vaccine dose (0.05 or 0.025), batch number, expiration date, and manufacturer. The drug's label data must be personally verified by the physician on the packaging and the vaccine ampoule. Before vaccination (revaccination), the physician and nurse must review the vaccine's instructions for use and inform the child's parents in advance about the immunization and potential local reactions to the BCG or BCG-M vaccine (informed consent). Newborn vaccination in the maternity hospital (newborn pathology department) is permitted in the nursery ward in the presence of a physician. All items required for BCG (BCG-M) vaccination (revaccination) (tables, sterilizing boxes, trays, cabinets, etc.) must be labeled. Vaccination in the maternity hospital is performed in the morning hours. To prevent contamination, no other parenteral manipulations or vaccinations are performed on the child on the vaccination day. Due to early discharge from obstetric hospitals provided for by Order of the Russian Ministry of Health No. 345 dated November 26, 1997, "On improving measures for the prevention of nosocomial infections in obstetric hospitals," in the absence of contraindications, newborn tuberculosis vaccination may be performed starting from the 3rd day of life. Discharge is possible one hour after vaccination if there is no reaction to it. Monitoring of vaccinated and revaccinated children is carried out by physicians and nurses in state and municipal healthcare organizations providing primary health care. The child development record notes the vaccination reaction at 1, 3, 6, and 12 months, recording the size and character of the local reaction (papule, pustule with crust formation, with or without discharge, scar, pigmentation, etc.). In cases of complications following BCG and BCG-M vaccine administration, data on the nature of the complications are recorded in medical record forms No. 063/u and No. 026/u (e.g., infiltrate up to 18 mm in diameter; lymphadenitis - 2.0 x 2.0 cm with a fistula, etc.). If a BCG or BCG-M vaccination complication is suspected, a consultation with a phthisiatrician is required, including a corresponding conclusion and management tactics for the child. For all cases of complications, a vaccination complication form is completed with the exact series, expiration date of the BCG or BCG-M vaccine, and manufacturing institute, which is sent to the Rospotrebnadzor center (district, city, regional) supervising vaccination quality. Copies of the forms are sent to the National Medical Research Center of Phthisiopulmonology and Infectious Diseases of the Ministry of Health of the Russian Federation (127473, Moscow, Dostoevskogo st., 4, building 2). In addition, information on the nature of complications is recorded in medical record forms No. 063/u and No. 112/u. Tuberculosis vaccinations must be performed strictly in accordance with the instructions for use of the BCG and BCG-M vaccines.

Vaccination is performed in newborns in the maternity hospital in the absence of contraindications; revaccination is performed once at 6–7 years of age⁶ in case of a negative Mantoux test with 2 TU.

⁵ Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021, "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (along with "SanPiN 3.3686-21. Sanitary Rules and Norms...") (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500)

⁶ Order of the Ministry of Health of the Russian Federation No. 125n dated March 21, 2014, "On Approval of the National Schedule of Preventive Vaccinations and the Schedule of Preventive Vaccinations for Epidemiological Indications."

6. Organization of Medical Care

The rules for providing medical care to patients with tuberculosis in medical organizations are established by the Procedure for Providing Medical Care to Tuberculosis Patients⁷

Note: Updated WHO recommendations are based on evidence obtained from systematic reviews.

Medical care for patients with tuberculosis can be provided in the following settings:

- outpatient setting (in conditions not requiring round-the-clock medical observation and treatment);

- day hospital setting (in conditions providing medical observation and treatment during daytime hours, not requiring round-the-clock medical observation and treatment);

- inpatient setting (in conditions providing round-the-clock medical observation and treatment).

From the date the diagnosis of tuberculosis is established, patients are subject to dispensary observation (follow-up) by a phthisiatrician at a tuberculosis dispensary, tuberculosis hospital, or Center. The duration of observation and the scope of necessary diagnostic, therapeutic, and anti-epidemic measures are determined taking into account the clinical form of tuberculosis, the presence of drug resistance of the tuberculosis pathogen, complications, underlying and comorbid conditions.

Indications for hospitalization of children in an inpatient medical organization (tuberculosis hospital):

1) active tuberculosis of any localization for treatment in the intensive phase;

2) respiratory tuberculosis with bacterial excretion (detected by microscopy, culture);

3) drug-resistant tuberculosis (confirmed or suspected);

4) widespread, destructive, complicated forms of tuberculosis;

5) conditions requiring medical care for life-threatening complications of tuberculosis (including hemoptysis);

6) the need for special methods, including surgical ones, for the diagnosis and differential diagnosis of tuberculosis;

7) tuberculosis with comorbid diseases and pathological conditions requiring inpatient treatment and observation (HIV infection, diabetes mellitus, etc.);

8) preparation for surgical treatment;

9) a combination of medical, epidemic, and social indications for hospitalization.

Indications for discharging a patient from a medical organization (tuberculosis hospital):

1) subsiding tuberculosis in the continuation phase of therapy;

2) cessation of bacterial excretion;

3) closure of decay cavities (caverns) in pulmonary tuberculosis;

4) smooth early postoperative period (no earlier than 2 weeks later).

After discharge from the tuberculosis hospital, the patient continues treatment under the supervision of a medical worker in an outpatient setting, a day hospital, or a sanatorium.

Outpatient settings or day hospitals can also be used to treat newly diagnosed patients with "minor" forms of respiratory tuberculosis without complications, with residual changes after spontaneous cure; without aggravating socio-epidemiological factors (socially adapted family, isolated adult TB patient).

Tuberculosis patients who have successfully completed the intensive phase of chemotherapy can continue treatment in a tuberculosis sanatorium⁸.

Placement in the medical rehabilitation center (MRC) is carried out taking into account age, clinical form of the disease (condition), and compensatory-adaptive capabilities for adaptation in an inpatient environment.

The MRC must provide all necessary conditions for the implementation of types of medical care aimed at the treatment, rehabilitation, and prevention of tuberculosis.

The functions of the MRC are:

- conducting controlled chemotherapy in the continuation phase of the main course of treatment, including after surgical treatment, for all categories of tuberculosis patients, as well as treatment of vaccination complications;

- carrying out the full main course of treatment for limited, uncomplicated, "minor" forms of tuberculosis without bacterial excretion;

- implementation of comprehensive rehabilitation measures (full medical, social, pedagogical, etc.), including with the participation of a multidisciplinary rehabilitation team and the development of an individual medical rehabilitation plan;

- carrying out preventive measures for individuals at high risk of developing tuberculosis;

- drawing up and implementing individual programs of medical rehabilitation and preventive treatment for patients with tuberculosis and the risk of its development;

- performing all methods of medical rehabilitation (natural therapeutic factors, drug therapy, non-medication therapy, etc.), prevention of complications, restoration of functional capabilities, and improvement of the quality of life of tuberculosis patients;

- introduction of modern medical rehabilitation methods into clinical practice;

- creation of conditions necessary to ensure the continuity of educational activities in accordance with preschool and school education standards among children undergoing treatment;

- participation in interdepartmental cooperation with educational organizations providing psychological and pedagogical rehabilitation, social protection organizations providing social rehabilitation, and law enforcement agencies;

- analysis of the organization, quality of delivery, and effectiveness of rehabilitation measures;

- collection and submission of reporting in the prescribed manner;

- maintenance of federal information systems and federal databases of tuberculosis patients, including ensuring the confidentiality of personal data contained therein in accordance with the legislation of the Russian Federation;

- provision of advisory, organizational, and methodological assistance to medical organizations and the population on issues of medical rehabilitation, tuberculosis prevention, and a healthy lifestyle.

- organization and implementation of measures aimed at ensuring epidemic safety and preventing the spread of infectious and parasitic diseases in the MRC;

- submission of reports by types, forms, within the timeframes, and in the scope established by the authorized federal executive body;

- provision of primary data on medical activities for healthcare information systems;

- other functions in accordance with the legislation of the Russian Federation.

⁷ Procedure for providing medical care to patients with tuberculosis (approved by Order (https://base.garant.ru/70340750/) of the Ministry of Health of the Russian Federation dated November 15, 2012, No. 932n)

⁸ Order of the Ministry of Health of the Russian Federation No. 932n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Tuberculosis", Appendix 23 "Rules for Organizing the Activities of a Sanatorium for the Treatment of All Forms of Tuberculosis"

7. Additional Information

HIV infection is the most serious known risk factor for the activation of latent infection caused by M. tuberculosis. For HIV-infected individuals, the risk of developing active tuberculosis is 5–10% per year, whereas for HIV-uninfected people, the risk is 5–10% over a lifetime. In comorbid HIV infection, the diagnosis of tuberculosis in children is complicated by the fact that some HIV-associated diseases clinically resemble tuberculosis, and immunological tests with tuberculosis antigens may be negative, which can lead to late diagnosis [77].

With a decrease in immunity, the proportion of patients with disseminated processes increases. Disseminated (generalized) tuberculosis in children with HIV infection is diagnosed 20 times more often under immunodeficiency than in the absence of immunodeficiency [78].

The outcome of the disease in TB-HIV coinfection can also be influenced by poor tolerability of antituberculosis drugs combined with antiretroviral drugs, which increases their toxicity [79].

HIV infection also increases the frequency of TB relapses, which may be associated with endogenous reactivation or exogenous reinfection [80].

When conducting diagnostic measures and prescribing treatment for children with HIV infection, it is necessary to take into account the immune status; below is the table of Classification of Immune Categories in Children by Age (Clinical Guidelines "HIV Infection in Children", 2022, ICD-10: B20, B21, B22, B23, B24, R75, Z21, Z20.6, CRF Rubricator, cr.minzdrav.gov.ru)

Classification of immune categories in children by age

Antiretroviral therapy (ART) is prescribed as early as possible—within 2 weeks of starting anti-tuberculosis treatment. Immune reconstitution inflammatory syndrome (IRIS) may develop after initiating ART (most commonly within the first month), presenting as a temporary worsening of the clinical condition and disease progression. Risk factors for IRIS include a low baseline CD4 count, disseminated severe TB, early initiation of ART, and a rapid immunological and virological response to ART.

For mild to moderate TB-associated IRIS, the use of nonsteroidal anti-inflammatory and antirheumatic drugs may be considered. For severe TB-associated IRIS, the use of glucocorticoids may be considered, while anti-tuberculosis and antiretroviral treatment are continued [84].

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary healthcare delivery to children with tuberculosis (ICD-10 codes: A15-A19)

Quality assessment criteria for specialized medical care delivery to children with tuberculosis (ICD-10 codes: A15-A19)

References

Appendix A1. Working Group Composition

Baryshnikova, Lada Anatolyevna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Barmina, Natalya Alexandrovna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Baronova, Olga Dmitrievna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Valiev, Ravil Shamilovich, Professor, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Vasilyeva, Irina Anatolyevna, Professor, MD, PhD, no conflict of interest, President of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Gaida, Anastasia Igorevna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Gubkina, Marina Fedorovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Dovgalyuk, Irina Fedorovna, Professor, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Dolzhenko, Elena Nikolaevna, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Eliseev, Platon Ivanovich, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Kazakov, Alexey Vladimirovich, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Klevno, Nadezhda Ivanovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Lovacheva, Olga Viktorovna, Professor, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Luginova, Evdokia Fedorovna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Motanova, Lyudmila Nikolaevna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Ovsiankina, Elena Sergeevna, Professor, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians;

Osina, Svetlana Leonidovna, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Pavlenok, Irina Viktorovna, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Panova, Anna Evgenyevna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Panova, Lyudmila Vladimirovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Panteleev, Alexander Mikhailovich, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Parolina, Lyubov Evgenyevna, MD, PhD, Professor, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Pakhlavonova, Aziza Damirovna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Poddubnaya, Lyudmila Vladimirovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Prodeus, Andrey Petrovich, MD, PhD, Professor, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Plehanova, Maria Alexandrovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Sagakyants, Ripsme Grigorievna, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Samoilova, Anastasia Gennadievna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Sevostyanova, Tatyana Alexandrovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Slogotskaya, Lyudmila Vladimirovna, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Tinkova, Valentina Vyacheslavovna, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Fatykhova, Ramziya Khamitovna, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians»;

Chugaev, Yuri Petrovich, Professor, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians».

Shurygin, Alexander Anatolyevich, Professor, MD, PhD, no conflict of interest, member of the All-Russian Public Organization «Russian Society of Phthisiatricians».

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for evidence collection/selection: Electronic database search. Publications were searched in the bibliographic databases PubMed, Cochrane Library, and the domestic scientific electronic library eLibrary.ru. The search depth was 33 years.

Target audience of the clinical guidelines:

In accordance with the list of medical worker positions:

Phthisiatrician; district phthisiatrician; infectious diseases physician; general practitioner (family physician); pediatrician; municipal (district) pediatrician; district pediatrician.

Significance assessment was performed in accordance with the rating scale for levels of evidence reliability (Tables 1-3).

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

Table 2. Scale for grading levels of evidence reliability (LER) for prevention, treatment, and rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

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

Related Documents

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

1. Federal Law of the Russian Federation No. 77-FZ dated June 18, 2001, «On Prevention of the Spread of Tuberculosis in the Russian Federation»;

2. Federal Law of the Russian Federation No. 323-FZ dated November 21, 2011, «On the Fundamentals of Protecting the Health of Citizens in the Russian Federation»;

3. Instructions for the use of the clinical classification of tuberculosis (Order of the Russian Ministry of Health No. 109 dated March 21, 2003)

4. Methodological recommendations for improving the diagnosis and treatment of respiratory tuberculosis (Order of the Russian Ministry of Health No. 951 dated December 29, 2014)

5. Methodological Guide «Screening examination of children and adolescents for the detection of tuberculous infection». Moscow, 2018, - 48 p. ISBN 978-5-9907438-7-8

6. Nomenclature of specialties for specialists with higher medical and pharmaceutical education (Order of the Russian Ministry of Health No. 700n dated October 7, 2015)

7. On approval of the Procedure for providing medical care to tuberculosis patients (Order of the Russian Ministry of Health No. 932n dated November 15, 2012)

8. Rules for organizing the activities of a sanatorium for the treatment of all forms of tuberculosis (Order of the Russian Ministry of Health No. 932n dated November 15, 2012)

9. Procedure for dispensary observation of tuberculosis patients, persons in contact or who have been in contact with a tuberculosis source, as well as persons with suspected tuberculosis and those cured of tuberculosis (Order of the Ministry of Health of the Russian Federation No. 127n dated March 13, 2019)

10. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 68n dated October 31, 2018, «On approval of the professional standard "Phthisiatrician"»

11. Order of the Ministry of Health of the Russian Federation No. 190n dated April 11, 2025, "On approval of the procedure and timeframe for preventive medical examinations of citizens for the purpose of tuberculosis detection"

12. Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022, «On the list of diseases or conditions (groups of diseases or conditions) for which the use of a medicinal product is permitted in accordance with the indications (characteristics) of the medicinal product not specified in its instructions for use»

Chemotherapy regimens

A chemotherapy regimen is a combination of antituberculosis and antibacterial drugs, the duration and frequency of their administration, the timing and content of follow-up examinations, as well as organizational forms of treatment. The chemotherapy regimen is determined based on the drug susceptibility of Mycobacterium tuberculosis isolated from pathological material, or on anamnestic data in their absence.

The choice of regimen is made taking into account the drug resistance profile of the isolated pathogen in the patient, or the expected drug sensitivity and resistance (contact with a patient with MDR/XDR-TB).

If bacterial excretion is present, the choice of the first-stage chemotherapy regimen is determined by the results of molecular genetic testing for drug resistance to at least isoniazid** and/or rifampicin**; and fluoroquinolones. Subsequent adjustments to the chemotherapy regimen are made based on the results of phenotypic drug susceptibility testing of the pathogen to first-line and reserve drugs (culture method).

Drugs for tuberculosis chemotherapy

Drugs for the treatment of drug-susceptible TB: isoniazid** and rifampicin** are effective anti-tuberculosis drugs with proven bactericidal effects. These drugs are effective against both extracellular and intracellular M. tuberculosis and are able to cross the blood-brain barrier. #Rifapentine, unlike rifampicin**, maintains bactericidal activity in tissues for a prolonged period and is therefore prescribed 2–3 times a week. The bactericidal effect of pyrazinamide** is somewhat lower; however, an important advantage of this drug is the retention of its activity in the acidic environment of caseous masses. #Ethambutol** inhibits the multiplication of M. tuberculosis and certain nontuberculous mycobacteria that are resistant to other anti-tuberculosis drugs. The combination of isoniazid**, rifampicin**, pyrazinamide**, and #ethambutol** is highly effective for patients with drug-susceptible tuberculosis (for administration methods, dosages of #rifapentine and #ethambutol**, and treatment duration in children, see Appendix A3, Table 9).

In cases of M. tuberculosis resistance to isoniazid** and rifampicin**, pyrazinamide** and #ethambutol** may be included in treatment regimens for patients with MDR-TB provided that confirmed susceptibility of the pathogen to these drugs is established (for administration methods, #ethambutol** dosage, and treatment duration in children, see Appendix A3, Table 9).

Drugs for the treatment of drug-resistant TB: fluoroquinolones (#levofloxacin**, #moxifloxacin**) are always included in the chemotherapy regimens for patients with MDR-TB due to their bactericidal effect on M. tuberculosis. #Moxifloxacin** leads to QT interval prolongation more frequently than #levofloxacin**; therefore, #levofloxacin** is the drug of choice for children. Many researchers consider cross-resistance within this class of drugs to be high. The presence of M. tuberculosis resistance to fluoroquinolones significantly increases the risk of treatment failure in patients with MDR-TB. Unfortunately, M. tuberculosis resistance to fluoroquinolones is already widespread. One of the most common causes of its development is the uncontrolled intake of medications and the unjustified use of fluoroquinolones in empirical tuberculosis chemotherapy regimens when the drug susceptibility of M. tuberculosis to other anti-tuberculosis drugs is unknown (for administration methods, dosages of #levofloxacin** and #moxifloxacin**, and treatment duration in children, see Appendix A3, Table 9).

#Bedaquiline** is a member of the diarylquinoline class (ATC code: J04AK Other drugs for treatment of tuberculosis) and is a highly effective novel drug for the treatment of MDR-TB. The drug exerts a bactericidal effect on M. tuberculosis. It exhibits no cross-resistance with other anti-tuberculosis drugs used in the Russian Federation due to its unique mechanism of action (it targets mycobacterial adenosine-5'-triphosphate (ATP) synthase). #Bedaquiline** is currently the backbone of all treatment regimens for patients with MDR-TB, as its high efficacy has been repeatedly proven in clinical and observational studies, and it is recommended by the WHO for the treatment of MDR-TB in children of any age (child weight > 3 kg) (for administration method, #bedaquiline** dosage, and treatment duration in children, see Appendix A3, Table 9).

#Linezolid**, a systemic antibacterial drug of the oxazolidinone class (ATC code: J01XX Other antibacterials), is highly active against Mycobacterium tuberculosis. The administration of #linezolid** significantly increases treatment efficacy in patients with MDR-TB (for administration method, #linezolid** dosage, and treatment duration in children, see Appendix A3, Table 9).

Cycloserine** (from 3 years of age) / #cycloserine** (under 3 years of age) / #terizidone** are most frequently associated with successful treatment outcomes in patients with MDR-TB and are recommended for inclusion in treatment regimens. #Terizidone** contains two cycloserine molecules, exhibits similar efficacy but better tolerability, and may be used as an alternative (for administration method, #terizidone** dosage, and treatment duration in children, see Appendix A3, Table 9).

#Delamanid** is a novel anti-tuberculosis drug. The pharmacological mechanism of action of #delamanid** involves the inhibition of the synthesis of mycobacterial cell wall components—namely, methoxy-mycolic and keto-mycolic acids. #Delamanid** is capable of exerting a potent bactericidal effect against Mycobacterium tuberculosis and is also effective against intracellular forms of M. tuberculosis at the macrophage level. It is absorbed in the gastrointestinal tract, and its efficacy is enhanced when taken with food. According to the 2022 WHO recommendations, the combined use of #delamanid** and #bedaquiline** is safe (for administration methods, dosages of #terizidone** and #bedaquiline**, and treatment duration in children, see Appendix A3, Table 9).

Systemic antibacterial drugs of the carbapenem class (#imipenem+[cilastatin]**, #meropenem**) may be prescribed to patients with MDR/XDR-TB when it is impossible to construct a chemotherapy regimen from 4 drugs with known drug susceptibility (including #bedaquiline** and #linezolid**). Due to the highest activity of carbapenems against M. tuberculosis in the presence of clavulanic acid, #imipenem+cilastatin** and #meropenem** must be prescribed with the mandatory inclusion of #amoxicillin+clavulanic_acid** in the chemotherapy regimen at a dose of 125 mg of clavulanic acid every 8–12 hours (for administration methods, dosages of #imipenem+[cilastatin]**, #meropenem**, #bedaquiline**, #linezolid**, and #amoxicillin+clavulanic_acid**, and treatment duration in children, see Appendix A3, Table 9).

Thioamides (ATC code: J04AD Thiocarbamide derivatives) (ethionamide** / prothionamide**) have been shown in a number of studies to increase treatment efficacy in patients with MDR-TB; however, if M. tuberculosis is resistant to isoniazid** due to a mutation in the inhA gene, thioamides (ATC code: J04AD Thiocarbamide derivatives) cannot be considered effective drugs due to cross-resistance with isoniazid** when mutations in this gene are present. With the advent of new bactericidal anti-tuberculosis drugs, the role of thioamides (ATC code: J04AD Thiocarbamide derivatives) in MDR-TB treatment regimens is decreasing.

Aminosalicylic acid** is included in MDR-TB chemotherapy regimens when it is not possible to assemble a regimen of 4 effective drugs. This medicinal product ranks first in the frequency of serious adverse events among other anti-tuberculosis and systemic antibacterial drugs. The combined administration of ethionamide** / prothionamide** and aminosalicylic acid** is accompanied by frequent gastrointestinal side effects as well as the development of hypothyroidism, which complicates their concurrent use.

Injectable drugs #amikacin**, kanamycin**, and #capreomycin** are used in modern chemotherapy regimens only by decision of the medical commission and with great caution due to severe adverse reactions.

Cross-resistance. Mutations causing resistance to one drug may also cause resistance to some or all drugs in the same group and, more rarely, to drugs from other groups. For instance, resistance to the aminoglycoside kanamycin** highly likely implies cross-resistance to #amikacin**. Conversely, cross-resistance between aminoglycosides, kanamycin**, and streptomycin** is typically low. Furthermore, M. tuberculosis strains isolated from patients that are resistant to high doses of kanamycin** may exhibit resistance to #capreomycin** (for administration methods, dosages of #amikacin** and #capreomycin**, and treatment duration in children, see Appendix A3, Table 9).

Cross-resistance of anti-tuberculosis drugs is presented in Table 7.

Table 4. Cross-resistance of anti-tuberculosis drugs

Dosing frequency and daily doses of drugs

Systemic anti-tuberculosis and antibacterial drugs are prescribed taking into account body weight with dose adjustment as it increases. Daily doses of anti-tuberculosis drugs (ATDs) – isoniazid**, rifampicin**, #rifapentine, #ethambutol**, kanamycin**, #amikacin**, #capreomycin**, #levofloxacin**, #moxifloxacin** – are prescribed in a single dose, which creates a high peak serum drug concentration. The daily dose of pyrazinamide** may be divided into three doses if the drug is poorly tolerated, although a single daily dose is preferred. Daily doses of prothionamide**, ethionamide**, cycloserine**, #terizidone**, aminosalicylic acid**, and other drugs can be divided into two or three doses depending on individual drug tolerance; for outpatient treatment, a single dose of the entire daily amount is preferred (for the route of administration, dose of #rifapentine, #ethambutol**, #amikacin**, #capreomycin**, #levofloxacin**, #moxifloxacin**, #terizidone**, and duration of use in children, see Appendix A3, Table 9).

Table 6. Tuberculosis chemotherapy regimens in children.

* Lfx/Mfx is prescribed when proven susceptibility to a specific fluoroquinolone is maintained.

H – isoniazid**, R – rifampicin**, P – #rifapentine, Z – pyrazinamide**, E – #ethambutol**, S – streptomycin**, Km – kanamycin**, Am – #amikacin**, Cm – #capreomycin**, Lfx – #levofloxacin**, Mfx – #moxifloxacin**, Pto – prothionamide**, Eto – ethionamide**, Bq – #bedaquiline**, Lzd – #linezolid**, Dlm – #delamanid**, Imp – #imipenem + [cilastatin]**, Mp – #meropenem**, Cs – cycloserine**, Trd – #terizidone**, Cfz – #clofazimine, PAS – aminosalicylic acid**, Pa – #pretomanid.

Table 7. Most common adverse reactions occurring with ATDs used to treat MDR TB

*Regular monitoring of electrocardiogram parameters is required when prescribing drugs capable of prolonging the QT interval (fluoroquinolones, #bedaquiline**, #delamanid**, #clofazimine). An ECG should preferably be performed before starting treatment, at two and four weeks after initiation, and then every four weeks until the end of therapy, as well as at any time if clinically indicated, regardless of the number of cardiotoxic drugs in the regimen. In children and adolescents, the risk of severe QT interval prolongation (QTcF ≥500 ms) is low. If frequent monitoring is not feasible, an ECG may be performed before treatment, at 4, 8, and 24 weeks after initiation, and at any time based on clinical indications.

**Patients receiving #Lzd** experience bone marrow toxicity (anemia, thrombocytopenia, or neutropenia). The risk of adverse reactions increases with the duration of treatment. When using #Lzd**, it is advisable to perform a complete blood count with a differential leukocyte count before starting treatment, and then every two weeks for two months, followed by every four weeks. This approach allows for the early detection of adverse reactions. Anemia, thrombocytopenia, and neutropenia are usually reversible and resolve after #Lzd** is discontinued; subsequently, it can be re-administered at a lower dose. If the adverse reactions are irreversible, #linezolid** must be discontinued.

***Monitoring for neuropsychiatric adverse reactions, including hallucinations, is important for children receiving drugs with known neuropsychiatric side effects—#delamanid** and #cycloserine**.

****Hypothyroidism is an adverse effect of #ethionamide and aminosalicylic acid**. The risk of its occurrence increases when these drugs are combined. Symptoms of hypothyroidism are non-specific, and their assessment in young children may be difficult. Hypothyroidism can negatively affect nervous system development in young children. It is important to regularly (every two months) monitor the child's thyroid function laboratory parameters throughout the entire period of using any such drugs and to prescribe levothyroxine preparations if clinical or laboratory signs of hypothyroidism are present.

Assessment of hepatotoxicity: drug combinations frequently cause hepatotoxic reactions. Before starting treatment, alanine aminotransferase (ALT) activity, aspartate aminotransferase (AST) activity, and total bilirubin levels in the child's blood must be determined. Hepatotoxicity monitoring consists of repeating the general biochemical blood panel every 4 weeks (monthly) for the first 6 months, and then every 8 weeks, as well as additionally when clinically indicated. In case of jaundice, elevated bilirubin levels combined with elevated ALT, or in the presence of clinical symptoms with ALT exceeding the upper limit of normal more than three-fold, or in the absence of symptoms with ALT exceeding the upper limit of normal more than five-fold, all anti-tuberculosis drugs should be discontinued immediately. Liver enzyme levels normalize after discontinuation. If clinically indicated, anti-tuberculosis drugs can be cautiously resumed one by one.

In case of unmanageable adverse reactions in the chemotherapy regimen, the drug that caused the adverse reaction must be replaced with an alternative anti-tuberculosis drug.

It must be remembered that:

some adverse drug reactions can be life-threatening if not diagnosed and managed in a timely manner;

if adverse drug reactions are not properly managed, there is a high risk of treatment abandonment and treatment failure;

most adverse drug reactions are moderate and easily manageable without compromising anti-tuberculosis therapy;

since patients receive combination chemotherapy, it is sometimes difficult to determine which drug caused the reaction;

adverse drug reactions may occur due to drug-drug interactions;

in all cases of adverse drug reactions, other causes (somatic and infectious diseases) that could cause similar manifestations must first be ruled out and addressed.

The following algorithm is used to manage adverse drug reactions (see Table 8):

direct management of adverse reactions using standard regimens;

dose reduction of the drug(s) most likely to have caused the adverse reactions;

drug discontinuation (in cases of life-threatening adverse drug reactions, drug discontinuation is performed immediately).

Table 8. Management of adverse drug reactions during chemotherapy (The interventions presented do not negate the need to monitor for other adverse reactions, rule out other causes of the described conditions, and specify and/or prescribe other types of therapy in a specific clinical situation in accordance with clinical guidelines for these conditions.

The prescription of these medical interventions, including drug therapy, is carried out in accordance with medical care delivery procedures and other regulatory legal acts in the healthcare field in force in the Russian Federation)

Table 9. Off-label daily dosages of medications for children*.

*Note: dosage range is presented in accordance with the drug prescribing information and WHO recommendations [84]; drugs are prescribed subject to informed consent of the patient's legal representative for their use;

#ethambutol** is prescribed to children under 13 years of age by decision of the medical panel in accordance with the chemotherapy regimen [84];

#amikacin** is prescribed to children over 2 years of age by decision of the medical panel, in accordance with the chemotherapy regimen, at a dose of 15-25 mg/kg/day [84];

#levofloxacin** is prescribed to children by decision of the medical panel in accordance with the chemotherapy regimen. The safety of #levofloxacin** use in children under 15 years of age at a dose of 15-20 mg/kg/day for 6 months has been proven, and it is also recommended by the WHO for the treatment of MDR-TB in children [84];

#moxifloxacin** is prescribed to children by decision of the medical panel in accordance with the chemotherapy regimen. Use at a dose of 10-15 mg/kg/day is recommended for the treatment of MDR-TB in children [84];

#bedaquiline** is prescribed to children by decision of the medical panel in accordance with the chemotherapy regimen at the doses specified in Table 9 [84];

#linezolid** is prescribed to children by decision of the medical panel in accordance with the chemotherapy regimen; in children weighing less than 15 kg, it is prescribed at a dose of 15 mg/kg/day, and in children weighing more than 15 kg, at 10-12 mg/kg/day [84];

#meropenem** and #imipenem + [cilastatin]** are prescribed to children by decision of the medical panel, in accordance with the chemotherapy regimen, at a dose of 20-40 mg/kg every 8 hours in combination with #amoxicillin + clavulanic acid** at a dose of 80 mg/kg/day divided into 3 doses [84];

#capreomycin** is prescribed to children by decision of the medical panel for life-saving indications in accordance with the chemotherapy regimen when it is impossible to include other reserve-line drugs in the regimen [13];

#Clofazimine – is prescribed to children by decision of the medical panel in accordance with the chemotherapy regimen [84];

#Pretomanid – prescribed only as part of short 6-month MDR- and pre-XDR-TB regimens [139, 140].

Table 10. Duration of sanatorium-resort treatment for children depending on the form of tuberculosis and the course of the disease

Table 11. Penetration of anti-tuberculosis drugs for MDR-TB treatment into the cerebrospinal fluid [84].

Appendix B. Physician Action Algorithms

Diagnostic algorithm for respiratory tuberculosis in children

Includes several stages of the diagnostic search.

1.1. Identification of individuals at risk for developing tuberculosis in primary health care (PHC) facilities

Detection of tuberculosis in children is carried out proactively⁹. For this purpose, annual screening for tuberculosis in the pediatric population is conducted in Russia using immunodiagnosis and fluorographic (radiological) examination methods: up to 7 years of age inclusive, an intradermal test with tuberculosis allergen using bacterial allergens** is performed (Mantoux test with 2 TU); from 8 to 14 years of age inclusive, an intradermal test with tuberculosis allergen using recombinant tuberculosis allergen (TRA)** is performed; from 15 to 17 years of age inclusive, an intradermal test with tuberculosis allergen using TRA** or chest fluorography (radiography) is performed. The results of blood interferon-gamma release assays (IGRA tests) for Mycobacterium tuberculosis complex antigens performed during preventive examinations may be taken into account.

Based on the results of the preventive examination, individuals with suspected tuberculosis are referred to a phthisiatrician:

- abnormal reactions to immunodiagnostic tests (positive and doubtful reactions to the intradermal test with tuberculosis allergen using TRA**, positive or doubtful results of blood interferon-gamma release assays (IGRA tests) for Mycobacterium tuberculosis complex antigens, newly positive or increasing reactions to the intradermal test with tuberculosis allergen using bacterial allergens** (Mantoux test with 2 TU);

- pathological changes on the chest fluorogram (radiogram).

- in the presence of clinical symptoms suggestive of tuberculosis, regardless of the results of immunodiagnostic tests.

1.2. Further evaluation in a specialized tuberculosis service.

Patients selected at the first stage must undergo a thorough examination by a phthisiatrician to rule out or confirm localized tuberculosis.

The following research methods are used for this purpose:

- Active elicitation of complaints from the child (parents):

• deterioration of general condition,

• fever,

• complaints indicating localized organ and system involvement – cough (dry or with sputum), chest pain, shortness of breath.

- Thorough collection of medical history:

• dynamics of intradermal tests with tuberculosis allergen and blood interferon-gamma release assays for Mycobacterium tuberculosis complex antigens,

• information on tuberculosis vaccination,

• contact with tuberculosis patients (duration, frequency),

• previous treatment by a phthisiatrician,

• concomitant pathology with conclusions from relevant specialists,

• prolonged treatment with any medications.

- Examination of the child's contacts for tuberculosis is mandatory – chest fluorography is performed for all family members.

- Objective examination:

Detection of intoxication symptoms, auscultation (presence of rales, etc.), state of peripheral lymph nodes.

Laboratory diagnostics

- clinical and biochemical blood tests (complete blood count, urinalysis, general clinical blood chemistry);

- bacteriological (etiologic) diagnostics (identification of the pathogen by various methods).

Radiological diagnostics

Chest CT is indicated for all children with a positive reaction to the TRA** test.

Additional diagnostic methods (ADM) are performed according to indications:

- Ultrasound of the thoracic cavity

- Ultrasound of the abdominal cavity (comprehensive) and kidneys.

- Lymph node ultrasound.

If any changes are detected during ADMs, the child must be consulted by specialists in extrapulmonary tuberculosis.

Invasive examination methods:

Tracheobronchoscopy is performed:

- when bronchial tree tuberculosis is suspected (atelectasis, extensive infiltrative changes with lung tissue destruction, bronchogenic dissemination foci, hacking cough);

- when verification of the diagnosis is necessary (tracheobronchoscopy with a complex of biopsies).

The examination flowchart for suspected respiratory tuberculosis in children is shown in Figure 1.

⁹ Order of the Ministry of Health of the Russian Federation No. 190n dated April 11, 2025, "On Approval of the Procedure and Timelines for Conducting Preventive Medical Examinations of Citizens for the Detection of Tuberculosis"

Table 11. Laboratory and instrumental monitoring of treatment

Appendix C. Patient Information

What is tuberculosis?

Tuberculosis is contagious and dangerous. Tuberculosis is an infectious disease transmitted to the environment by a sick person shedding mycobacteria (Koch's bacillus). Tuberculosis most commonly affects the lungs, and in children, the intrathoracic lymph nodes, but it can also develop in other organs (e.g., bones, brain, kidneys).

How could you contract tuberculosis?

The infection is most commonly transmitted via the respiratory tract, when microbes enter in large quantities with droplets of mucus and sputum released by adult and adolescent tuberculosis patients when sneezing, coughing, or talking. Mycobacteria are resistant to environmental factors and persist in the environment for a long time. An untreated patient with an infectious form of tuberculosis infects approximately 10–15 people per year. Relatives with tuberculosis (mothers, fathers, grandmothers, grandfathers, etc.) pose a particular danger to children. Tuberculosis can be contracted less frequently by consuming dairy products from animals with tuberculosis.

When does tuberculosis develop?

When the tuberculosis bacillus enters the body, a "battle" begins between the microbe and the host. The body's defense mechanisms (immunity) in most cases prevent tuberculosis from developing. Therefore, Mycobacterium tuberculosis can remain "dormant" in your body for a long time without causing illness. However, if immunity is weakened, or if the infection is massive and constantly enters the child's body (through contact), the disease—tuberculosis—eventually develops.

How does tuberculosis manifest?

Tuberculosis in children can begin and proceed asymptomatically. In some patients, the early signs of the disease resemble a common cold. In most cases, the disease develops gradually, and as it progresses, the following symptoms may appear:

• Increased fatigue;

• Intractable cough (lasting 2–3 weeks); Decreased appetite;

• Weight loss; Irritability, poor sleep;

• Evening low-grade fever (often 37.5–37.6 °C); Night sweats;

• If symptoms of the disease appear, you must consult a doctor!

How is tuberculosis detected?

In children, tuberculosis is detected using immunodiagnostic tests. Annually, starting at one year of age, children undergo tuberculin skin testing (Mantoux test with 2 TU); starting at 8 years of age, recombinant tuberculosis allergen in standard dilution** (RTA) is used. Radiological examination is then performed based on the test results. Immunodiagnostic tests are necessary for the early detection of tuberculosis, as its initial stages are asymptomatic.

How is tuberculosis treated?

Tuberculosis is a serious disease requiring careful and prolonged treatment under the supervision of a specialist (phthisiatrician). Treatment is long-term—6 months or more. With regular medication intake, tuberculosis is curable.

During the treatment course, your doctor will monitor the tolerability of antituberculosis drugs, checking bilirubin and liver enzymes in blood tests monthly. If complaints of nausea or vomiting occur, tests are prescribed ahead of schedule, and the doctor adjusts the medication regimen.

Tuberculosis prevention

Tuberculosis prevention begins in the maternity hospital. Healthy newborns receive the tuberculosis vaccine on the 3rd day of life. The vaccine protects young children from tuberculous meningitis, the development of which in unvaccinated children is fatal. In a tuberculosis infection focus (sick relatives), the following measures must be implemented: regular wet cleaning, isolation of the patient or the child from the patient (sanatorium), and terminal disinfection after the patient's isolation. Children from contact environments are prescribed preventive antituberculosis treatment for 3–6 months to prevent the development of the disease.

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

Information is not available.