Inoculation from tuberculosis

Tuberculosis is the most important problem in the world, 24,000 people get sick every day, and 7,000 people die. The vaccination against tuberculosis is included in the WHO Expanded Program on Immunization; it is carried out in more than 200 countries, over 150 countries implement it in the first days after the birth of the child. 59 countries are revaccinating. A number of developed countries with a low (10 per 100 000) incidence of tuberculosis (USA, Canada, Italy, Spain, Germany) are vaccinated only in at-risk groups.

The incidence of tuberculosis in Russia has increased from 34 in 1991 to 85.4 per 100,000 in 2002, in 2004-2007, it declined slightly and is in the range of 70-74 per 100 000. The incidence of children aged 0-14 years in recent years has changed little (14-15 per 100 000), among all those with tuberculosis they are 3-4%, and in children often there is a hyperdiagnosis due to the so-called small forms. The incidence of adolescents is 15-17 years old, in 2007 it was 18.69 per 100 000. Naturally, in Russia, mass vaccination against tuberculosis is necessary, vaccinations only for children at social risk and contact groups, as is the case in the USA, Germany and other countries with a low incidence of tuberculosis, is unacceptable for our conditions, although, taking into account the frequency of BCG osteitis, the inoculation of vaccination in more affluent areas to older age suggests.

[1], [2], [3], [4], [5], [6], [7], [8],

Indications for vaccination against tuberculosis

Vaccination is carried out by a practically healthy new-born BCG-M vaccine at the age of 3-7 days. The BCG vaccine is used in newborns in subjects of the Russian Federation with incidence rates above 80 per 100 thousand population, and also in the presence of patients with tuberculosis.

BCG vaccines registered in Russia

Vaccine	Content	Dosage
BCG - live lyophilized tuberculosis vaccine, Microgen, Russia	1 dose - 0.05 mg in 0.1 ml of solvent (0.5-1.5 million viable cells)	Ampoules 0.5 or 1.0 mg (10 or 20 doses), solvent - saline solution about 1.0 or 2.0 ml
BCG-M - live lyophilized tuberculosis vaccine with a reduced number of microbial cells, Microgen, Russia	1 inoculation dose - 0.025 mg in 0.1 ml of solvent (0.5-0.75 viable cells, ie with a lower limit, like BCG)	Ampoules of 0.5 mg vaccine (20 doses), solvent (0.9% sodium chloride solution) 2.0 ml.

Newborns with contraindications are treated in the departments of neonatal pathology (stage 2), where they should be vaccinated before discharge, which will ensure a high level of coverage and reduce the number of children vaccinated in the clinic. Children who are not vaccinated during the newborn period should be vaccinated within 1-6 months. Life, children older than 2 months. Grafted with a negative result of the Mantoux reaction.

Revaccination is performed by tuberculosis-negative children who are not infected with tuberculosis at the age of 7 and 14 years. With the incidence of tuberculosis below 40 per 100 thousand population, revaccination against tuberculosis at 14 years is carried out by tuberculo-negative children who were not vaccinated at 7 years of age.

The experience of VA. Aksenova in the Moscow region showed the validity of revaccination not in 7, but in 14 years. Vaccination of the newborn leads to a long (up to 10 years and more) preservation of immunity with postvaccinal or infra-allergies, followed by the development of a more pronounced sensitivity to tuberculin. Postponement of revaccination to the age of 14 does not increase the incidence of tuberculosis in children and adolescents in regions with a satisfactory epidemiological situation. Refusal of revaccination at 7 years reduces the number and severity of positive Mantoux reactions, which facilitates the detection of infection, reducing the number of diagnostic errors by 4 times.

Characteristics of the vaccine against tuberculosis

The BCG vaccine contains both living and dying cells in the manufacture of cells. In the BCG-M vaccine, the proportion of living cells is higher, which allows a lower dose to obtain a satisfactory result and a minimum of undesirable reactions. Both vaccines are from the M.bovis sub-strain - BCG-1 Russia, which, with high immunogenicity, has an average residual virulence. Both BCG preparations meet WHO requirements. Storage and transportation conditions: the preparations are stored at a temperature of no more than 8 ° C. The shelf life of the vaccines BCG-2 years, BCG-M-1 year.

[27], [28], [29], [30],

Method of administration of the vaccine against tuberculosis and dosage

BCG and BCG-M vaccines are given intravenously at a dose of 0.1 ml, for which the ampoule is transferred with a sterile syringe with a long needle. The vaccine forms a suspension for 1 minute after 2-3 times shaking, it is protected from light (a cylinder of black paper) and consumed immediately.

Before each set, the vaccine is carefully mixed with a syringe 2-3 times. For one inoculation, 0.2 ml (2 doses) are collected by a sterile syringe, then 0.1 ml of the vaccine is released through a needle into the cotton swab to expel the air and bring the syringe plunger to the desired calibration of 0.1 ml. A single syringe can be administered to only one child. It is forbidden to use syringes and needles with expired shelf life and needleless injectors. The vaccine is administered strictly intradermally at the border of the upper and middle third of the outer surface of the left shoulder after treatment with 70% alcohol. Bandages and treatment of the place of administration of the vaccine with iodine and other disinfectants are prohibited.

The effectiveness of vaccination against tuberculosis

Mycobacteria of BCG-1 strain, multiplying in the grafted organism, create a long-term immunity to tuberculosis 6-8 weeks after immunization, providing protection against generalized forms of primary tuberculosis, but not protecting against the disease in case of close contact with bacillus and without preventing the development of secondary forms of tuberculosis . Vaccination reduces the infection of contacts. The prophylactic effectiveness of vaccination of newborns is 70-85%, almost completely protecting against disseminated tuberculosis and tuberculous meningitis. A 60-year follow-up of a high-risk group for tuberculosis (Indians and Eskimos USA) showed a 52% reduction in the incidence of vaccinees over the entire period compared with those receiving placebo (66 and 132 per 100,000 person-years). More advanced vaccines are being developed, including from M. Hominis.

Contraindications to the use of the vaccine against tuberculosis

Contraindication to BCG vaccination is prematurity (as well as intrauterine hypotrophy of 3-4 degrees) - body weight at birth less than 2500 g. The use of the BCG-M vaccine is acceptable starting from the weight of 2000. Premature babies are grafted with restoring the initial body weight - the day before discharge from the hospital (department of the third stage). In newborns, the withdrawal from BCG is usually associated with a purulent-septic disease, hemolytic disease, severe CNS lesions.

Contraindication to vaccination - the primary immunodeficiency - it should be remembered if other children in the family had a generalized form of BCG, or death from an unclear cause (probability of immunodeficiency). WHO does not recommend the vaccination of children with HIV-infected mothers until they find out their HIV status (although it recommends this practice in regions with a high tuberculosis infection in the absence of identification of HIV-infected children). Although perinatally infected children of HIV remain immunocompetent for a long time and the vaccine process is normal, if they develop AIDS, it is possible to develop generalized BCG-ita. Moreover, during the chemotherapy of HIV-infected children, "inflammatory syndrome of immunological reconstitution" with multiple granulomatous foci develops in 15-25%.

It is important to avoid subjective approaches to newborn BCG and to organize vaccinations in the second stage of nursing, since it is among the non-vaccinated children (only 2-4% of them) that the majority of severe forms of tuberculosis are registered and up to 70-80% of all deaths.

Contraindications for revaccination are:

1. Immunodeficiency states, malignant blood diseases and neoplasms. In the appointment of immunosuppressants and radiation therapy, the vaccine is given no earlier than 12 months. After the end of treatment.
2. Active or transferred tuberculosis, infection with mycobacteria.
3. Positive and questionable Mantoux reaction with 2 TE PPD-L.
4. Complicated reactions to previous administration of BCG vaccine (keloid scars, lymphadenitis, etc.).

In the presence of acute or exacerbation of a chronic disease, the inoculation is carried out 1 month after its termination. When contacting an infectious patient, vaccinations are carried out at the end of the quarantine period (or the maximum incubation period).

[9], [10], [11], [12], [13], [14], [15], [16], [17],

Response to the introduction of the vaccine against tuberculosis and complications

Reactions

At the site of intradermal injection of BCG and BCG-M, an infiltrate 5-10 mm in size with a nodule in the center and crusty in type of smallpox, sometimes a pustule or a small necrosis with a scanty serous discharge develops. In newborns, the reaction appears after 4-6 weeks; after revaccination is sometimes already on the 1st week. The reverse development occurs within 2-4 months, sometimes more, in 90-95% of the grafted remains a hem of 3-10 mm.

Complications

Complications are divided into 4 categories:

1. Local lesions (subcutaneous infiltrates, cold abscesses, ulcers) and regional lymphadenitis.
2. Persistent and disseminated. BCG infection without a lethal outcome (lupus, osteitis, etc.).
3. Disseminated BCG infection, generalized lethal outcome, which is observed with congenital immunodeficiency.
4. Post-BCG syndrome (manifestations of a disease that arose shortly after BCG vaccination, mainly of an allergic nature: erythema nodosum, annular granuloma, rash, etc.).

Among all post-vaccination complications in Russia, the bulk is associated with BCG, their number is about 300 cases per year (0.05-0.08% grafted).

The decrease in the indicator in comparison with 1995 occurred against the background of the introduction of a new method of registration, as evidenced by an increase in the number of complications in 1998-2000.

Among children with local complications, BCG is three times more vaccinated than BCG-M grafted, indicating greater reactogenicity of the first (although there is no exact data on the proportion of vaccines given by different vaccines), which served as the basis for switching to BCG-M for vaccination newborns.

The incidence of complications per 100,000 in 1995 and 2002-2003.

Complication	Vaccination		Revaccination
	1995	2002-03	1995	2002-03
Lymphadenitis	19.6	16.7	2.9	1.8
Infiltrate	2.0	0.2	1.1	0.3
Cold abscess	7.8	7.3	3.9	3.2
Ulcer	1.0	0.3	2.5	0.7
Keloid, scar	0.2	0.1	0.6	0.2
Osteitis	0.1	3.2	-	-
Generalized BCG-it	-	0.2	-	-
All	30.9	28.1	10.9	6.1

Only 68% of children with complications from the primary vaccinated were vaccinated in the maternity hospital, 15% in the polyclinic, although only 3% of children are vaccinated there. Obviously, this is due to less experience of intradermal injections in nurses of polyclinics; The risk of complications in specially trained personnel is 4 times lower than that of those who have not received training. A disproportionately large number of children with complications vaccinated in the polyclinic dictates the need for maximum coverage of children with vaccination before discharge from the maternity hospital or the nursing department of newborns.

[18], [19],

Clinical forms of post-vaccination complications

An ulcer is a defect in the skin and subcutaneous tissue at the site of administration of a vaccine measuring 10-30 mm, the edges are pinched. Ulcers rarely (2.7%) are considered a serious complication. More often ulcers are reported during revaccination, BCG-M does not cause almost ulcers.

Infiltrate size of 15-30 mm or more, in the center of it may be ulceration, often with an increase in regional lymph nodes. And this complication is rarely recorded (1.5%), every third child with an infiltrate was vaccinated in the polyclinic.

Cold abscess (scrofuloderma) is a painless formation with fluctuations without changing the skin, often with an increase in axillary lymph nodes, rarely with fistula. In non-nursing form, 76% were children under 1 year, 16% - 5-7 years, 8% - 13-14 years. Only 60% of infants were vaccinated in the maternity hospital, 40% in the polyclinic.

Lymphadenitis - found mainly in young children. The enlargement of the lymph nodes is painless, more than 10 mm (only more than 15 mm are taken into account abroad); a size of 20-40 mm was observed in 17% of children. Their consistency at first soft, later dense. The skin above them is not changed or pinkish in color. The process can be accompanied by caseization with the breakout of caseous masses outward and the formation of a fistula. 80% Children were vaccinated in the maternity hospital, 10% in the polyclinic, 2.4% in the hospital, and 4% in the school. The share of vaccinated BCG vaccine - 84% - was significantly higher than among children with infiltrates and abscesses. Localization: in 87% - left-sided axillary, 5% - over-, rarely - subclavian nodes on the left, in cervical and right axillary.

Fistulas of lymphadenitis were observed only in children under 1 year after vaccination. 90% of children are vaccinated in the maternity hospital, 10% - in the polyclinic, BCG vaccine - 90%.

Keloid scar is a tumor-like formation in the place of administration of the vaccine, which rises above the level of the skin. Unlike the scar in the normal course of the vaccine process, the keloid has a cartilaginous consistency density with well-visible capillaries and a smooth, glossy surface from pale pink, pink to cyanotic, to brownish; sometimes accompanied by itching. They account for 1.5% of the total number of complications, 3/4 of them after the 2nd and only 1/4 - after the 1st revaccination.

Ostestheses are isolated foci in the bone tissue, often located in the femoral, humerus, sternum, and ribs.

Although to prove the connection of osteitis with BCG, it is necessary to obtain a culture of mycobacteria and to typify it. The order of the Ministry of Health and Social Protection of the Russian Federation No. 109 dated March 21, 2003 states that "if it is impossible to verify the causative agent M. Bovis BCG, the diagnosis of postvaccinal complications is established on the basis of a comprehensive examination (clinical, radiological, laboratory)." A practical criterion that allows one to reasonably assume the postvaccinal etiology of the bone process is the limited focus of the lesion in a child aged 6 months. Up to 1-2 years, not having other tuberculous lesions. This approach is justified, since infection with tuberculosis at this age is accompanied by the development of generalized and / or pulmonary forms of the disease, and bone injuries, if they occur, are of multiple nature (Spina ventosa). Until recently, in Russia, many cases of BCG-osteitis are registered as bone tuberculosis, which allowed them to be treated free of charge; so a report of 132 cases of osteitis in 7 years should be compared with the number of cases of "isolated tuberculosis of bones" in children 1-2 years old. The need to diagnose bone tuberculosis instead of BCG-osteitis has disappeared in connection with the publication of the Order of the Ministry of Health of the Russian Federation of 21.03.2003 No. 109, which led, most likely, to an increase in the registration of BCG-osteitis, whose share among all complications reached 10%.

For 2002-03 years. 63 cases of osteitis were registered; in the same years 163 cases of isolated bone tuberculosis in children under 2 years of age, i.е. In total we can talk about 226 cases. During these years, 2.7 million newborns were vaccinated, so that when recounting to the number of primary vaccinated the frequency was 9.7 per 100,000.

According to foreign sources, the frequency of osteitis and non-lethal disseminated forms after vaccination with BCG has a very wide range, according to WHO - from 1: 3,000-1: 100 million, and a smaller spread is indicated - 0.37-1.28 per 1 million vaccinated. Our data on the frequency of osteites are comparable only with data published in Sweden (1.2-19.0 per 100,000 vaccinated), Czech (3.7), and Finland (6.4-36.9), which served as the basis for the abolition of BCG vaccination there; in Chile, with an osteitis rate of 3.2 per 100,000, the vaccination of newborns was not discontinued.

Cases of osteitis were noted, mainly in children under 1 year. Most of the children were vaccinated in the hospital (98%). BCG received 85% of patients with BCG, and 15% with BCG-M. 94% of children required surgical treatment.

Immunological examination (Institute of Immunology of the Ministry of Health and the Ministry of Health of the Russian Federation), 9 children with osteitis chronic granulomatous disease (CGD) was detected in 1 child, the deficit of production of interferon-γ - in 4 children. The remaining children had less severe disturbances in the interferon-γ system: inhibition factors, a violation of receptor activity, a defect in the IL-12 receptor, and a deficiency of surface molecules involved in the response to PHA. It is known that these defects are detected in generalized complications of BCG, and their carriers are highly susceptible to mycobacterial infections. Therefore, there is no reason to associate these complications with defects in vaccination techniques, combining neonatal immunizations against tuberculosis and hepatitis B, and especially with the quality of the vaccine (cases of osteitis are rare and occur with different vaccine series).

Generalized BCG-it is the most severe complication of BCG vaccination, which occurs in newborns with defects in cellular immunity. Foreign authors give the frequency of generalized BCG-ita - 0.06 - 1.56 per 1 million vaccinated.

For 6 years in Russia there were 4 such complications (0.2% of the total number). During this period, about 8 million newborns were vaccinated, so the frequency of generalized BCG-it was about 1 per 1 million vaccinations.

Most often, children are diagnosed with HBB, less often with hyper IgM syndrome, total combined immunological failure (1 child successfully underwent bone marrow transplantation). Boys accounted for 89%, which is natural, since chronic granulomatous disease has X-linked heredity. All children were under the age of 1 year. Children were vaccinated most often in the hospital with BCG or BCG-M vaccines.

The possible interaction of BCG and hepatitis B vaccines with introduction in the neonatal period was discussed for a number of years. Most experts, based on domestic and foreign data, rejected the possibility of an adverse result of such a combination, which is not supported by facts. This provision was fixed by Order No. 673 of October 30, 2007.

[20], [21], [22], [23], [24], [25], [26]