RU2158606C2 - Complex method for treating the patients suffering from russian tick-borne encephalitis - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves intravenously administering human immunoglobulin against Russian tick-borne encephalitis depending on infection form and severity degree. The preparation is administered at a single dose of 25.0 ml once a day daily during to 6 days in the cases of meningoencephalitis. The total course requires to 150.0 ml. The preparation is administered at a single dose of 25.0 ml twice a day daily during 6 days in the cases of focal encephalitis. The total course requires at least 300.0 ml. EFFECT: enhanced effectiveness of treatment. 5 tbl

Description

 The invention relates to medicine and relates to serotherapy of viral diseases, can be implemented in the practice of neurological and infectious clinics.

 Tick-borne encephalitis (TBE) therapy is multicomponent and is determined by the severity of the clinical course and the severity of symptoms and syndromes. Mild infections are usually treatable by symptomatic treatments. The technique of serotherapy of moderate and severe forms of tick-borne encephalitis (TBE) [6, 4] with human immunoglobulin (IG) for intramuscular administration has long been known and widely used [3].

 However, the low, not always adequate severity of the course of certain forms of tick-borne encephalitis, doses of specific intramuscular immunoglobulin against TBE do not allow to achieve sufficiently effective results, do not have a pronounced effect on the regression of the main symptoms and syndromes, to a small extent contribute to the prevention of disability and the achievement of labor rehabilitation for moderate and severe tick-borne encephalitis, especially inherent in the Far Eastern region of Russia.

 Against the background of NTD-regulated immunotherapy technology for tick-borne encephalitis therapy, separate attempts have been made to use higher doses of intramuscular anti-tick-borne immunoglobulin [7].

Later, on the basis of extended controlled clinical and immunological tests, a method was patented in which indications and optimal regimens for the commercial use of the commercial preparation of human IG against EC for intramuscular administration in doses exceeding the regulated NTD were developed [1]:
- with the meningeal form of infection, the drug is prescribed daily in a daily dose of 6.0-12.0 for at least 5 days until the patient's general condition improves according to objective indicators. On the course of treatment - from 30.0 to 60.0 ml.

 - in focal forms, depending on the severity of the disease, the drug is administered daily in a daily dose of 12.0-18.0 ml for at least 5-6 days to lower body temperature and stabilize neurological symptoms. On the course of treatment - from 60.0 to 108.0 ml.

 However, intramuscular administration of immunoglobulin has disadvantages associated with the loss of the immune protein during absorption from the tissue and slow entry into the blood, the impossibility of an unlimited increase in the dose of the protein preparation administered intramuscularly at a time to achieve the desired therapeutic effect.

 In order to quickly administer specific antibodies to the bloodstream simultaneously, to eliminate the undesirable effects of simultaneous intramuscular injection of large doses of a protein preparation, to increase the effectiveness of treatment of tick-borne encephalitis patients in the febrile stage of the acute period of the disease, the development of a human immunoglobulin preparation for intravenous administration was started [8, 9, 10] .

The human immunoglobulin preparation against tick-borne encephalitis for intravenous administration is an immunologically active fraction isolated from human plasma or blood serum of donors that contains antibodies to tick-borne encephalitis virus, purified and concentrated by ethyl alcohol fractionation at a temperature below 0 ^o C. The preparation does not contain preservatives and antibiotics. It lacks antibodies to HIV, surface antigen to hepatitis B virus and antibodies to hepatitis C. The drug is deprived of anticomplementary properties as a result of treatment with a small amount of pepsin in a weakly acidic medium followed by removal of the enzyme with aluminum hydroxide.

 The latter distinguishes it from the well-known immunoglobulin preparation against tick-borne encephalitis for intramuscular administration and allows it to be administered intravenously.

 The drug at the development stage was monitored for compliance with the design documentation in the specialized laboratories of the GISK named after L.A. Tarasevich and was authorized by the IIBP Committee for testing in the clinic. Tests of the new drug were carried out in accordance with the Program approved by the IIBP Committee of the Ministry of Health of the Russian Federation (N 01-07 / 219 dated 12.07.94) [2] in the neurological clinics of. Khabarovsk and Yekaterinburg [9, 5]. The program proposed a method for the therapeutic use of human immunoglobulin against tick-borne encephalitis for intravenous administration, which is partially described in the publication [5]: course doses were 50 or 100 ml of the drug for patients of the 1st group; 100.0 or 200.0 ml for patients of the 2nd group. The daily dose in the 1st group was 25 ml; in the 2nd group of 50 ml. The control was an intramuscular anti-encephalitis immunoglobulin in various course doses (regulated - hereinafter “small” and elevated - hereinafter “large”).

 A preliminary assessment of the programmed pattern indicated a positive effect of the drug being developed on the regression of leading symptoms in severe forms of tick-borne encephalitis [9.5]. However, in these publications, which are the prototype of the proposed method, information on the effectiveness of the new immunoglobulin preparation against tick-borne encephalitis for intravenous administration is general, non-specific and purely preliminary.

 In this prototype, with the meningeal form of CE, it was proposed to use a daily dose of 25.0 ml and a course volume of 50.0-100.0 ml; with focal forms of CE, the proposed daily dose was 50.0 ml, and the course volume was from 100.0 to 200.0 ml. These parameters determine the duration of the course of immunotherapy in two - maximum four days with a single injection of immunoglobulin, the frequency of administration of a single dose during the day or the interval between administrations is not specified.

 However, already at the very beginning of the tests, it was stated that in order to achieve a pronounced therapeutic effect of the test drug, an increase in the duration of its administration and doses is necessary compared to the programmed and partially described in the prototype.

 In addition, to date, Russia has begun to use modern international standards for calculating therapeutic and prophylactic doses of various immunobiological preparations based on the patient’s body weight.

 These factors were taken into account when performing the full volume of clinical and immunological tests. Upon completion of work, on the basis of a multidimensional analysis of the clinical and virological-immunological results obtained, the following method of complex treatment of tick-borne encephalitis patients by administering human immunoglobulin against tick-borne encephalitis for intravenous administration, in which the dose and duration of treatment depends on the form and severity of tick-borne encephalitis, has been developed as well as the patient’s body weight. Human immunoglobulin against tick-borne encephalitis for intravenous administration is administered in a single dose of 15 mg (0.3 ml) / kg body weight.

Patients with meningeal form of tick-borne encephalitis drug is administered once a day, daily, up to 6 days,
patients with focal forms of infection - twice a day daily, at least 6 days.

 The most effective is the earliest possible application of the method from the day the disease begins.

 In a state trial, at the end of which the proposed method was formulated, specific anti-TB immunoglobulin for intravenous administration was used in the complex treatment of 47 patients with meningeal (29 people) and focal (18 people) forms of TBE.

 The new drug used in the proposed method was harmless and areactogenic.

 A total of 90 patients with TBE participated in the comparative trial, including 58 men and 32 women aged 25 to 60 years.

 Transfusion therapy with human immunoglobulin against tick-borne encephalitis was combined with the use of a complex of non-specific therapeutic agents (corticosteroid drugs, cardiovascular agents, saline solutions, vitamins, microcirculants, nootropil, symptomatic agents).

 At the end of the febrile stage, depending on the leading clinical syndrome, comprehensive rehabilitation treatment was performed.

 Patients with bulbar and respiratory disorders were placed in the intensive care unit. Artificial ventilation of the lungs was carried out by a method adopted in intensive care practice.

 The effectiveness of the proposed method was compared with the prototype, with the results of treatment of patients with TBE who received intramuscular IG in accordance with the instructions for use from 1987 ("small" doses), and in doses exceeding the regulated ("high") ones, the first and second analogues. Another comparison group received therapy only with pathogenetic agents, excluding IG.

The effectiveness of therapy was evaluated by six quantitative indicators:
The days from the onset of the disease were taken into account, for which patients:
- body temperature normalizes;
- the general condition is normalized;
- cerebral symptoms regress;
- meningeal symptoms regress;
- sanitized cerebrospinal fluid;
- motor disorders begin to regress (in patients with focal forms of TBE).

 In addition to clinical data, the terms and levels of the formation of specific antibodies against the TBE virus, the levels and duration of antigenemia, the dynamics and normalization periods of cellular immunity indicators, the quantitative and qualitative characteristics of the general serum immunoglobulins of the main classes were taken into account. Quantitative assessment of nonparametric criteria (general condition, severity of cerebral, meningeal symptoms, motor disorders) was carried out using a scoring characteristic. This was the basis for the formation of the comparable groups of patients adequate for the severity of the disease who received intravenous IG against TB and intramuscular drug against TB: 10.29 and 11.55 with the meningeal form and 14.72 and 15.53 with focal TB forms, respectively.

 Materials on the effectiveness of treating patients with TBE in new and compared ways are presented in tables 1, 2, 3, 4, 5, and are also illustrated by examples of specific case histories.

 The difference from the prototype is the principle of calculating a single dose of the used immunoglobulin against tick-borne encephalitis for intravenous administration, based on the patient’s body weight, an increase in the course dose of the drug, and longer immunotherapy from the moment it starts.

 The proposed method using a human immunoglobulin preparation for intravenous administration in complex treatment of tick-borne encephalitis patients is more effective than symptomatic treatment and serotherapy with anti-TB immunoglobulin in regulated doses, is more effective in a number of indicators or coincides in therapeutic effect with high doses of intramuscular preparation.

 A method of complex treatment using intravenous IG in adequate dosages for patients with a meningeal form of infection, more effective than symptomatic therapy and serotherapy with "small" doses of intramuscular IG according to such indicators as the normalization and rehabilitation of cerebrospinal fluid, the onset of regression of meningeal symptoms (an average of 3.7; 15.7; 5.6 days earlier, p <0.05; 3.4; 6.7; 2.4 days earlier, p <0.05, respectively, when compared with symptomatic treatment and exposure to "small" doses of intramuscular IG). Somewhat earlier than with symptomatic treatment, cerebral symptoms regressed. On the timing of normalization of temperature in the meningeal form of CE, a pronounced effect of intravenous IG was not noted.

 A comparison of the effectiveness of the proposed method with the effect of "high" doses of intramuscular IG on the course of the meningeal form of EC showed a positive effect on the timing of the regression of meningeal symptoms, normalization, and rehabilitation of the cerebrospinal fluid. At the same time, there was some advantage of “large” doses of an intramuscular preparation when acting on accelerating normalization of temperature and regression of cerebral symptoms.

 In focal forms of TBE, the therapeutic effect of intravenous IG was statistically significantly (p <0.05) higher in terms of reduction in the onset of regression of meningeal symptoms (4.2 days earlier) and cerebrospinal fluid rehabilitation (12.7 days earlier) compared with symptomatic treatment means. On average, 1.2 days earlier, the patient's condition returned to normal.

 The greater effectiveness of the method compared with the effect of "small" doses of intramuscular IG is expressed in shortening the period of rehabilitation of the cerebrospinal fluid (9 days earlier). For other signs, the effect of the drugs was almost unambiguous.

 The effect of IG intravenous and intramuscular in "large" doses when used for the treatment of severe forms of TBE was similar. Normalization of the general condition occurred with the use of "high" doses of intramuscular IG earlier (by 3.0 days, p <0.05).

 The issue of therapy of patients with extremely severe course of EC requires special consideration. Its success depends on the degree of damage to the central nervous system and the characteristics of the macroorganism. Mortality in such patients who do not receive resuscitation benefits and specific treatment is 100%. The proposed method of complex therapy allows you to save the life of up to 20% of such patients.

 The need for the earliest possible initiation of specific treatment using IG intravenous by the proposed method is shown. Thus, in the treatment of the meningeal form of infection, all average statistical efficacy indicators were better during immunotherapy in the first 6 days of illness. Most demonstratively this is to accelerate the timing of the regression of meningeal symptoms.

 Intravenous IG in adequate doses is more effective in the early stages and in the treatment of focal forms of the disease. It contributes to a significantly faster regression of meningeal symptoms, and CSF sanitation (an average of 10 days earlier, p <0.05).

 However, treatment started later also has a positive effect on the course of infection and contributes to a more rapid normalization of CSF and shortens the duration of treatment.

 In a comparative test of the proposed method, prototype and analogue methods, the most effective duration of immunotherapy was determined, which is up to 6 or more days, depending on the severity of the course and the clinical form of the infection.

 Information on the comparability of the following specific examples by baseline, clinical forms of infection, age, and the timing of symptom regression in specific patients is given in the table.

 Example 1. The medical history N 8224. Patient P., 35 years old, was hospitalized in the clinic on the 6th day of the disease in moderate condition with severe general infection, cerebral and meningeal symptoms. In cerebrospinal fluid - protein - 0.271 g / l, cytosis - 79 cells (lymphocytes predominate). Diagnosis: tick-borne encephalitis, meningeal form (confirmed by specific diagnostics). On the day of admission, along with symptomatic treatment, anti-TB immunoglobulin therapy was started for intravenous administration of 25.0 ml per day for 4 days at a course dose of 100.0 ml.

 Normalization of body temperature - on the 12th day of illness, condition - on the 14th day, regression of meningeal, cerebral symptoms on 11 and 14 days, respectively, rehabilitation of the cerebrospinal fluid - by the day of discharge from the hospital (third week of illness) did not occur. Discharged from the hospital in satisfactory condition with mild asthenic manifestations.

 Example 2. Case history No. 12211 Patient S., 54 years old, was hospitalized in the clinic on the 7th day of the disease in a state of moderate severity with severe general infection, moderate cerebral and meningeal symptoms. In cerebrospinal fluid - protein 0.260 g / l, cytosis - 60 cells (lymphocytes). Diagnosis: tick-borne encephalitis, meningeal form (confirmed by specific diagnostics). On the day of admission, on the 7th day of the disease, IG therapy against EC was started for intravenous administration, 25.0 ml once a day for 6 days. Heading dose of 150.0 ml. Normalization of body temperature - from the 14th day of illness, condition - from the 12th day, regression of meningeal and cerebral symptoms on the 12th and 10th days of the disease, respectively. Sanitation of cerebrospinal fluid by the time the patient was discharged from the hospital (3 weeks of illness) did not occur. The patient was discharged from the clinic in satisfactory condition with the phenomena of astheno-vegetative syndrome.

 Example 3. The medical history N 9152. Patient D., 38 years old, was hospitalized in the clinic on the 2nd day of the disease in serious condition with severe general infection and meningeal symptoms. In neurological status - inhibited, disoriented, bilateral reflexes of oral automatism, moderate paresis in the left extremities with increased tone, revitalization of tendon and periosteal reflexes, pathological hand and foot signs. In cerebrospinal fluid - protein - 0.24 g / l, cytosis - 74 cells (lymphocytes predominate). Diagnosis: tick-borne encephalitis, meningoencephalitis form (confirmed by specific diagnostics). On the 3rd day of the disease, immunoglobulin therapy against tick-borne encephalitis was started for intravenous administration of 50.0 ml per day for 4 days at a course dose of 200.0 ml.

 Normalization of body temperature - from the 14th day of illness, the state from 18th day, regression of cerebral and meningeal symptoms - on the 15th and 18th days, respectively, of the rehabilitation of the cerebrospinal fluid by the time the patient was discharged from the hospital (24th day of illness), the degree decreased hemiparesis. The patient was discharged from the hospital in satisfactory condition with symptoms of mild left-side hemiparesis, astheno-vegetative syndrome.

 Example 4. Case history 12208. Patient B., 34 years old, was hospitalized in the clinic on the 3rd day of the disease in serious condition with severe general infection, cerebral and meningeal symptoms. In neurological status: excited, disoriented, poorly accessible to productive contact. There are gross reflexes of oral automatism. In cerebrospinal fluid - protein 0.460 g / l, cytosis of 176 cells (lymphocytes predominate). Diagnosis: tick-borne encephalitis, meningoencephalitic form (serologically confirmed). From the day of admission to the blade, on the 3rd day of the disease, IG anti-TBE therapy was started for intravenous administration of 25.0 ml 2 times a day for 6 days. The course dose is 300.0 ml.

 The inclusion in the complex therapy of TBE of a new specific preparation of IG for intravenous administration in the proposed dosages does not cause immunosuppressive effects. There are changes in the immune status characteristic of the course of the infectious process with the corresponding clinical forms of infection. Along with this method allows you to positively affect the T-link of immunity. Thus, the content of T-suppressor cells in the blood of patients receiving IVH therapy at 2-4 weeks of illness is significantly lower than in the control (8.2-6.0% versus 13.6-14.3%). Normally, this indicator comes to 4-6 weeks after the onset of the disease.

 Evidence has been obtained of the positive effect of immunotherapy with intravenous IG on earlier and more effective immunorehabilitation compared with symptomatic treatment (table 5).

 In patients receiving intravenous anti-TB immunoglobulin, specific antibodies of the IgM class were determined in maximum titers only at 2-3 weeks of illness. By the end of their stay in the hospital, their level decreased, which indicates the absence of the effect of the new drug on the prolongation of the synthesis of IgM antibodies, which, if present, is an unfavorable prognostic sign of the course of CE. The method contributes to an earlier switch of the synthesis of early antibodies to IgG antibodies.

 Dynamic monitoring of a number of patients for two years from the time of the disease and treatment in the IG complex against EC for intravenous administration did not reveal a deterioration in the state of convalescents, cases of the transition of the acute course of the disease to progredient.

 Conducting specific therapy for TBE by the proposed method, contributes to faster labor rehabilitation. Patients with a meningeal form of infection experienced clinical recovery without limiting their ability to work. In patients with severe CE, without vital disorders, the proposed method allowed to achieve full recovery in 50% of cases. The rest, who received immunoglobulin anti-TB immunotherapy for intravenous administration, had coarse residual effects that made it possible to rationally employ convalescents.

 A method for treating tick-borne encephalitis patients using a complex of human anti-TB immunoglobulin preparation for intravenous administration of the patient’s body allows, unlike analogues, to increase the dose of the immune protein entering immediately into the bloodstream and reduce the loss of the immune protein at the stages of administration to the body. Intravenous transfusion of the drug is less traumatic and painful for the patient than simultaneous intramuscular injection of a significant amount of protein solution. New clinically-immunologically substantiated and tested doses of the human immunoglobulin anti-TBE drug for intravenous administration, a new calculation principle that differ from the prototype, as well as a corrected precise administration schedule allow reducing the normalization of leading symptoms depending on the severity of the infection, and contribute to faster immunorehabilitation , a decrease in mortality and disability in severe cases of tick-borne encephalitis.

 The method is recommended for use in neurological and infectious disease clinics.

Literature:
1. Bereta L.D. Zakharycheva T.A., Skupchenko V.V., Aleksandrov V.I., Nikolaeva S.P., Method for the treatment of patients with tick-borne encephalitis. Patent N 1837230 dated 03.20.93.

 2. Bereta L.A., Nikolaev S.P., Zakharychev R.A., Voronkova G.M., et al. , The program and methodology for assessing the therapeutic effectiveness of the drug "Human immunoglobulin against tick-borne encephalitis for intravenous administration." Approved by the Committee IIBP MH PC) 07/12/94

 3. Human immunoglobulin against tick-borne encephalitis for intramuscular administration. FS 42-3155-95.

 4. Clinic, diagnosis and treatment of tick-borne encephalitis. Methodical instructions. - M., 1990. - p. 20-21.

 5. Maltseva O. V., Lazykina A. V., Sharygin S. L., Zaitseva G. A., Matveev G. A. Actual issues of substitution immunotherapy for tick-borne encephalitis. / Bulletin of the blood service of Russia N 1, 1997, p. 31-33.

 6. Guidelines for the clinic, epidemiology, laboratory diagnostics, epidemiology and prevention (specific and non-specific) of tick-borne encephalitis. M., 1981, p. fourteen.

 7. Nikolaeva S.P., Stepanenko L.M., Vereta L.A., Aleksandrov V.I., On the effectiveness of treatment of tick-borne encephalitis with an immunoglobulin preparation manufactured by the Khabarovsk Research Institute of Nuclear Medicine. / Sat Proceedings of Natural focal infections and invasions of the Far East, Khabarovsk, 1980, p. 14-17.

 8. Nikolaeva S.P., Vereta L.A., Mikheeva E.I. Development of an immunoglobulin preparation against tick-borne encephalitis for intravenous administration. / Sat abstract The infectious pathology in the Primorsky Territory. Vladivostok, Dalnauka, 1994, p. 158-159.

 9. Nikolaeva S.P., Zakharycheva T.A., Voronkova G.M. Alexandrov V.I. et al. Specific immunoglobulins in the treatment of tick-borne encephalitis. / Sat Blood products and blood substitutes - production, control and clinical use. Kirov, 1995, p. 58-59.

 10. Sharygin S.A. The program for the creation of domestic specific immunoglobulins for intravenous administration on the basis of the Kirov Research Institute of Scientific and Practical Research. / Sat Blood products and blood substitutes - production, control and clinical use. Kirov, 1995, p. 19-21.

Claims (1)

 A method for the complex treatment of tick-borne encephalitis patients by administering a human immunoglobulin against tick-borne encephalitis for intravenous administration in combination with non-specific therapeutic agents, characterized in that a human immunoglobulin against tick-borne encephalitis for intravenous administration is used in doses depending on the form and severity of the infection: patients with meningeal form tick-borne encephalitis, the drug is administered in a single dose of 25 ml once a day daily for up to 6 days, up to 150 ml per course; patients with focal forms of tick-borne encephalitis in a single dose of 25 ml twice a day daily for at least 6 days, at least 300 ml per treatment course.

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