TUBERCULOSIS TREATMENT AND PROPHYLAXIS

TUBERCULOSIS TREATMENT

The treatment of tuberculosis patients is the principal component of the combat measures aimed at the illness, as due to the patients’ healing, the sources of infection are annuled and tuberculosis epidemiological situation improves. Under present conditions a prominent place is occupied by complex, differential treatment, starting from the moment of diagnosing an illness until reaching clinical recovery.

The complex treatment of pulmonary tuberculosis patients includes: antimycobacterial therapy, pathogenetic treatment, colapsotherapy and surgical methods of treatment, symptomatic therapy and urgent aid at tuberculosis complications.

ANTIMYCOBACTERIAL DRUGS

Antimycobacterial therapy is the principal method of treating tuberculosis patients of various organs and systems. According to their effectiveness antimycobacterial drugs are divided into three groups.

Group I (A) includes the most effective drugs: isoniaizdum (and its derivatives) and rifampicinum.

Group II (B) includes the drugs of average effectiveness: streptomycin, pyrazinamidum, kanamicini, florimycini, ethambutolum, ethionamidum and cycloserinum, morphazinamidum, ofloxacin, capreomycinum.

Group III (C) includes the least effective chemodrugs: PAS and thioacethazonum. In general the most active antimycobacterial drugs are isoniazidum, rifampicinum, then streptomycin and pyrazinamidum.

The effectiveness of the drugs is assessed for their bacteriostatic or bactericidal activity, ability to penetrate through cell and tissue membranes; their action to MBT of intracellular location and to MBT multiplying rapidly as well as to persisting forms. Bactericidal action in therapeutic doses is only characteristic of rifampicinum.

 

By the way, in our opinion, the optimal is distribution antimycobacterial  preparations on lines (the table 1).

                                                                                                       Table 1

Names of antitubercular preparations and their reductions

 

Antitubercular preparations	№	Names of antitubercular preparations	Symbol of antitubercular preparations
1 line	1 2 3 4 5	Isoniazidum Rifampicinum Streptomycin Ethambutolum Pyrazinamidum	H R S E Z
2 line	6 7 8 9 10 11 12 13 14	Amikacin Kanamycin Ethionamidum Prothionamidum Cycloserinum Ofloxacin Ciprofloxacin Capreomycin Natrii paraaminosalicylic acid	A K Et Pt C Of Cf Cp PASA
Others	15 16 17 18 19 20 21 22	Rifabutinum Clarythromycin Amoxicillin/clavulanic acid Clofazimin Florimycin Phthivazidum Flurenizid Thioacetazonum	Rb Cl Am Clo F Ph Fl T

 

Isoniazidum – is the principal representative of hydrazide isonicotine acid group (HINA), the most effective among all antimycobacterial drugs, strictly specific only against MBT, penetrates through cell and tissue membranes and through haematoencephalic barrier well. Isoniazidum acts to the MBT located extra- and intracellularly, to MBT that multiply rapidly and to a less degree to those that multiply slowly.

 The action mechanism of the drug is conditioned by blocking or inactivation of enzymes and co-enzymes of a microbic cell, resulting in the disturbance of protein metabolism, DNA, RNA and phospholipids synthesis, as well as MBT oxidicreducing processes. Isoniazidum is rapidly absorbed after peroral intake and in 1,5-3 hours the maximum drug concentration in the blood is noted. During 12 hours isoniazidum is excreted with urine.

Isoniazidum is manufactured in tablets of 0,1 g, 0,2 g, 0,3 g, as well as in ampules of 5 ml of 10 % solution. A daily dosage of the drug is 8-10 mg/kg, for adults 0,3-0,6 g, after meal, is administered to be taken at once or in two intakes. Isoniazidum may be introduced intravenously, intramuscularly and in aerosols (fig.1, 2).

Fig. 1. Isoniazidum in tablets

Fig. 2. Isoniazidum (10 % solution)

         Side effect and complications of isoniazidum: headache, vertigo, sleeplessness, euphoria, lowering of memory, cardialgy, arthralgia, hepatitis, peripheral neuritis, hypersensibility, psychosis, spasms, allergic eruption, gynecomastia, menometroragia. The prophylaxis of neurotoxic complications are vitamins B₁, B₆.

Isoniazidum derivatives: Phthivazidum, 0,5 g three times a day (30-40 mg/kg); Methazidum 0,3 g three times a day (20 mg/kg); Larusanum 0,5 g 2-3 times a day as well as Saluzidum of 0,5 g 2-3 times a day (20 mg/kg). Saluzidum is manufactured in ampules in the form of 10 % or 5 % solution, for endobronchial and intrapleural introduction.

Rifampicinum is a semisynthetic antibiotic with a wide action spectrum. The drug possesses an expressed bacteriostatic activity to MBT, which are distributed extracellularly and in the cells (intracellularly), as well as to the ones that multiply quickly and slowly. It penetrates well through hemato-encephalic barrier, into various tissues of an organism, areas of specific lesion, caseose. Rifampicinum concentration peak in the blood comes in 1,5-4 hours after its intake, and the drug bacteriostatic concentration in the blood is preserved for over 12 hours. Rifampicinum tuberculostatic action mechanism consists in depression the synthesis of ribonucleic acid of tuberculosis micobacteria, by blocking RNA-polymerase.

Rifampicinum is manufactured in capsules of 0,15 g, 0,3 g and in ampules. A daily dosage is 8-10 mg/kg, in average for an adult of 0,45-0,6 g at once perorally, 30 minutes before a meal. Rifampicinum may be introduced intravenously drop by drop and endobronchially (fig. 3, 4).

Fig. 3. Rifampicinum in capsules.

Side effect and complications: hyperthermia, rhinitis, myalgia, arthralgia, dyspeptic disturbances, obstructive respiratory disturbances, skin eruptions, hae-matologic complications (erythrocyte hemolysis), hemorrhages, hepatitis, liver-renal insufficiency, anaphylactic reactions.

During treatment with Isoniazidum and Rifampicinum hepatotoxic reactions are possible. Hepatoprotectors (vitamins, carsil, essentiale, legalon. thiotriasolin), antioxidants (tocoferol acetat, galascorbin) and hypoxants (calcium manganat, pyracetam), vitamins B₁, B₆, C are prescribed with a prophylactic purpose.

 

 

Fig. 4. Rifocine in ampules.

At irregular dose of Rifampicinum, antibodies to the drug may form resulting in erythrocytes hemolysis, acute renal or renal-liver insufficiency. In such cases Rifampicinum is immediately cancelled, corticosteroid hormones are prescribed, hemodialysis is applied. Rifampicinum is contraindicated at hepatites, kidney diseases.

Streptomycini group: Streptomycini sulfas, Dihydrostreptomycini sulfas, Streptomycini et calcii chloridum. They are all antibiotics, of which Streptomycini sulfas is most often used. In therapeutic doses it acts bacteriostatically only on MBT, that rapidly multiply and are distributed extracellularly. Streptomycini inhibits oxidation process and protein synthesis in a bacterial cell due to transport RNA binding. In the processes of Streptomycini treatment phagocytosis activates, as well as forming of granulation tissue, while in the healing processes fibrotization and encapsulation of specific nidi prevail.

The peak of Streptomycini concentration in blood after intramuscular infusion comes in 2 hours. A daily Streptomycini dosage is 15-20 mg/kg (averagely for an adult – 0,75-1,0 g). Except for intramuscular infusion, the drug may be administered intrapleurally, endobronchially, in aerosols. For endolumbar administration only Streptomycini et calcii chloridum in the dose of 0,1-0,2 g is used (fig. 5).

      

Fig. 5. Streptomycini

Side effect and complications: analgesic action with hyperemia and skin and mucous membranes eruptions, Quincke’s oedema, bronchospasm, anaphylactic shock, neurotoxicity, ototoxicity, nephrotoxicity, cardiotoxic action.

At anaphylactic shock noradrenalin, prednisolon are infused intravenously drop by drop; at bronchospasm – euphilin. With the purpose of ototoxic complications prophylaxis, calcii pantotenatum is prescribed of 0,4 g twice a day or 2 ml of 20 % solution twice a day intramuscularly.

Kanamycini sulfas belongs to aminoglycozide antibiotics. Bacteriostatic action on MBT is lower, in comparison to Streptomycini, and toxicity is higher. The mechanism of tuberculostatic action on MBT is analogous to that of Streptomycini, dosages and methods of administration, side effect and complications (ototoxicity and nephrotoxicity) (fig. 6).

 Florimycini sulfas or Viomycini sulfas is an antibiotic, close according to its properties to Streptomycini and Kanamycini, however its bacteriostatic activity on MBT is lower and toxicity higher. Florimycini acts on MBT, stable to Streptomycini and

 

Fig. 6. Kanamycini sulfas

         Kanamycini, however a bacterium, resistant to Florimycini, is at the same time insensitive to both antibiotics. Thus, these antibiotics are administered in a certain succession: Streptomycini, Kanamycini, Florimycini.

Capreomycinum is an antibiotic produced by Streptomyces capreolus. Production form: 0,5 g or 1 g bottles. Pharmacological features. Capreomycinum effects tuberculous mycobacteria which are especially stable to other antibiotics preparations and is little active as regard other microorganisms. After the intramuscular administration the maximum content in the blood is observed in an hour, it remains for 2-3 hours and in 24 hours the preparation is totally eliminated.

         It is prescribed at all clinical tuberculous forms and localizations. It is administered intramuscularly in 0,015-0,02 g/kg dose (about 1g/day) daily for 2 months, after that – twice a week up to the completion of the treatment. For children it is administered on the basis of 0,015g/kg dose.

         Counterindications, warnings, side effects and complications are the same as for streptomycin.

 

Ofloxacin. Synonymes: tarivid, ofloxin, ciprofloxacin, zanocin. Production form: 0,2 g drugs. Pharmocological capacities. Ofloxacin is an antibiotic of the wide range of action, including tuberculosis mycobacteria. The period of semiwithdrawal – 6 hours. It is administered at all clinical forms and localizations of tuberculosis on the basis of 0,008-0,015 g/kg per day. Average doses: for one time – 0,5-1 g, daily – 0,5-1g.

Counterindications: elevated sensibility to ofloxacin, epilepsy; pregnant and breast-feeding women, children and teenagers with incomplete skeleton growth. Warnings: it is not recommended to administer ofloxacin together with drugs which lower the acidity of stomach content (antacydes).

Side effect and complications: allergic reactions in type of skin eruptions, face swelling, swelling of vocal cords, shock is also possible. In individual cases there can be observed: abdominal pain, nausea, vomiting, diarrhea, headache, dizziness, sleep infringement, bilirubin level rise in blood serum.

Ethambutolum is a chemosynthetic antituberculous drug, which inhibits only the MBT, that multiply rapidly, distributed extra- and intracellularly. The mechanism of Ethambutolum action on MBT consists in blocking and exclusion from metabolic processes of Magnesium ions and suppression of nucleic acids synthesis. The drug absorbs well from the digestive canal into the blood, in which maximum of its concentration forms in 3-4 hours and bacteriostatic activity is maintained during 6 hours.

Ethambutolum is manufactured in tablets of doses 0,1g, 0,2g and 0,4g. A daily dosage is 20-25 mg/kg, an average dose for an adult is from 0,8 to 1,8 g, at once after breakfast (fig. 7).

Side effect and complications: retrobulbar neuritis with lowering the sharpness and narrowing the visual field to the green and red light, pain and gripes in the eyes, paresthesias, giddiness, epileptiform phenomena, hepatite, rash.

 

Before administering and in the process of Ethambutolum treatment the function of visual analyser is systematically tested. If necessary tocoferol acetat is administered – 1 capsule (0,05-0,1) once or twice a day. The drug is contraindicated at eye diseases, first and foremost – neuritis and retinitis.

Fig. 7. Ethambutolum

Pyrazinamidum is a specific chemodrug, which acts only on MBT, besides that in an acidic medium, i.e. in caseose. Pyrazinamidum is more active conformably to phagocytic MBT, in comparison to the ones distributed extracellularly. The drug being applied in the process of combined chemotherapy, the relapse risk decreases considerably, so as it acts on the MBT that multiply dilatorily in makrophages. The mechanism of tuberculostatic action of Pyrazinamidum consists in MBT oxygen intake suppression.

The drug absorbs well in the digestive canal, the maximum concentration in the blood comes in 3 hours after an intake; is has good diffusive properties; penetrates through hemato-encephalic barrier. The manufacturing form is in tablets of 0,5 g. A daily dosage is 25-30 mg/kg (for an adult – 0,5 g three times or 1 g twice a day) after meal (fig. 8).

Fig. 8. Pyrazinamidum

Side effect and complications: dispeptic disturbances, arthralgia, disturbances of blood hemostatic function, allergic dermatites, hyperthermia, hepatotoxic action. To prevent toxic injures of liver hepatoprotectors, vitamins B6, B12 are administered. Pyrazinamidum is contraindicated at severe diabetes, liver diseases, podagra.

Morphazinamidun 2-3 g/day. Pharmacological features, administration, indications, counterindications, warnings, side effects and complications are the same as with pyrasinamid. Ethionamidum and Protionamidum are chemosynthetic drugs, similar as to the chemical structure and the action mechanism, which is manifested only as to MBT. Bacteriostatic activity of Ethionamidum is 10 times lower, comparing to isoniazidum. The mechanism of Ethionamidum action consists in inhibiting the penetration of Sulphur, Phosphorus and Carbon into the protein and DNA of a microbic cell, the protein synthesis is disturbed, resulting in the MBT multiplying impediment. The drug acts efficiently in the acidic medium, suppresses MBT, which multiply rapidly, distributed extracellularly and intracellularly. The concentration peak in the blood comes in 3-6 hours after peroral intake. The manufacturing form is in tablets of 0,25 g. A daily dosage is 10-12 mg/kg (for adults – 0,25 g three times a day) after meal. In bottles of 0,5 g Ethionamidum chloride, for intravenous drop by drop infusion (fig. 9).

  

Fig. 9. Ethionamidum and Protionamidum

         Side effect: dyspeptic phenomena, headache, sleeplessness, neurities, depression, psychic discords, cardialgia, hepatite, endocrine disturbances (gynecomastia, impotence, uterine flooding), pellagrous phenomena, skin pigmentation and rash (shedding), hair shedding, allergic responses. To prevent Ethionamidum side effect, nicotinamid, group B vitamins, enveloping means are administered simultaneously. Ethionamidum is contraindicated at hepatites, the digestive canal illnesses, during pregnancy (due to teratogenous action).

Cycloserinum is a synthetic antibiotic of a wide spectrum action, which inhibits the growth of the majority of Gram positive and Gram negative bacteria, rickettsiae, spirochetes. Bacteriostatic activity of Cycloserinum on MBT is 10 times as low as that of Streptomycini. Cycloserinum action mechanism consists in the violation of mycobacteria protein metabolism as a result of pyridoxalphosphate blocking. In addition to this, it binds a number of microelements, which play an important part as catalysts of oxidation processes. Cycloserinum acts on the MBT that multiply rapidly and those distributed intra- and extracellularly.

The drug is rapidly absorbed and its concentration peak in the blood comes in 3-4 hours, it efficiently penetrates into various organs and tissues. Cycloserinum is manufactured in tablets form of 0,25 g. A daily dosage is 10-20 mg/kg (for an adult – 0,25 g three times a day), before meals.

Side effect: functional disturbances of the central nervous system, nervous-psychonosis, headache, sleeplessness, depression, hallucinations, psychoses, cramps, peripheral neurities, cardialgia, dyspepsy.

With a view to prevent and suppress Cycloserinum side effect, glutamine acid, vitamins B1, B6 and ATP are administered. Natrii paraaminosalicylatis or PASA is Natrum (Sodium) is a sodium-specific antituberculous preparation.

Production form: powder and 0,5 g tablets; 3% solution in 250-500 ml bottles. PASA-sodium suppresses the growth of tuberculous mycobacteria. Concentration peak in blood in case of oral administration takes place in two hours and in 8 hours only the medicine traces are observed. It is administered at all clinical forms and localizations of the process 0,15-0,2 g/kg a day. Average doses: per one time – 4-12 g, per day – 9-12 g. Intravenously 300-500 ml of the 3% solution of PASA -sodium.

         Counterindications: diseases of kidneys, liver, blood, hypofunction of thyroid gland, cardiovascular insufficiency of stage III, stomach and duodenum ulceric disease, elevated sensibility to PASA. Side-effects and complications: dyspeptic disorders, allergy, anemia, hepatitis, agranulocytosis, pain in the heart area. Bepasum is a para-benzoilaminosalicytate of calcium. Production form: tablets, powder – 0,5 g. Pharmacological features, administration, indications, counterindications, warnings, side effects and complications are similar to PASA.

At present time the preparation is applied very rarely because of its inconsiderable bacteriostatic activity conformably to MBT and its frequent side responses.

 

Thioacethazonum is a chemosynthetic drug with a weak bacteriostatic activity and rather high toxicity. Thioacethazonum action mechanism consists in aminooxidase activity suppression and the disturbance of microbic metabolic processes. The drug acts only on the MBT multiplying rapidly.

After peroral intake the drug is rapidly absorbed and the concentration peak comes in 2 hours. Thioacethazonum is the most effective at tuberculosis of mucous membranes, lymphatic nodes, skin. It is manufactured in tablets of 0,025 g and 0,05 g. A daily dosage is 2-2,5 mg/kg for an adult, 0,05 g three times a day. For endobronchial and aerosol intake, dissoluble Thioacethazonum – Soluthisonum in ampules of 2 ml of 2 % solution is used.

Side effect: hepatotoxicity and neurotoxicity, dyspeptic phenomena, allergic responses, giddiness; frequently suppresses blood formation, which may be manifested in the form of leucopenia, thrombocytopenia and agranulocytosis.

Thioacethazonum is contraindicated at the diseases of liver, kidneys, bloodforming organs, diabetes.

The following drugs are used for the treatment of tuberculosis patients at present time: flurenizidum, rifabutin, rifapentin and also ofloxacin, cyprofloxacin, pefloxacin and lomefloxacin (of Fluarinechinilines group), roksitromycinum, azitromycini and claritromycini (of Macrolides group), amykacinum (of Aminoglycoside group). Combined antimycobacterial drugs: rifater,  mairini and macox.

Mairin is produced in tablets, each containing 225 mg of etambutol, 120 g of riphadin, 60 mg of isoniaside and 300 mg of pyrasinamid. The average daily dose for adults – 5 tablets.

Macox is produced in tablets, each containing 225 mg of rifampicinum, 750 mg of pyrasinamid, 150 mg of isoniaside. The average daily dose for adults – 2 tablets.

 

Ofloxacinum, cyprofloxacinum, pefloxacinum, lomefloxacinum, roksitromycinum, azitromycini and claritromycini are successfully used in combination with tuberculostatics, first and foremost rifampicinum and isoniazidum. Amoxicilini/clavulanic acid or thienam are applied at tuberculous process progressing against the background of the treatment with antimycobacterial drugs.

During the recent years the effectiveness of tuberculosis patients treatment has deteriorated. The frequency of bacterioemission and the healing of destruction cavities decrease. One of the reasons of that situation are resistant or stable forms of tuberculosis. It’s proved that treatment schemes recommended by WHO are the most optimum and effective for the treatment of various categories of patients, including the patients with resistant tuberculosis. However, those schemes at various clinical tuberculosis forms, including the chemioresistant one, require essential correction; doctors may change them relating to the sensibility of MBT to antimycobacterial preparations and to the regimes of previous treatment.

From the clinical point of view, all antimycobacterial preparations are divided into main, “standard” preparations (isoniasidum, rifampicinum, streptomycini, ethambutolum, pirazinamidum) and reserve ones. Table 2 shows antimycobacterial preparations which are used for the treatment of patients with chemioresistant tuberculosis.

                                                                                                       Table 2

 

Antimycobacterial preparations used for the treatment of patients with chemioresistant tuberculosis

 

Preparation name	Average dose for an adult, g
	per one time	per day
Rifampicinum	0,6	0,6
Isoniazidum	0,3-0,6	0,45-0,6
Ethambutolum	1,2-2	1,2-2
Streptomycini	1	1
Pyrazinamidum	1,5-2	1,5-2
PASA-sodium	4-12	9-12
Ethionamidum	0,5-0,75	0,5-1
Cycloserinum	0,25	0,75
Kanamycini	1	1
Amykacinum	1	1
Rifabutin	0,45	0,45
Cefalosporinum	1	2
Cyprofloxacinum	0,5-0,75	1
Ofloxacinum	0,5-1	0,5-1
Pefloxacinum	0,4-0,8	0,4-0,8
Lomefloxacinum	0,4	0,4
Morphazinamidum	1,5-2	2-3
Roksitromycinum	0,3	0,4
Azitromycini	0,5	0,5
Claritromycini	0,5	0,5
Thienam	1	1
Amoxicilini/clavulanic acid	1,2	1,2
Capreomycinum	1	1

 

THE MAIN PRINCIPLES AND METHODS OF TUBERCULOSIS TREATMENT

         Antimycobacterial therapy is the main method of treating tuberculosis patients of any localization, following herewith certain principles:

1. Early and timely treatment, which should be started at early stages of the development of tuberculosis and immediately after its revealing. At early diagnostics of tuberculosis recovery comes in 100 %, at timely one – in 95-100 %, at untimely – in 89 % and at late diagnostics – in 10-15 % of cases.

2. The duration of treatment. The effectiveness of tuberculosis patients treatment depends on its duration. The optimum duration of the main course is from 6 to 18 months. The action of antimycobacterial drugs, on the whole, is bacteriostatic and therefore untimely cessation of treatment results in the reversal of persisting MBT into their initial forms and the emergence of aggravations and relapses of the specific process.

3. The continuity of treatment. Pauses in antimycobacterial drugs intake result in the development of medicinal stableness of MBT.

4. Multistage treatment includes: stationary + sanatorium + dispensary treatment.Generally, in a hospital (antitubercular hospital) at first (2-3 months) intensive, daily treatment with 3-4 antituberculous drugs is performed. At the second stage (4-8 months), when the MBT population has sharply decreased, the treatment may be proceeded with two drugs, in particular, by the intermittent method.

5. Combined chemotherapy. Perspectivelessness of monotherapy with any drug, resulting in rapid development of MBT stableness to it, has been proved. It is only the usage of 3-4 antituberculous drugs that can prevent the development of MBT medicinal stableness. The combination should include isoniazidum, rifampicinum, streptomycini or ethambutolum. These drugs are effective in 95 % of cases.

6. Controlled chemotherapy. The treatment of tuberculosis patients must be controlled since the patients often irregularly or arbitrarily terminate their treatment. At a hospital patients should take antimycobacterial drugs under the supervision of the medical staff, and during the ambulant intermittent therapy it is performed in a dispensary. All this enables 10-15 % increase of the treatment efficiency.

7. Complex treatment. It is a combined chemotherapy by means of antimycobacterial drugs, pathogenetic means as well as surgical intervention.

To pathogenetic means belong antihistamine and hormonal drugs, vitamins B₁ and B₆, antioxidants, proteinases inhibitors, tuberculin, immunomodulators, biogenic stimulators. In addition to this, phyto-, api- and phytoncidotherapy are applied.

Surgical treatment of tuberculosis patients includes the following methods:

1) radical (various kinds of lung resection, pleural ectomies); 2) collapsosurgical (thoracoplasty); 3) collapsotherapeutic (medicinal pneumothorax, pneumoperitoneum); 4) intermittent (cavernoplasticity, cavern drainage).

For treating a lung tuberculosis patient, the most effective regimen of chemotherapy should be applied, adequate to the process spreadness, availability of a decay cavity, bacterial excretion, as well as depending on the previous treatment and MBT sensitivity to antimycobacterial drugs. An important criterion of the treatment efficiency is bacterial excretion termination and decay cavities healing.

At firstly diagnosed small forms of tuberculosis without MBT after two months (initial stage) intensive treatment with three antimycobacterial drugs (isoniazidum, rifampicinum, streptomycin or pyrazinamidum), during 4 more months (continual stage) two drugs are administered for daily usage or in the intermittent regimen. Thus, the main course of treatment lasts for 6-8 months.

At firstly diagnosed destructive lung tuberculosis, for the first two months the treatment is performed with four antimycobacterial drugs, later on, prior to cavern healing, with three chemodrugs. After that patients are treated with two chemodrugs during 2-4 months. Hence, the main course of antimycobacterial therapy lasts for 6-12 months.

 

After successfully completed main course of antimycobacterial therapy, 2-months courses of antirelapse treatment with isoniazidum is performed for two more years in spring and autumn.

In patients with lung tuberculosis reactivation (aggravation, relapse), taking into account possible resistance of mycobacteria to one or a few drugs, 5 antimycobacterial drugs (isoniazidum, rifampicinum, streptomycin, pyrazinamidum, ethambutolum) are applied at the initial 3-months stage of the treatment. After the initial stage of antimycobacterial therapy has been successfully completed, the proceeding stage is started with two-three drugs (predominantly isoniazidum, rifampicinum, pyrazinamidum or ethambutolum), during 4-8 months.

Antimycobacterial therapy of previously treated chronic forms of lung tuberculosis patients is strictly individual (4-6 drugs), taking into account of various factors, first and foremost, drug sensitivity of mycobacteria, their tolerance, complications and accompanying pathology etc. The average duration of the treatment is 18-20 months.

In general, ethiothropic treatment of tuberculosis patients is performed differentially, depending on the clinical form of tuberculosis, drug tolerance and mycobacterial sensitivity to them. According to the data of world literature the most effective schemes are those recommended by the WHO, which have justified themselves on many thousands of patients in various countries of the world. That is why the regimens of chemotherapy mentioned above are recommended to be used here, since they are also provided for by the valid order of the MPH of Ukraine.

Antimycobacterial therapy, as has beeoted, consists of two stages: initial (intensive) and proceeding stage (rehabilitation), and all patients are divided into four categories, for which the WHO recommends appropriate schemes of treatment.

Category 1.

 

Category 1 includes the firstly detected patients with bacterial tuberculosis of lungs and the firstly detected patients with grave tuberculosis forms. There are patients with tuberculous meningitis, tuberculous pericarditis, peritonitis, pleuritis, spinal tuberculosis with neurologic complications, lungs tuberculosis without bacterioemission with destructive affection of parenchyma, tuberculosis of digestive and urinogenital organs (Tabl 3).

Table 3

Treatment scheme for patients of category I

Recommended preparations	Treatment duration	Preparation dose depending on patient’s body mass
		under 33 kg	33-50 kg	over 50 kg
1. Initial stage	2 months
isoniazidum	2 months	0,2 g daily	0,3 g daily	0,3 g daily
rifampicinum	2 months	0,3 g daily	0,45 g daily	0,6 g daily
pyrazinamidum +	2 months	1 g daily	1,5 g daily	2 g daily
ethambutolum	2 months	0,8 g daily	0,8 g daily	1,2 g daily
or
streptomicini	2 months	0,5 g daily	0,75 g daily	1 g daily
2. Continual stage:	4 months
isoniazidum +	4 months	0,2 g three times a week	0,3 g three times a week	0,4 g three times a week
rifampicinum	4 months	0,3 g three times a week	0,45 g three times a week	0,6 g three times a week

Category 2.

 

Category 2 includes patients with tuberculosis reactivation (exacerbation, recidivation) and those in whom treatment didn’t yield the expected results and the bacterioemission continues (Tabl 4).

Table 4

Treatment scheme for patients of category II

Recommended preparations	Treatment duration	Preparation dose depending on patient’s body mass
		under 33 kg	33-50 kg	over 50 kg
1. Initial stage	3 months
isoniazidum	3 months	0,2 g daily	0,3 g daily	0,3 g daily
rifampicinum	3 months	0,3 g daily	0,45 g daily	0,6 g daily
pyrazinamidum	3 months	1 g daily	1,5 g daily	2 g daily
ethambutolum	3 months	0,8 g daily	0,8 g daily	1,2 g daily
Streptomicin1	2 months	0,5 g daily	0,75 g daily	1 g daily
2. Continual stage:	5 months
isoniazidum +	5 months	0,2 g three times a week	0,3 g three times a week	0,4 g three times a week
rifampicinum +	5 months	0,3 g three times a week	0,45 g three times a week	0,6 g three times a week
ethambutolum2	5 months	0,8 g three times a week	1,2 g three times a week	1,6 g three times a week
1 Streptomicin should be  administered during the first two months of the starting phase. 2 If isoniazidum + rifampicinum + ethambutolum are administered for daily administration in the phase of continuity, then their doses are the same as in the initial phase.

Category 3.

Category 3 includes patients with firstly detected bacteriologically unconfirmed tuberculosis, lungs tuberculosis and with limited affection of lung parenchyma, and also patients with extralungs tuberculosis who don’t belong to category 1 (Tabl 5).

 

Table 5

Treatment scheme for patients of category III

Recommended preparations	Treatment duration	Preparation dose depending on patient’s body mass
		under 33 kg	33-50 kg	over 50 kg
1. Initial stage	2 months
isoniazidum	2 months	0,2 g daily	0,3 g daily	0,3 g daily
rifampicinum	2 months	0,3 g daily	0,45 g daily	0,6 g daily
pyrazinamidum	2 months	1 g daily	1,5 g daily	2 g daily
2. Continual stage:	4 months
isoniazidum +	4 months	0,2 g three times a week	0,3 g three times a week	0,4 g three times a week
rifampicinum	4 months	0,3 g  three times a week	0,45 g three times a week	0,6 g three times a week

 

Category 4.

Category 4 includes patients with chronic lungs tuberculosis. The characteristic feature of those patients is tuberculosis mycobacteria resistivity to antimycobacterial preparations, low effectiveness of treatment despite the durable stational cure.

          Patients with chronic forms of lung tuberculosis are treated individually with 4-6 drugs, with the consideration of MBT sensitivity and other factors, by the termination of bacterial excretion. In addition, the most effective regimens of chemotherapy are supposed to be: a) isoniazidum + rifampicinum + pyrazinamidum (or ethambutolum); b) isoniazidum + rifampicinum + pyrazinamidum + streptomycini + ethambutolum; c) isoniazidum + rifampicinum + pyrazinamidum + kanamycini + ethambutolum + thioacetasonum et al. In some cases of tolerance to isoniazidum, it may be injected intravenously as the 5-6th drug.

PATHOGENETIC TREATMENT OF TUBERCULOSIS

It is aimed at solving the following tasks:

1. Decreasing exudative pneumonic phenomena in a lesioidus, speeding up its resolution and healing with minimum residual changes;

2. Correction of metabolic processes and disfunctions of various organs and systems disturbed by tuberculous intoxication and antimycobacterial drugs;

3. Strengthening of feebly-expressed inflammatory reactions and stimulation

of repairing processes.

The following methods of rational therapy are applied to realize these tasks:

I. Common means of pathogenetic therapy, which include:

1. Hygienic-dietary regimen, which from strict bed care widens to spare diet, training and to labour adaptation regimen;

2. Rational high calory and vitaminized diet (No 11 diet according to Peuzner);

3. Physical metods and LFA: aero-, helio-, hydrotherapy, climatotherapy;

4. Psychotherapy and autogenous training;

5. Means of metabolic detoxication and correction, in particular protein and water- electrolytic metabolism; oxidation-reduction processes, acidicalkaline equilibrium, regulation of hemodynamics and diuresis.

The following means are used for reaching these purposes:

a) preperations of anabolic action: insulinum – 4-5 UN intramuscularly in the morning; anabolic steroid preparations (metandrostenolon or dianobol 0,005 g 1-2 times a day orally, fenobolil or durabolin, nerebolin – 1,0 ml intramuscularly once a week, retabolil – 1,0 ml 5 % oil solution 1 time per 2 weeks, methyltestosteron – 0,005 g  unde r the tongue 1-3 times a day);

b) energy metabolism stimulators (kokarboxylase hydrochloridum – 0,05 g intramuscularly once a day, ATA – 1,0 ml intramuscularly once a day, lipoyev acid 0,025-0,05 g orally 2-3 times a day);

c) polyvitamins, especially vitamin C 0,1 g orally three times a day, group B –  pentovit 3 drugs orally three times a day, among them with microelements: vitamax or vitamaxplus – 1 caps. orally once a day, multitubs – 1 drug orally once a day, unicup – 1 drug orally once a day;

d) antioxidants (tokoferol acetat – 1 caps. (0,05-0,1 g) orally 1-2 times a day, sodium thiosulfate 30 % solution 5,0 ml intravenously once a day, galascorbinum – 0,5 g orally three times/day);0

e) antihypoxantes (sodium oxibutyrat – 0,75 g orally 2-3 tjmes/day);

f) preparations of combined and immunotrophic action (riboxine – 0,2-0,4 g orally  before meals three times/day);

g) electrolytic solutions (neohemodesis, neocompensan, glyconeodesis, Ringer-Lock solution, reopolyglucin – 200-400 ml intravenously once/day), panangin – 1-2 dr. orally three times/day, calcium pangamat – 0,05-0,1 g orally three times/day; at expressed acidosis – 4 % solution of sodium hydrocarbonate 100-200 ml;

h) blood, plasma – 200 ml intravenously drop by drop once a week; albumin, protein transfusions – 100-200 мл intravenously drop by drop 1-2 times a week;

i) means of correcting misfunctions of internal organs and systems.

II. Immunocorrecting therapy. It is performed after studying the function of T-lymphocytes system (cell immunity), B-lymphocytes (humoral immunity), unspecific defence factors. Among immunocorrectors the following drugs are used: thymalin 0,005-0,01 g intramuscularly daily, tactivin 0,01 % solution (1-2 mkg/kg) subcutaneously at night during 10 days, sodium nucleinat 0,5 g orally after meals 3-4 times /day, splenin 2,0 ml intramuscularly daily during three weeks, than – 1,0 ml in a day during two months; levamisol or decaris0,15 g orally once a day during three days, than – once a week during three weeks; interferon – 5 drops iose 1-2 times/day, prodigiosan – 0,005 % solution 0,5 ml intramuscularly once at 5-7 days, during 3-6 weeks; ethymisol – o,1 g orally after meals three times/day, histaglobulin – 1,0 ml intramuscularly, than  – 2,0-3,0 ml once  at 3 days, course 5 – 10 injections.

Of unmedicamental treating methods for immunocorrection and as antiinflammatory methods enterosorption, hemosorption, speleotherapy, magnetotherapy, laser-therapy etc. are applied.

Immunocorrecting therapy should be performed after a patient’s intoxication liquidation.

III. Antiinflammatory drugs of unspecific action, which decrease excessive exudative-pneumonic reactions. They include:

1) corticosteroids: 2% hydrocortison suspension per 1,0 ml together with antimycobacterial preparations for inhalations at larynx and bronchi tuberculosis; prednisolon (starting with 0,02-0,04 g/day orally, having divided for 4-5 administrations, then the dose is decreased up to 0,005-0,01 g/day), dexamethason 0,002-0,003 g/day, triamcinolon  0,004-0,016 g/day orally in 3-4 administrations;

2) nonhormonal antiinflammatory means: pirasolon derivatives (butadion 0,15 g orally after meals 3 times/day, pirobutal 1 dragee orally after meals 3 times/day, bruphen 0,2 g orally after meals 3 times/day); phenotiasin derivatives (chlorochin, delagil 0,25 g orally after meals once a day); antihistaminic preparations (dimedrol 0,05g orally 1-3 times/day, phencarol 0,025-0,05g orally after meals 1-3 times/day, diprasin or pipolphen 0,025g orally after meals 2-3 times/day, diasolin 0,01-0,02g orally 2-3 times/day, suprastin 0,025g orally with meals 2-3 times/day, tavegil 0,001g orally twice/day);

3) proteolitic enzymes (tripsin, chimotripsin 0,005-0,01g intramuscularly 1-2 times/day or 0,005-0,01g  5ml of isotonic solution of sodium chloride or of the distilled water, for inhalations or endobronchial infusions);

4) inhibitors of proteolytic enzymes (contrical 10000-20000 units, gordox 100000-300000 units in 300-500ml of the physiological solution of sodium chloride intravenously drop by drop once a day, EAKK, amben);

5) dimexid possesses an expressed antiinflammatory effect and is able to transport other drugs into the tissue the 5-10% solution is administered 1,0-2,0ml together with heparin, novokain, antibacterial and corticosteroid preparations for inhalations, rinsing of purulent pleural cavity and tracheobronchial tree;

6) a group of biologically active drugs has an inflammatory and antiallergic effect, in particular pirogenal – 25-50 MDP intramuscularly once per 3 days and increasing it up to the body temperature rise up to 37,5-38° C, but not more than up to 1000 MPD of the preparation, and then the dose is gradually decreased up to the initial one; heparin – 5-10 thousand of units 2 times/day intramuscularly;

7) ethymisol –  0,1g orally after meals 3 times/day within 1 month;

8) physiotherapy (electrophoresis, intraorganal electrophoresis, inhalations);

9) phytotherapy with medicinal plants infusions and tinctures of antiin-flammatory (jointweed, knot-grass, greater celandine, st. John’s wort, marigolds, onion, garlic etc.) and adaptogenous (eleutherococus, ginseng et al.) action; they are used internally and for inhalations;

10) psychotherapeutic methods (autogenous training, psychotherapy, musictherapy, hypnosis and meditation).

IV. Stimulators of repairing processes and cavern healing. They are generally applied in 3-4 months, in the second stage of antimycobacterial therapy. They they include tuberculin, desoxicortikosteron acetate – 0,0025-0,005g under the tongue once/day or in a day, somatotropnin – 4 units intramuscularly in the morning before meals once a day, biostimulators (vitreous body – 1,0-2,0ml subcutaneously daily, plasmol – 1,0ml subcutaneously daily or in a day, aloe extract – 1,0ml subcutaneously, FIBS per 1,0ml subcutaneously, placenta extract per 2,0ml subcutaneously once – 7-10days, antireticular cytotoxic serum (ACS) – 0,5-0,75ml subcutaneously 2-3 times with the interval of 2-3 days; anabolic enzymes (nerobol, dianobol, retabolil, phenobolil), blood and its preparations (plasma, albumin, protein).

Skillful application of pathogenetic therapy alongside with antimycobacterial preparations increases the treatment effectiveness.

The tracheobronchial tree sanation occupies one of the most prominent places in a complex treatment of respiratory organs tuberculosis patients. The sanative methods may be passive and active. To the former belong postural drainage, administering expectorants, to the latter ones – all methods that consist in aspiration of the tracheobronchial tree contents and immediate administration of medicines into it.

With a view to increase sputum excretion the following preparations are applied:

1) preparations stimulating expectoration on account of passive secretion of bronchial glands, decreasing sputum tenacity, increasing activity of twinkling epithelium and peristalsis of bronchioles:

a) preparations of reflex action:sodium benzonat of 0,2-0,5 g internally 3-4 times a day, terpinhydrate of 0,25-0,5 g internally three times a day, Althea officialis L. root tincture (6,0:180,0) of one spoonful internally every three hours, Glycyrrhiza glabra L. root tincture (6,0:180,0) of one spoonful internally every three hours, Tussilago forfara L. leaves tincture (5,0-10,0:200,0 ) of one spoonful 4-6 times a day, licoryn of 0,0001 g internally 3 times a day.

b) preparations of resorptive (or direct) action: Potassium iodide 1-3 % solution, one spoonful internally 3-5 times a day, sodium iodide 0,3 g internally 3 times a day, ammonium chloride 0,2-0,5 g internally 3 times a day, sal ammoniacanis drops, 10-15 drops internally 3 times a day, anis oil, 3 drops internally 1-2 times a day etc.

 

2) Mucolytic (secretomotory) preparations which promote expectoration on account of the sputum thinning and stimulating endobronchial contents production:

a) proteolytic enzymes: tripsin, chemotripsin, chemopsin, ribonuclease, desoxyribonuclease 0,2 % solution, of 3 ml for inhalations and endobronchial infusion;

b) synthetic preparations: acetylcystein 20 % solution, of 4 ml per inhalation 2-3 times a day or 10 % solution for endobronchial infusion; bromhexyn 0,016 g internally 3 times a day; lazolvan.

In addition to this, much warm drink (up to 1-1,5 l a day) is recommended (milk with soda and honey, mineral water ’’Borzhomi”, “Luzhanska” etc.).

Active sanation methods include inhalations, intrabronchial pouring of antimycobacterial preparations, pathogenetic drugs. They are often combined with glucocorticosteroid preparations, stimulating regeneration (pentoxil of 0,3 g internally after meal, 3 times a day; methyluracil, 0,5 g internally during meal 3 times a day), antifungal (sodium salt of nistatine or levorine of 500000 AU internally 3 times a day, nisoral, 1 tablet a day, phungison etc.). At tuberculous endobronchitis expedient are inhalations of the mixture of euphylini 24 % – 0,5 ml; dimedrol 1 % – 0,5 ml, novocaini 0,5 % – 0,5 ml, isoniazidum 5% – 5 ml, rifampcinum (0,15 g) – 1,0 ml, hydrocortizon hemysuccinate or prednisolon chloride (0,0125-0,025 g) 0,5-1,0 ml without cancelling herewith the basic antimycobacterial therapy. In case of haemoptysis haemostatic drugs are used (thrombin of 60-125 e.a. for inhalation, haemophobin – 5,0 ml per inhalation).

Specific allergenic immunotherapy (tuberculinotherapy) of tuberculosis is the usage of tuberculin with the medicative purpose. It possesses both stimulating and desensibilizing action and is used at pulmonary and extrapulmonary tuberculosis.

 

METHODS AND MEANS OF POPULAR MEDICINE IN COMPLEX

TREATMENT OF TUBERCULOSIS

The interest for the popular and nontraditional medicine is growing worldwide, and first and foremost in Ukraine. In 1992 for the first time the Kyiv Medical Institute of the Ukrainian association of popular medicine was founded, in which, in addition to the classical programme of state medical institutions of higher education, the teaching of trends of popular and nontraditional medicine was additionaly introduced (homeopathy, phytotherapy, manual and bioenergoinformational medicine, reflexotherapy, iridodiagnostics etc.).

Phytotherapy is therapy by means of medicinal plants. Here are some of them, recommended for treating lung tuberculosis patients: Aloe arhorescens Mill., Acorus calamus L., Veronica officinalis L., Geum urbanum L., Capsella bursa pastoris (L.) Medic., Achillea millefolium L., Delphinium consolidum L., Urtica dioica L., Artemisia absinthium L., Polemonium coeruleum L., Pinus silvestris L., Polygonum Aviculare L., Equisetum arvense L., Pulmonaria officinale L., etc.

Fresh or tin aloe juice is used in phthisiology, which patients take – 1 tea spoonful 2-3 times a day, in courses 3-4 times a year.

Phytoncidotherapy (Gr. phyton + Lat. caedo – kill + heal) is a variant of phytotherapy, when biologically active substances are used with a medicinal purpose; they are formed by plants and they kill or suppress the growth and propagation of microorganisms.

The following means are used with a medicinal purpose: horse-radish roots (Cochleria armoracia) (it contains Lisocine, phytoncides, vitamin C etc.); fresh onion leaves and bulbs (Allium cepa), garlic (Allium sativum L.) (it contains antibiotic alicin, vitamins A and B, iodine), in the form of fresh juice, water-spirit tincture of peroral and inhalation methods of infusion.

 

Apiotherapy (Lat. apis – a bee + therapia – treatment) is the application of bee vital activity factors (honey, propolis, poison) with a medicinal purpose. Honey is composed of approximately 300 various substances, including hydrocarbons, enzymes, aminoacids, organic acids, microelements, aromatic compounds. Honey possesses bactericidal properties, which are higher in honey of burstine and dark-burstine colour.

Propolisotherapy is a variant of apiotheapy. Propolis is composed of plant resins, bees-wax, volatile oils, pollen, excretions of bee salivary glands and microelements. Propolis possesses antimicrobic, antitoxic, antiinflammatory, biogenously stimulating, pain-killing action. The preparation stimulates the organism’s defence reaction against infection.

Propolis is used at tuberculosis in the forms of: extract (it is taken 20 drops, three times a day, 1 hour before meals, during 4-10 months); oil (1 tea spoonful three times a day, 1 hour before meals, during 4-10 months); spirit solution (20-40 drops three times a day, 1 hour before meals, with warm milk), inhalations during 10 min. in the morning and in the evening (phytoncidic action).

COLLAPSOTHERAPEUTIC METHODS OF TREATMENT

They occupy an intermediate place between conservative and operative treatment. Their revival is observed nowadays. It concerns to artificial pneumothorax and pneumoperitoneum.

Artificial pneumothorax is introduction of the air into the pleural cavity with a medicinal purpose. Indications for applying artificial pneumothorax are limited forms of lung tuberculosis in a decay stage (infiltrative, nidal, limited disseminated), as well as in cases of:

1) intolerance to antimycobacterial preparations or MBT polyresistance;

2) patients of asocial behaviour (alcoholism, drug addiction);

3) patient’s refusal from surgical intervention;

4) unfavourable epidemiological conditions, first and foremost contact with children;

5) haemorrhages of fresh decay cavities and caverns, when haemostatic therapy has exhausted itself and surgical intervention is impossible;

6) combination of tuberculosis with pregnancy, diabetes.

At primary application of artificial pneumothorax about 250-350 ml of air is introduced. During the first 10 days the insufflation of air is performed at the interval of 2-3 days at constant roentgenologic control. After forming a gasbubble (collapse of the lung not less than 1/3), the intervals between air insufflations is 5-7 days, and the volume of the air comprises 400-500 ml.

Pneumoperitoneum is the introduction of the air into the abdominal hollow with a medicinal purpose, with a view of limiting the diaphragm excursion and pressing the lungs. Indications:

1) bilateral infiltrative and disseminated processes in the decay phase with a disposition to haemorrhages;

2) the same clinical forms of tuberculosis of females immediately after delivary;

3) retarding of lung expansion and a residual pleural cavity after phtisiosurgical interventions.

Technic: to the left and 2 cm lower from the umbilicus, a puncture of the abdominal hollow wall is made with a needle, keeping to all the rules of asepsis and antisepsis. Predominantly 400-600 ml of air is introduced. At the succeeding insufflations – 800-1000 ml with an interval of 7-10 days.

SURGICAL METHODS OF TREATMENT

Surgical treatment of lung tuberculosis patients is a component of complex treatment. At present conditions of continual rise of the epidemy of tuberculosis, the role of surgical treatment will increase.

The absolute indications to surgical treatment are:

1) stable bacterial excretion after 6-months antimycobacterial therapy with cavern presence;

2) incurable residual changes – bronchoectases, ruined (lung) part, pronounced bronchostenosis;

3) suspicion of tuberculosis combination with a malignant growth;

4) large fibrous-caseous nidi (tuberculoma, caseoma) without bacterial excretion;

5) life-threatening haemorrhages;

6) thin-walled caverns without bacterial excretion of epidemiological considerations (children institutions employees).

Optimum terms for surgical treatment of lung tuberculosis patients against the background of intensive ethiopathogenetic therapy comprise 3-9 months. Hence, the patients have a chance to undergo a complete course of antimycobacterial therapy, which ineffectiveness serves as an indication to a surgical intervention. Besides, patients with satisfactory indeces of their general state, without phenomena of cardiac decompensation, absence of pronounced respiratory violation and nonreversible disturbances of the function of other internal organs and systems are due to surgical treatment. It is desirable to perform surgaical interventions in the phase of remission and compensation of tuberculous process. At urgent indications (pulmonary haemorrhages, tense pneumothorax etc.) an acute phase of tuberculous process should not be an obstacle to a surgical liquidation of the symptoms threatening a patient’s life.

Surgical methods of treating pulmonary tuberculosis patients are divided into radical, collapsosurgical and intermediate operations. Radical operations include: segmental resection, combined resection, lobectomy, pneumonectomy, pleurectomy. Collapsosurgical operations include extrapleural pneumolysis and thoracoplasty. To the intermediate group belong operations of immediate action on a cavern (cavernotomy, cavernoplastics), bronchus or branch of pulmonary artery ligature.

In addition to this, indications to surgical treatment of tuberculosis patients may be planned or urgent ones.

PROPHYLAXIS  OF  TUBERCULOSIS

Prophylactic principle of health protection generally and, as far as tuberculosis is concerned, in particular should be a priority. Prophyaxis of tuberculosis consists of a complex of various measures. Social, sanitary, specific (inoculation and revaccination) and chemoprophylaxis are discriminated.

Social prophylaxis is carried out by means of performing prophylactic measures of social-economic character of the national scale. These are allnation measures, since they should be organized not only by the state organs, but also by a wide range of antitubercular institutions, civic and other organizations. The social prophylaxis is aimed at organizing the people’s healthy way of life by improving the environmental conditions, increasing the population’s material well-being, strengthening its health through the development of mass physical culture, sports, rest homes, sanatoriums, improvement of nourishment and home living conditions, as well as fighting alcoholism and other harmful habits.

Sanitary prophylaxis is a systematic organization and performance of a system of sanitary-hygienic and prophylactic measures, aimed at warning healthy people against infecting and catching tuberculosis. Essentially, sanitary prophylaxis is a component part of social prophylaxis of tuberculosis. It is aimed at the improvement of sanitary conditions of the nidi of tuberculous infection, performance of sanitary – educative work, veterinary control, early and timely detection as well as treatment of tuberculosis patients. Sanitary prophylaxis is generally performed in the centre of tuberculous infection. An epidemiologic nidus of tuberculosis is meant as a tuberculosis patient, who excretes mycobacteria, his dwelling and the people sharing it with him.

 To antiepidemic measures in the cenrte of tuberculous infection belong disinfection, contacts investigation, their chemoprophylaxis, isolation of children from the bacteriocarrier, sanitary-hygienic education of a patient and the members of his family, improving the living conditions as well as the patient’s treatment. The prophylactic work is realized in the centre according to its epidemiological danger defined jointly by a phthisiologist and an epidemiologist, taking into account the following factors: 1) the volume of bacterial excretion; 2) presence of children and teenagers in the family; 3) sanitary conditions under which a patient and his family live.

Thus, the criteria of epidemiological danger of a nidus of tuberculous infection are the mass scale and continuity of MBT excretion by a patient, his family life conditions, behaviour, general culture and sanitary enlightenment of the patient and his surrounding.

Depending on the mass scale and the term of bacterial excretion, it is discriminated as: A. massive, when over 100 colonies of MBT are revealed at a simple bacterioscopy or by a sowing method; B. moderate, if 20-100 colonies are revealed; C. scanty (meagre), if MBT are revealed only by bacteriological research, not more than 20 colonies; D. conditioned (formal): 1) at firstly diagnosed tuberculosis, when the cessation of bacterial excretion is reached as a result of treatment and is confirmed by double negative result of bacterioscopic and cultural methods with 2-3 months intervals (during 10-12 months from the moment of the examinatioegative result); 2) at chronic pulmonary tuberculosis, when the cessation of bacterial excretion as a result of treatment is confirmed by repeated examinations with bacterioscopic and cultural methods with 2-3 months intervals during 1,5-2 years from the moment of the first negative result.

According to these conditions the nidi of tuberculous infection are divided into 3 groups.

To the first, the most dangerous, group belong nidi, where patients with abundant or meagre bacterial excretion live, but there are children and teenagers in the family or aggravating circumstances exist: poor living conditions, violation of hygienic rules, abuse of alcohol. An epidemiologist and a district phthisiologist should visit such a nidus once a quarter, a district nurse – not less than once a month.

To the second group, epidemiologically less dangerous, belong nidi of tuberculous infection, in which patients with meagre bacterial excretion live and the unfavourable factors, enumerated above, or patients, considered to be conditional bacterial excretors, are absent, but there are children and teenagers in the family or there exists at least one of the aggravating factors mentioned above. A doctor pays a visit to these nidi once half a year, and a medical nurse once every two months.

To the third group belong the nidi, where only adults live and the patients are formal bacterial excretors and any aggravating circumstances are absent. To this group belong families in whose private farms there is cattle injured with tuberculosis. A doctor visits these nidi once a year, a medical nurse – once half a year.

The complex of prophylactic measures in a centre of tuberculous infection includes performing a current and conclusive disinfection, isolation of children from the bacterial excretor by means of his hospitalization or sending the children to specialized children’s institutions, vaccinization of newly borns and revaccinization of noninfected contactual with BCG vaccine, regular examination of contactuals, performing chemoprophylaxis for them, sanitary-hygienic education of patients and the members of their families, improving their living conditions, intensive treatment of a patient in a clinic, followed by controlled chemotherapy at the dispensary stage (fig. 10).

After the hospitalization of the firstly diagnosed bacillar tuberculosis patient a conclusive disinfection of the patient’s dwelling is performed by a local epidemiological station or disinfecting station. The conclusive disinfection is made in all cases of the patient’s temporary or constant departing (hospitalization, change of the dwelling place, after death at home). Objects of small value are desirable to be burnt. The ceiling, the walls, the floor, the furniture (except polished one) are irrigated with 5 % solution of chloramine and the lodging is tightly closed for 2 hours. Afterwards it is aired and tidied. An effective method of disinfestation of lodgings is ultraviolet radiation. This pertains, first and foremost, to expensive objects, which are easily spoilt with disinfectant solutions; they are radiated with bactericidal lamps (fig. 11).

 

Fig. 10. Classification of an epidemiologic nidi of tuberculous infection.

 

Before a patient’s hospitalization or when he stays at home for various reasons, current disinfection is systematically done by the patient himself or by the members of his family which consists in the following:

1) Daily airing and wet tiding of the lodging and objects of home use. The bacterial excretor should use only his personal table utensils, towels, bedding which are systematically disinfestated.

2) Sputum collection into an individual sputum flask, which is filled to a quarter of the volume with 5 % chloramine solution and its disinfestation, as is done with the table utensils and meal remnants. 3) Collection, putting into sacks, isolated keeping of used underclothes and its future disinfestation.

Generally, disinfection is done by means of physical methods (boiling, autoclaving, chamber disinfestation, burning, quartzing, insolation, airing, hot ironing) and chemical means (chlorinated lime, chloramine, benzylphenol etc.) (fig. 12).

After a tuberculosis patient hospitalization all persons, who contacted him, are examined. Adults and teenagers have to undergo fluorography of the thoracic cage, children undergo roentgenography, children and teenagers also undergo Mantoux test with 2 TU. The contactual persons are registered into the IV group of dispensary observation and chemoprophylaxis is administered to them.

Many species of mammals and birds suffer from tuberculosis. However, most often the greatest danger for a human being is the cattle, rarelier – fowl, goats, pigs, cats, dogs. It is the veterinary service that is responsible for preventing tuberculosis revealing among animals. The examination of the cattle is done by means of tuberculinodiagnostics. Farmworkers undergo fluorographic examination every year. Tuberculosis patients are not permitted to work at farms.

A successful solution of the main tasks of phthisiological service (prophylaxis, timely revealing, treatment, measures in a nidus of tuberculous infection) to a considerable degree depend on the sanitary enlightenment work among medical personnel, population and patients.

 

 

Fig. 11. Prophylactic measures in the nidi of tuberculous infection.

Antituberculous vaccination and revaccination. The most efficient method of specific prophylaxis of tuberculosis is vaccination and revaccination with BCG vaccine or vaccinoprophylaxis. In 1921 Calmette and Guerin used BCG vaccine for a baby from bacillar surrounding. In 1923 the Hygienic Committee of the Nations League took a decision as to the wide use of the BCG vaccine (fig. 13) for vaccination against tuberculosis in all the countries of the world. In Ukraine a tuberculous vaccine (BCG) is used for active specific prophylaxis of tuberculosis – dry for intracutaneoud transfusion. These are live mycobacteria of vaccine strain, lyophilicly dried in 1,5 % solution of sodium glutaminate. It looks like a white dried mass. It is manufactured in ampullas of 1 mg of vaccine, which contains 20 doses, each of 0,05 mg of the preparation. BCG vaccine is used intracutaneously in a dose of 0,05 mg in the volume of 0,1 ml. The primary vaccination is done to healthy, delivered at the right time newly borns on the 3-5th day of their life.

Fig. 12. Disinfection of tuberculosis.

In addition to BCG vaccine, BCG-M vaccine is manufactured in a half dose (0,5 mg in an ampulla, which contains 20 doses, each of 0,025 mg of the preparation), which is meant for vaccinating prematurely newly borns and children who were not immunised at birth in connection with contraindications, as well as for vaccination and revaccination of children, who live in the territories (areas) contaminated with radionuclides (III-IV zone).

 

 

Fig. 13. Dry BCG-vaccine.

For each inoculation one should have 1-gram syringes valid for use once and a suitable vaccine. The dry vaccine (1 ampulla) is dissolved in 2 ml of isotonic solution and the cultivation is the result, i.e. 1 dose in 0,1 ml of the solution. The vaccine is used during 2-3 hours, the remnant is destroyed by boiling. 0,2 ml of the dissolved vaccine is taken into 1-gram syringe after mixing, the air and part of the preparation up to 0,1 ml mark is evacuated through the needle. The vaccine is injected strictly intracutaneously on the limit between the upper and the middle third part of the shoulder, having previously rubbed the skin with 70 ° spirit. At the proper technic a whitish papule of 5-6 mm in diameter is formed, which resolves in 15-20 minutes. In 3-4 weeks a small infiltration is formed in the site of the injection – a nodule of cyanotic colour, in which in 50 % of cases a small fistula with cereous secretion is formed. Later on a crust of brown colour is formed, which drops off in 2-4 months and a pink seam (of 4-10 mm in diameter) appears, which gradually undergoes depigmentation. At the proper vaccination technic the seam is formed in 90-95 % of cases, testifying the efficiency of inoculation.

Contraindications for BCG vaccination are:

1) a prematurely born child, when the body mass at birth is less than 2000 g;

2) intrauterine infection;

3) purulent-septic illnesses;

4) hemolytic disease of newly-borns (moderate and severeforms);

5) severe puerperal traumas with neurologic symptomatics;

6) generalized skin wounds;

7) any acute illnesses;

8) generalized BCG infection of other children in the family.

Children (babies), not immunised at a maternity home, in connection with contraindications are vaccinated after recovery at a children’s polyclinic or hospital-assistant’s health station with BCG-M vaccine during 1-6 months. However, if a baby has reached a 2-months age and more, the Mantoux test with 2 TU should be done before inoculation. Children with negative tuberculine reaction are vaccinated. The interval between Mantoux test and vaccination must be not less than 3 days and not more than 2 weeks.

The immunity after vaccination develops in 6-8 weeks, therefore vaccinated children from the family of tuberculosis patient are isolated from bacterial excretor for the period of the immunity formation, i.e. not less than 2 months.

In children BCG vaccinated at birth the immunity is preserved during 5-7 years. After this the necessity of revaccintion arises, which is obligatory on the territory of Ukraine at the age of 7 and 14. Only healthy persons with negative Mantoux test are revaccinated. Vaccination and revaccination of BCG is an effective means of prophylaxis and it allows to prevent the illness five times more, and if it develops, then its course is much milder and has a restricted character. The revaccination technic is the same as that of BCG vaccination. Tuberculin diagnostics (selection for revaccination) is realized by trained medical specialists, members of specialized teams, headed by a pediatrician.

Contraindications for revaccination of children and teenagers:

1) tuberculosis infestation or previously suffered tuberculosis;

2) acute and chronic illnesses in the aggravation period;

3) complication to previous BCG vaccine injection;

4) allergic illnesses in the aggravation stage;

5) malignant blood diseases and neoplasms;

6) immunodeficite states, treatment with immunodepressors;

7) HIV-infestated children.

Other prophylactic inoculations may be done not earlier than in 2 months after revaccination.

In revaccinated persons the local reactions begin to develop earlier, already in a week, but their reverse development also lasts for 2-4 months. Tuberculin allergy develops in vaccinated children – positive tuberculin reactions (2 TU) in 55-65 %, while at using 100 TU – in 90 % of immunized children and teenagers. Postvaccine seam and a positive tuberculin reaction are the criteria of vaccination quality and formation of antituberculous immunity. A local pediatrician does the observation for the development of local postvaccinal reaction and writes it down in the medical documentation in 1, 3 and 12 months after inoculation (fig. 14).

 

    

Fig. 14.  The development of local postvaccinal reaction.

         The postvaccinal seam being absent and at negative tuberculin reaction the immunisation is considered to be ineffective. Under unfavourable conditions the inoculation of such children and teenagers should be repeated, but not earlier than in 2 years after vaccination and in a year after revaccination.

The application of BCG vaccine may result into various complications. The frequency of complications after vaccination and revaccination varies within 0,02 – 4,0 %. Most frequently complications occur after inoculation, BCG revaccinations have a local character and are rarely observed (0,02 %).

The WHO International Union of Fighting Tuberculosis classifies postvaccinal complications according to 4 categories:

1 category – local skin lesions (cold abscesses, ulcers, keloid seams, regional lymphadenites);

2 category – persisting and disseminated BCG – infection without a lethal result (lupus, ostites etc.);

3 category – disseminated BCG – infection, generalized lesions with a lethal result, which are noticed at a marked immunodeficiency;

4 category – post-BCG-syndrome (an illness, that arises immediately after BCG vaccination, mainly of allergic character, nodal fever, eruption, keloid seams).

The most frequently observed are: subcutaneous cold abscesses, surface ulcers of 10 mm and more in diametre on the spot of intracutaneous injection of BCG vaccine (fig. 15); lymphadenites of regional lymphatic nodes (groin, neck, supra- and subclavian), the size of 1,5 cm and more; keloid seams of 10 mm and more in diametre (fig. 16.).

 

Fig. 15. Subcutaneous cold abscesses, surface ulcers.

Chemoprophylaxis. Specific prophylaxis is aimed not only to the increase of the body resistance to tuberculous infection by means of active immunisation (vaccination, revaccination), but also by using antimycobacterial means (chemo-prophylaxis).

  

Fig. 16. Lymphadenites of regional lymphatic nodes, keloid seam.

If effectiveness of BCG vaccination and revaccination sets in after 1-1,5 months, so chemoprophylaxis is viewed as an urgent prophylaxis of tuberculosis, as its preventive action develops from the first hours after taking an antimycobacterial drug. Chemoprophylaxis is recognized to be the most efficient of all methods of tuberculosis prophylaxis.

   New Vaccines against Tuberculosis

The current vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), is a live vaccine derived from an attenuated strain of Mycobacterium bovis. BCG protects against severe childhood forms of the disease, but fails to protect against adult pulmonary TB in countries in which it is endemic. For more than 80 years, no new TB vaccine has successfully been developed. With TB eradication on the horizon, new vaccines with better protection than BCG are urgently needed.

The development of an effective TB vaccine seemed impossible until only a few years ago. In the last ten years of work with experimental laboratory models, many vaccine candidates have been developed. They include protein or DNA-subunit vaccines, modified BCG, and attenuated  Mycobacterium tuberculosis. Some of these candidates are now being tested for safety and immunogenicity in human volunteers. For the first time, Phase I clinical trials of new TB vaccine candidates

have started. Many of these new trials involve recombinant BCG or improved BCG immunity by boosting with vaccines consisting of subunits or attenuated Vaccinia virus expressing TB antigens. However, effective vaccination against TB presents diverse and complex challenges. For example, TB infection can become reactivated years later and infection does not guarantee resistance to a subsequent second infection. A truly effective TB vaccine may, therefore, have to elicit an immune re-

sponse that is greater than that induced  by natural infection. In addition, various different populations have to be protected: they include those vaccinated with BCG, and those infected with M. tuberculosis or with HIV. The goal is a new generation of vaccines effective against the transmissible respi ratory forms of TB. Good candidate vaccines able to boost BCG, thereby improv ing protection, could be a reality in the short term. The second step is to obtain a new generation of vaccines able to replace the currently used BCG and make the eradication of TB feasible. These new vaccines can be expected in the middle term, and live vaccines are reliable and promising candidates. Indeed, these ultimate

goals may require safe live vaccines.

Historical view

BCG is the only vaccine available for prevention of TB in humans. BCG is an attenuated live vaccine that was obtained after 230 successive passages in the laboratory between 1908 and 1921 from a pathogenic strain of M. bovis. It is an inexpensive vaccine that has been applied since the early ’20s and it has been given to more than 2.5 billion people since 1948. It has a long-established safety profile and an outstanding adjuvant activity, eliciting both humoral and cell-mediated immune responses. It can be given at birth or at any time thereafter, and a single dose can produce long-lasting immunity. Recent studies with long-term follow-up of American Indians demonstrated that a single dose in childhood maintains immunization for up to 50–60 years after vaccination . However, different studies in other parts of the world have shown that protection provided by BCG wanes over time, and the efficacy of BCG in adolescent and adult populations is reported

to be highly variable among different geographical regions BCG protects against severe forms of childhood TB, including miliary TB andextrapulmonary localization, such as the often fatal tuberculous meningitis. This iswhy BCG continues to be recommended in the vaccination calendar of the WHO in countries with a high TB prevalence and incidence. BCG vaccination is currently compulsory in at least 64 countries and administered in more than 167. Indeed, BCG remains the most

widely used vaccine in the world  In addition, BCG confers protection against leprosy and it has also been licensed as a treatment for bladder cancer.The level of protection conferred by BCG  is very variable: it differs according to the form of pulmonary TB and can be affected in those cases in which TB is asso  ciated with AIDS. The efficacy of BCG vaccines against pulmonary TB varies between populations, showing no protection in India but 50-80 % protection in the United Kingdom. The lack of protection against pulmonary TB in endemic regions has enormous importance from the point of view of public health as regards eradi cation of TB . The reasons for  the failure of BCG have been widely debated, and remain the topic of active research. Natural exposure to environmental mycobacteria is thought to exert an important influence on the immune response, and this may mask or otherwise inhibit  the effect of BCG vaccination in tropical countries. This theory has been supported by the fact that exposure to environ mental mycobacteria is prevalent in those countries where BCG confers low pro tection, and by a number of studies showing that exposure to environmental myco bacteria has an impact on the protection afforded by BCG in animal models . This phenomenon has been proposed as a plausible explanation for the North-South gradient in the effective ness of BCG . Host-related differences, such as genetic and host immune status, use of different BCG preparations, diverse levels of nutrition, and socio-economic issues should also impact BCG efficacy in different populations. It has been recently demonstrated that cross reaction is due to antigens shared be tween BCG and environmental mycobacteria . New vaccines deprived of major antigens shared with environmental mycobacteria will overcome the problem of the antagonistic effect of BCG to previous environmental myco bacterial exposure. In parallel, neonatal vaccination with BCG  has been reported as effective in re ducing the incidence of childhood TB in endemic areas. The risk of disseminated BCG among adult AIDS patients with childhood BCG immunization is very low, and in addition, childhood BCG immunization is associated with protection of344   New Vaccines against Tuberculosis adults with advanced AIDS against bacteremia with M. tuberculosis. Studies in Zambia have shown that bacteremia due to BCG or M. tuberculosis is rare among children who have BCG immunization (even recent) and symptomatic HIV infec tion.

Since 1921, when BCG was used for the first time, different laboratories throughout the world have continued to sub-culture BCG, giving rise to the appearance of different variants, such as BCG Pasteur, BCG Moscow or BCG Brazil. These vari ous BCG strains are different from each other and from their ancestors, such that it is prudent to refer to BCG vaccines in the plural because differences in protection and effectiveness could be due to variations between strains, and for this reason, the WHO has recommended lyophilization of BCG vaccine stocks and storage at 80˚C . BCG vaccines have been classified into two major groups. BCG Tokyo, Moreau, Russia, and Sweden secrete large amounts of the MPB70 gene, have two copies of the insertion sequence IS6110, and contain methoxymycolate and MPB64 genes. In contrast, BCG Pasteur, Copenhagen, Glaxo and Tice secrete little MPB70, have a single copy of the insertion sequence IS6110, and do not contain the methoxymycolate and MPB64 genes . Comparative genomic analysis has revealed the existence of several M. tuberculo sis-specific regions that have been deleted from BCG with the loss of more than 100 genes These genomic comparisons have made it possible to de  termine the order of genetic events, including deletions and duplications, and changes in the IS6110 copy number which occurred between its first use in 1921and the 1961 These complex genomic rearrangements in BCG strains have undoubtedly led to phenotypic and  immunological differences and may con tribute to the variability in vaccine efficacy. All these points reinforce (require ment for vaccines that are more effective than the currently used BCG vaccines against the respiratory forms and that are able to eradicate TB. Problems of sub strain variability and protective efficacy of the current BCG vaccines could be overcome by new rationally-constructed live vaccines, for which the attenuation factor and immunity are known.10.4. New vaccines: from the bench to clinical trials   345 10.4. New vaccines: from the bench to clinical trials Even if BCG has been demonstrated to be extremely useful and at the moment is the most utilized vaccine in the world  (World Health Organization 1995), the de  velopment of new vaccines against pulmonary TB, which are able to replace the current BCG vaccine, is an important challenge (Kaufmann 2005). Since humans are the only reservoir of M. tuberculosis, the development of vaccines more effec tive than BCG could make TB eradication possible  The lung is the portal of entry of M. tuberculosis in most human infections and provides a suitable environment for this  slowly replicating pathogen. Infection is established in alveolar macrophages of the distal alveoli before it is recognized by the adaptive immune response 5-6 weeks later. CD4+ and CD8+ T cells are re cruited through the lung, inducing protective immunity. Both CD4+ and CD8+ T cells are essential for protective immunity against M. tuberculosis. Resistance to M. tuberculosis involves the activation of mycobacte rial-specific CD4+ and CD8+ T cells by dendritic cells, which migrate from the site of the infection in the alveoli to the  draining lymph nodes. The development of interferon-gamma (INF-γ)-secreting CD4+ T cells is dependent on the secretion of IL-12 by infected dendritic cells. Subjects deficient in receptors for INF-γ and IL- 12 are extremely susceptible to mycobacterial infections, confirming the absolute requirement for T helper 1 (Th1)-like T cells for host immunity .

The nature of an effective immune response to TB is incompletely understood, but the most effective vaccination strategies in animal models are those that stimulate T-cell responses, both CD4+ and CD8+,  to produce Th1-associated cytokines. Therefore, formulations that induce the production of enduring Th1 responses are desirable, and doubtless an essential element of a successful vaccine. Several adju vants or live vaccines capable of inducing potent T-cell responses have been devel ped and some have entered clinical testing. 0.4.1 Challenges for tuberculosis vaccine development  third of the population worldwide is estimated to be infected with M. tuberculo  is. Therefore, any new TB vaccine should protect pre-exposure people from de eloping infection, as well as post-exposure, latently infected, healthy individuals rom developing the disease, or should be used as an immunotherapeutic agent to ct with antimicrobials to increase the rate of clearance of M. tuberculosis. additional challenge is that as a large percentage of the human population has vready been immunized with BCG, and so any new generation vaccines against B must also be able to protect the population that has already been vaccinated ith BCG. Obviously, new vaccines must also be safe enough to be used in HIV- nfected individuals . dvances in the characterization of genes and antigens of M. tuberculosis and the echnological development , with the help of the genome se  ences of different mycobacterial species have provided insights into he tubercle bacillus In addition, the current progress of myco acterial genetics has made the inactivation of selected genes possible, allowing the ational attenuation of M. tuberculosis . Finally, the improvement in omprehension of the basic immune mechanisms involved in TB has considerably ontributed to the rational design of the next generation of vaccines.

 Subunit vaccine candidates

Due to safety reasons, non-viable sub-unit vaccines are the first to be considered or human trials. Subunit vaccines have been selected by various rational and ex erimental approaches. Results with non-viable subunit vaccines are ncouraging but their protective effects have to be at least equivalent to that of CG before they can be considered for testing in humans.

Potential TB subunit vaccines have been obtained by using immunodominant TB ntigens, for example ESAT-6 [6-kiloDalton (kDa) early secretory antigenic tar get], which confers some degree of protection against M. tuberculosis in mice (Ol-sen 2004) and recently ion-human primates (Langermans 2005).  The vaccine induced efficient immu ological memory, which remained stable at 30 weeks post vaccinationdevelopment harmaceutical comp any or research group antigens

 Subunit vaccines for boosting BCG

Since acellular vaccines have never been demonstrated to confer better protectionthan BCG in preclinical testing, they have been proposed to be used for boosting CG. Heterologous prime-boost immunization strategies can evoke powerful T cell mmune responses and may be of value  in developing an improved TB vaccine. mportantly, this regimen of vaccination expands pre-existing memory T cells gainst antigenic epitopes shared by BCG and the booster vaccine. Experiments sing protein subunits in animals previously vaccinated with BCG have given very ood results (Brooks 2001). These experiments used Ag85A, because it was previ  usly demonstrated that most CD4+ T cells accumulating in the lungs of memory- mmune mice after challenge recognize this antigen. This vaccine strategy may ave applications in the prevention of reactivation of TB in the elderly. nhanced immunogenicity and protective efficacy against M. tuberculosis has been emonstrated for BCG after boosting with a recombinant modified vaccinia virus alled Ankara. The recombinant virus, expressing M. tuberculosis Ag85A, strongly oosts BCG-induced Ag85A-specific CD4+ and CD8+ T cell responses in mice. rotection correlated with the induction of Ag85A-specific, IFN-γ-secreting T cells lymph nodes in the lung ). This vaccine was ested for the irst time in humans imilarly, a combination of vaccines has been shown to be more protective in pre  enting bovine TB in cattle than single vaccines. Tested in calves, prime-BCG oost strategies of vaccination were reported to induce cellular immune response Vordermeier 2006) and high levels of protection against challenge with virulent . bovis .

10.7. Recombinant BCG vaccines

Recombinant BCG (rBCG) techniques may be useful for the development of a ore effective mycobacterial vaccine than the parent BCG now in use. Various trategies have been used to develop recombinant BCG against mycobacterial dis  ases . One is based on rBCG producing large amounts of autologous rotective antigens; these supplementary antigens are designed to enhance immu nitu other BCG antigens by increasing the expression of their genes, as is the ase of the immunodominant TB antigens. rBCG vaccine (rBCG30), which ex- resses and secretes the 30 kDa major secreted protein of M. tuberculosis, also eferred to as a-antigen and antigen Ag85B, is associated with etter host survival after challenge than parental BCG in the highly

 Conclusions

Although the efficacy of the BCG vaccine continues to be discussed, live attenu- ted BCG is still the only vaccine in use  for the prevention of TB in humans be cause it is effective against the severe forms of TB and its use prevents a large umber of deaths that would otherwise be caused by TB every year. te choice of the BCG strain to be used for vaccination is a very important issue. It s currently difficult to determine which strain should be used, and further detailed nalysis of the genomics and immunogenicity of BCG sub-strains may provide an answer to this important question. The World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) could then identify the BCG sub-strains that provide the best protection and recommend them for future vaccination worldwide . For many years, the discovery of new TB vaccines effective against pulmonary TB

has been considered an elusive quest, but the TB vaccine field has blossomed in the last decade. Research to develop improved TB vaccines seems to be at a decisive point in time. More than 200 vaccine candidates have been proposed as the result of work over recent years in experimental laboratory models, and some are now approaching clinical testing. The transition from laboratory to clinical trials has a10.9. Conclusions   355 wide range of strategic and technical implications. In particular, facilities and funding need to be provided for the production of any successful vaccine appropria te for clinical use. After the Madrid Conference in March 1995 “Definition of a coordinated strategy towards a new TB vaccine” organized by the WHO and the IUATLD, a joint effort was established involving diverse governmental organiza tions in Europe (FP5 and FP6 Framework Programmes) and the USA by NIH, and recently by the AERAS Foundation.

For the first time, after 80 years of widespread use of BCG, evaluations of new candidates in humans are available including recombinant vaccine virus . Nevertheless, the development of a new vaccine conferring better protection than BCG, and able to replace it, remains a challenge for the scientific community. If eradication of TB is to be possible and affordable, appropriate new vaccines must be found. Subunit vaccines have potential advantages over live mycobacterial vaccines in terms of safety and quality control of the manufactured vaccine, and are good can didates to improve the effect of BCG. However, in order to confer the complex immunity required to protect against TB, it is possible that more than single anti-

gens will be necessary. Progress to date with live attenuated M. tuberculosis vacc ines indicates that it is possible to design strains that are highly attenuated, even for immunodeficient animals. These “classical” vaccine candidates have to mimic natural infection as closely as possible without causing disease (Young 2003). The goal of evolving an effective licensed vaccine by the year 2015 has been pro posed by Stop TB/WHO. It is estimated that at least 20 vaccine candidates should enter Phase I safety trials, with around half going forward for immunological evaluation in Phase II trials, leading to four Phase III efficacy trials . Vaccination is expected to make a major contribution to the goal of eliminating TB

worldwide by 2050. Still, developing a new effective vaccine will require innova tion in scientific research, a proactive approach to clinical trials of new vaccine candidates and application of vaccines as a part of an integrated approach to dis ease control (Young 2006).

The primary and the secondary chemoprophylaxis are discriminated. The primary chemoprophylaxis is performed to noninfected persons, who react negatively to tuberculin. The secondary chemoprophylaxis is performed with a view to prevent the development of tuberculosis of persons infestated earlier, the ones who react positively to tuberculin and in whom active clinico-roentgenological manifestations of tuberculosis are absent.

Persons undergoing chemoprophylaxis:

1) clinically healthly children, teenagers and persons of young age up to 30, who are firstly MBT infestated;

2) persons with stable hyperergic reactions to tuberculin or their 6 mm and more increase comparing to the previous results;

3) children, teenagers and adults, who are in contact with epidemiologically dangerous tuberculosis patients;

4) persons, who have nonactive tuberculous changes, pregnancy or unfavou-rable factors being present (acute illnesses, operations, traumas), capable of provoking tuberculosis relapse;

5) persons with traces of previously suffered tuberculosis, their illnesses being present (bronchial asthma, collagenose, sarcoidosis,stomach ulcer), which are treated with various drugs, including corticosteroid hormones, which may provoke complications or tuberculosis relapse.

Among the persons, who underwent chemoprophylaxis, the number of tuberculosis cases is 5-7 times less in comparison to the corresponding groups of people, who did not receive it.

Chemoprophylaxis is performed with isoniazidum or phtivasidum during 2-3 months, and, at the preservation of epidemiological danger, it is repeated twice a year. For adults and teenagers a daily dose of isoniazidum, when used every day, is 0,3 g, for children – 8-10 mg/kg of a body mass. A complex of vitamins is administered in 30 minutes after the intake of the drug with an obligatory inclusion of vitamin B₆ (30-50 mg daily) and vitamin C.

ORGANIZATION  OF  ANTITUBERCULOUS  ACTIVITY  IN  THE  PERIOD  OF  TUBERCULOSIS  EPIDEMY

Tuberculosis is a social disease and is a mirror of social-economic prosperity of the state and the well-being of its people, therefore antituberculous measures under present conditions must be taken on the national level by the government of the country.

At present time, the principal task in fighting tuberculosis in Ukraine is to take the epidemy of the illness under control (I stage), to stabilize the epidemiological indices (infestation, morbidity, sickliness and death rate) of tuberculosis (2 stage), and then their gradual decrease (3 stage).

For the successful organization of antituberculous measures close cooperation of the medical system, sanitary-epidemiological service and the organs of the state power is necessary. The general organization and methodological guidance of antituberculosis activity in this country is realized by the Ministry of Health Protection of Ukraine and Acad. F.G.Yanovsky Ukrainian phthisiology and pulmonology research institute (scheme 1).

 

Scheme 1

 

STRUCTURE OF ANTITUBERCULOSIS SERVICE

 

IN UKRAINIAN

 

 

		The Ministry of Health Protection
		Acad. F.G.Yanovsky Ukrainian phthisiology and pulmonology research institute
		Regional of antituberculous dispensary
		Distric(town) of antituberculous dispensaries
		Tubcabinet
At child’s policlinic		At policlinic		At medical parts

 

Antituberculous dispensary (Engl. dispensation – distribution) is a specialized medicative-prophylactic institution, which work is aimed at lowering morbidity, sikliness, infestation with tuberculosis and death rate caused by it as well as at conducting a complex of organizational and methodical, prophylactic antituberculous measures among the district population.

The main tasks of an antituberculous dispensary are:

1) prophylaxis;

2) early revealing;

3) treatment of tuberculosis patients;

4) registration of groups of tuberculosis patients and contingents of persons

with an increased risk of its development and their observation (fig. 17).

Additionally, the decisive in the organization of those main tasks is their active administration and, in the first turn, by the general medical net (prophylaxis and tuberculosis detection) and by antituberculous service (treatment and observation).

One of the priorities in the work of an antituberculous dispensary is conducting prophylactic antituberculous measures.

Other very important tasks of an antituberculous dispensary are revealing, registration and treating tuberculosis patients. The results of treating tuberculosis patients to a considerable degree depend on the disease being timely revealed. In this connection, firsty diagnozed tuberculosis patients are divided into three groups: timely, untimely and lately revealed. For children and teenagers the fourth group is separated – early revealing.

The main criteria of dividing patients into groups are the character of a specific process, the presence or absence of destruction (cavern) and bacterial excretion, peculiarities of the prognosis at treatment, the degree of a patient’s danger for healthy persons.

Children and teenagers, in whom the following factors are diagnosed, compose a group of early revealed:

 1) tuberculin test range;

2) primary tubinfestation;

3) hyperergic Mantoux test;

4) tuberculous intoxication.

To the first group – timely revealed belong patients with uncomplicated forms of primary tuberculosis: primary tuberculous complex, tuberculosis of intrathoracic lymphatic nodes, restricted (1-3 segments) forms of secondary tuberculosis: nidal, infiltrative, disseminated without decay; exudative pleurisy. Revealing MBT, the lung destruction being absent, does not exclude the possibility for a patient to belong to a group of timely revealed. At treating such patients the recovery reaches 100 %.

To the second group – untimely revealed – belong patients with complicated forms of primary tuberculosis, primary tuberculosis with a chronic course, nidal, infiltrative, tuberculoma, disseminated tuberculosis with a decay and MBT. Under conditions of modern antimycobacterial therapy the cessation of bacterial excretion sets in 88 % of cases, while the healing of decay cavities – in 76 %. The clinical recovery in such cases is frequently accompanied by the formation of big residual changes.

The third group – lately revealed (neglected tuberculosis) patients with fibrous-cavernous, cirrhotic, chronic disseminated with a cavern, pleural empyema. It is the most unfavourable group of patients with respect to clinic, prognosis and epidemiology. The reasons of untimely revealing of tuberculosis are peculiarities of the illness course (asymptomatic course, presence of accompanying maladies), inattentive and careless patient’s treatment of his health (alcohol and drug addiction, low sanitary competence), a doctor’s diagnostic errors (lowering the attention of doctors of general medical system to tuberculosis).

The principal ways of revealing tuberculosis:

1. Prophylactic examinations (children – tuberculinization; teenagers – tuber-culinization, and from the age of 15 – additionally fluorography; adults – fluorography).

2. Revealing at the application for medical aid.

3. Observing persons with higher risk of catching tuberculosis.

The principal methods of revealing tuberculosis are roentgenologaical, tuberculinodiagnostics and microbiological ones.

The principal method of early revealing of tuberculosis in children aged up to 14 is yearly mass prophylactic examinations with making Mantoux test with 2 TU. Teenagers (from 15 years of age), in addition to tuberculinodiagnostics, are examined fluorographically. The examination of persons aged before calling for service takes place at military registration and enlistment offices, if over 6 months have passed since the previous examination.

The complete (massive) examination of the population is performed from 18 years of age, once in two years. However, in areas, where tuberculosis statistics does not exceed 30 for 100000 of the population and the percentage of firstly diagnosed fibrous-cavernous tuberculosis does not exceed 0,5, the massive fluorographic examination is done once in 3 years.

 

During prophylactic fluorographic examinations special attention is paid to the socalled “obligatory contingents”. These are persons, who are in a direct contact with children and teenagers:

1. workers of medicative, health, educational institutions for children and teenagers up to 18 years of age, and maternity homes personnel;

2. workers of public catering, alimentary blocks, dairy farms, trade, i.e. persons who deal with foodstuffs;

3. workers of institutions of sanitary-hygienic population service, hotels, hostel tenants, students during the period of study at secondary special and higher educational institutions in professions that belong to the “obligatory contingents”. All these contingents are due to fluorographic examination while getting a job, and then – once a year. Prisoners, who stay in solitary confinement cells, are examined twice a year.

Tuberculosis revealing at applying for the medical aid reaches 50 % of cases. Their revealing, for the most part, depends on phthisiological attention of the general medical network, first and foremost, on therapeutists.

Groups with increased risk of catching tuberculosis. In polyclinics of general profile the object of observation are persons with stomach and duodenal ulcer, after operation due to these maladies; diabetes, dust professional pulmonary illnesses, LCI, after suffered exudative pleurisy, chronic insufficiency of adrenal glands, chronic unspecific illnesses, alcohol and drug addiction; persons who underwent protracted courses of corticosteroid and ray therapy; with small posttuberculous lung changes, as well as with extensive residual changes after unspecific pulmonary illnesses.

Pregnancy, postnatal period, AIDS are classified to the group of increased tuberculosis risk.

Persons, belonging to the risk group, are examined fluorographically once a year at medical institutions of the general profile.

The following groups of increased tuberculosis risk are under observation at antitubercular dispensaries.

DISPENSARY CATEGORY

 

Contingents of antitubercular dispensaries are divided into categories, which enables to examine them differentially, define the treatment tactics, perform prophylactic and rehabilitation actions.

Contingents of adult persons, children and teenagers due to being observed at an antitubercular dispensary, are divided into 5 dispensary categories: 1, 2, 3, 4 and 5.

To 5 categories (Cat 5) are referred dispensary contingents of risk to disease to a tuberculosis and its relapse.

Dispensary supervision over the persons subject to prophylactic medical examination at the doctor – phthisiatrician

 

Categories and groups of dispensary supervision		Control terms of inspection	Term of supervision	Medical and dispensary actions	Criteria of efficiency of treatment and prophylactic medical examination
№	Definition
1	2	3	4	5	6
Cat 1	Firstly diagnosed tuberculosis with bacterial excretion, and also other grave and dissemina-ted (with defeets of more than two segments or two and more bodies) forms of disease without bacterial excretion: miliary, disseminated, meningoencephalitis, exudative pleurisy, pericarditis, peritonitis, tuberculosis of intestine, tuberculosis of spine with neurologic complications, genitourinary tuberculosis	Not less  than  once a month in intensive and once in two months in supporting phases of treatment. Volumes and terms of radiological inspection, research sputum analysis are given for adults in the table 12, for children in table 13	Before treatment or the end of the basic course of treatment, or exclusion from a category because of  various reasons: ineffici-ent treatment, death, transferen-ce to an other clinic. A deadline of supervision – 2 years	Complex etiologic and pathogenetic treatment, under indications surgical intervention	Recovery discontinuance of bacterial excretion,  completion of the basic course of treatment
Cat 2	Relapses of tuberculosis with bacterial excretion and without bacterial excretion and firstly diagnosed tuberculosis, inefficient therapy with and without bacterial excretion, and also patients with interrupted treatment more than for 2 months (with and without bacterial excretion)	Analogically	Analogically	Analogically	Analogically
Cat 3	Firstly diagnosed tuberculosis without bacterial excretion, with the limited process in lungs (with defets iot more than two segments) and extrapulmonary tuberculosis which is not referred to the 1st category; a tubercular intoxication in children and  tuberculosis of intrathoracic lymphatic nodes or primary tuberculous complex in calcination phase  at the preservation of activity of the process.	Not less often than  once a month in an intensive phase and once in two months in supporting phase of treatment	Analogically	Analogically	Healing, the completion of the basic course of treatment
Cat 4	Chronic tuberculosis of various localization with bacterial excretion and without bacterial excretion	Not less often than  once a month in an intensive phase and once in two months in supporting phase of treatment. After the end of the basic treatment at the process remission  once in 3-6 months	Without time restriction	Complex etiologic and pathogenetic treatment, under indications surgical intervention	Healing, end of the basic course of treatment, liquidation of an aggravation of  tuberculosis, preservation of life
Group 5.1	Residual changes after healing of  tuberculosis  (RCTB) of various localization	In the first year of supervisioot less  than  once in 6 months. The next  years of supervision it is carried out not less  than  once in 12 months	Small residual changes of  tuberculosis – 3 years,  big residual changes of tuberculosis – 10 years, tuber-culoma in the size of more than 4 cm, prevalent cirrhosis of lungs – life supervision. Children and teenagers with RCTB are observed till 18 years of age	At presence or occurrence of factors which reduce resistibility of an organism to carry out antirelapse  courses with antitubercular preparations during 2-3 months	Absence of relapses
Group 5.2	Contacts – the persons who are in contact with bacterial excretors (for children and teenagers also with active tuberculosis patients) or with tuberculous agricultural animals	Not less often than once in 6 months. In the period of antirelapse treatment it depends on a technique of its  realization	During all time of contact, and also 12 months after removal from the observation, death or departure	The actions directed to the improvement of the center of tubercular infection and the increase of the resistibility of an organism contacting will be carried out chemoprophylaxis, revaccination of non-infected children ВСG	Absence of relapses of tuberculosis disease
Group 5.3	Adults with tubercular changes of organs of breath of uncertain activity who are notunder supervision of an antitubercular establishment	At out-patient treatment depend on a technique of its realization	3 months	High-grade inspection. In case of need, realization of trial chemotherapy about 3 months	Putting under observation in 1 or 5 category, depending on the activity of tuberculosis
Group 5.4	Children and  teenagers infected with tuberculosis, from groups of risk ( tuberculin test range, hyperergy reaction on tuberculin, increase of tuberculin sensitivity 6 mm for one year, and also children with chronic somatic diseases             Children who were not ВСG inoculated  in  neonate period                     Children with postvaccinal ВСG complications	Control inspections twice a year. During chemopro-phylaxis 3 times a month                   Nonvaccinated  children before ВСG  vaccination are subject to observation once in 3 months by phthisio-pediatrists and respective experts in children’s polyclinics   Under medical indications, but not less often than once in 3 months	At favourable course of an infection during one year, at preservation of hyperergy reactions on tuberculin, and also infected with the chronic centers of a nonspecific infection during 2 years Before realization of vaccination                   1 year	Disposable three-months course of controlled chemoprophylaxis  under observation. At preservation of hyperergy the course of  chemoprophylaxis is appointed during 3 months         Chemoprophylaxis and improvement are carried out in sanatorium conditions, in a sanatorium day nursery, kindergartens,  boarding schools, wood schools, and also in children’s and teenagers establishments of the general type Chemoprophylaxis is carried out in differentiation, according to the condition of the child and dissemination of medicamentous МВT resistance in the region and the centers of an infection	Absence of  tuberculosis cases
Group 5.5	Children and teenagers, in whom it is necessary to specify  the etiology of sensitivity to tuberculin (postvaccination or  infectious allergy), or the character of changes in lungs and other organs with the purpose of differential diagnostics. Children and teenagers with tubercular changes in organs of breath of uncertain activity	Under indications. During chemotherapy owing to postvaccinal complications 3 times per one month	About 6 months	Tuberculinodiagnostics and clinic-radiological inspection in a clinic, iecessary cases in a hospital for differential diagnostics with the purpose of revealing a tubercular infection. Treatment from 2 to about 4 months with repeated clinic-radiological inspection for the decision of a question to etiology or the activity of  the process	Transferred to 1, 3 categories or to 5.4 group

 

Volumes of observation of contingents of the adults who are on dispensary registration at a doctor – phthisiatrician

 

Categories and groups	Roentgenological observation	Laboratory analysis	Analysis of sputum, bronchial lavage water, gastric, bioptates (bacterioscopy and inoculation)	Tuberculin tests
1	2	3	4	5
Cat 1, 2, 3	At registration or receipt in a hospital – inspection roentgenography and in lateral projections, the subsequent examinations are repeated each 2 months. The tomogram of the injured sites of the lungs is carried out at receipt in the clinic, and then each 2 months before the  healing of cavities, and also at an extraction. Under indications – computer tomography of lungs. After  cavities healing of examination once in 3-4 months	Registration take the general analysis of blood and urine, in blood a level of bilirubin, alanine aminotranspherase. At receipt in a hospital in addition it is necessary to define a group of blood, a Rhesus factor, sugar in blood and urine, inspection of blood analysis on Hbs-Ag, AIDS, Wassermann reaction. During the application of antituberculous preparations monthly to carry out the analysis of blood, urine, biochemical analysis (bilirubin, aminotranspherases).	At registration triple  sputum  analysis (washout from bronchial tubes) on МВT by method bacterioscopy, and triple analysis of the material by a method of crop outrient media with obligatory definition of medicinal sensitivity of МВT, further each month two-multiple analogical analysis before the termination of bacterial  МВT excretion and healing of cavities in lungs. The termination of  МВTexcretion  proves to be true by not less than two consecutive negative bacterioscopic and bacteriological ranalyses during 2-3 months	Registration Mantoux test  with 2 TU PPD-L
Cat 4	At an aggravation examina-tion is carried out as in patients of the 1st category. During remission once in 3-6 months	During treatment in a hospital similarly to the volume and terms of examination of the 1-st category patients. During remissioot less than once in 3 months to make the general analysis of blood and urine	During treatment by antitubercular preparations once a month microscopy and crop of a material on МВT, with obligatory research of medicamental resistance to preparations of 1 and 2 lines. During remission of once in 3 months	Similarly
Group 5.1	In the first year of supervision the roentgenogram (fluorogram) once in 6 months, further not less than once per one year before removal from observation. The tomogram under indications	Once in 6 months the first year, further once a year	Once in 6 months the first year of supervision, further under indications	Under indications
Group 5.2	Not less than once in 6 months, and in the period of chemoprophylaxis they are defined by a technique of its realization	Once in 6 months	At suspicion of  tuberculosis	Once a year
Group 5.3	The roentgenogram and the tomogram if registered; further on once in 2 months	The general analysis of blood and urine once a month	At registration, further – once in 2 months	At registration

 

                                                                                                                                                                        

WORKING CAPACITY EXAMINATION

The working capacity examination of a pulmonary tuberculosis patient starts from the moment of a diagnosis establishment. In practical activity the two principal kinds of losing one’s working capacity are possible – temporary and steady ones. Furthermore, the loss of one’s working capacity may be partial or complete.

Temporary disabled or invalid patients are considered the one for whom real prospects for reviving their working capacity, during regulated by respective resolutions terms, exist. The examination of temporary invalidism is done by medicinal consultative committees (MCC), which specify the duration of invalidism, relegate patients to MSCE (medico-social commission of experts) with a view to prolong the sick leave for the maximum permitted term; relegate to MSCE for establishing the group of invalidism and issue a patient references with recommendations of rational employment.

Temporary disabled patients with firstly diagnosed tuberculosis, relapse or the process aggravation are issued sick leavels from 2 to 10 months (with MSCE agreement up to 12 months) depending on the character of tuberculous process and its dynamics under the influence of the treatment. Patients of chronic forms of tuberculosis as well as tuberculosis working invalids at the process aggravation or progressing are entitled to getting a sick leave for up to 4 months uninterruptedly or with intervals not more than 5 months during a calendar year.

The steady loss of one’s working capacity is specified when, in spite of treat-ment, the disturbance of the body functions has acquired a stable character and a patient is unable of doing his daily professional duties, i.e. he becomes an invalid.

The partial invalidism or disability is established in cases, when a patient temporarily cannot work according to his speciality, but without any harm for his health he can do another job.

The complete invalidism or disability is meant as a state, when a patient is ieed of constant special regimen and treatment.

 

In dependence with the degree of the working capacity loss MSCE establishes the III, II (for a year) and the I (for 2 years) group of invalidity. The III group of invalidity is established at inessential loss of working capacity; at a more essential loss of working capacity, when a patient at the presence of essential (considerable, marked) disturbances as a result of tuberculosis, which have become an obstacle for his labour activity, but there is no need in outside supervision – the II group of invalidity. The I group of invalidity is established at complete stable and protracted (durable) loss of working capacity of patients who need outside care.

Permanent invalidity is established for males aged 60 and for females aged 55 with severe chronic irreversible tuberculosis, as well as after pulmonectomy and at essential deformations of the thoracic cage.

MSCE is obliged to give invalids specific recommendations pertaining to their employment, having analyzed the conditions of work and real possibilities of their improvement. The renewal of working capacity of a person, who suffered and recovered from tuberculosis, is an important task of medicine. Medical, professional and social rehabilitation after a patient’s recovery are discriminated. The medical rehabilitation is the renewal after treatment of the lost or weakened functions of an organism.

The aim of the professional rehabilitation is returning of persons recovered from tuberculosis, to their previous work or their retraining and mastering new accessible professions and skills. The social rehabilitation consists in rational profiting by residual working capacity of sick people and invalids. It positively influences the psychics and the emotional state of a man, makes him useful for the society.