Secondary immunodeficiency

Significant prevalence in the population of chronic infectious and inflammatory diseases, torpid in general treatment and accompanying many somatic diseases; severe course of acute infectious diseases, sometimes ending lethal; septic complications after surgical interventions, severe injuries, stress, burns; infectious complications on the background of chemoradiation treatment; high prevalence of often and long-term sick people, which accounts for up to 40% of all labor losses; the emergence of such an infectious disease of the immune system, like AIDS, determined the appearance of the term secondary immunodeficiency.

Secondary immunodeficiency is represented by disorders of the immune system that develop in the late postnatal period in adults and children and are not the result of some genetic defect. They have a heterogeneous mechanism of origin, leading to an increased infectious morbidity; atypical course of infectious and inflammatory process of different localization and etiology, torpid to adequately selected etiotropic treatment. Secondary immunodeficiency is characterized by the mandatory presence of an infection of the purulent-inflammatory process. It should be noted that the infection itself can be both a manifestation and a cause of a violation of the immune response.

Under the influence of various factors (infections, pharmacotherapy, radiotherapy, various stressful situations, traumas, etc.), the immunity of the immune response may be formed, leading to the development of both transient and irreversible changes in the immune response. These changes may be the reason for the weakening of anti-infectious protection.

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What causes secondary immunodeficiency?

PM The most common and accepted classification of secondary immunodeficiencies is suggested by PM Haiton. They distinguish three forms of secondary immunodeficiencies.

1. acquired secondary immunodeficiency (AIDS);
2. induced;
3. spontaneous.

Induced secondary immunodeficiency arises from the effects of external causes that caused its appearance: infections, X-rays, cytostatic treatment, the use of glucocorticoids, injuries and surgical interventions. Also to the induced form include immunity disorders that develop secondary to the underlying disease (diabetes, liver disease, kidney, malignant neoplasms). If there is a specific cause, leading to an irreversible defect in the immune system, a secondary immune deficiency with characteristic clinical manifestations and principles of treatment is formed. For example, against the backdrop of radiation therapy and chemotherapy, irreversible damage to the pool of cells responsible for the synthesis of immunoglobulins is possible, and then these patients, in their clinical course and principles of treatment, resemble patients with PID with a defeat of the humoral immunity unit. In the XX century, mankind first encountered a viral infection of HIV, in which the virus irreversibly damages the cells of the immune system, resulting in the development of a serious infectious disease of AIDS. This disease is characterized by a high percentage of mortality, its epidemiological features, its complex of clinical manifestations and principles of treatment. In this case, the inducer of development of immunodeficiency is the immunotropic virus, which irreversibly damages the lymphocytes, causing secondary immunodeficiency. Given the immediate irreversible damage by the virus of immunocompetent cells (T-lymphocytes), as well as the severity and epidemiological features of the course of this disease, it was identified as a separate group of genetically not deterministic immunodeficiency, namely the secondary acquired immunodeficiency - AIDS.

With a reversible defect, an independent disease does not appear in the immune system, but there is an increase in infectious morbidity in the background of the underlying disease (diabetes mellitus, kidney disease, liver, malignant neoplasms, etc.) or against inducers (infections, stress, pharmacotherapy, ). Such secondary immunodeficiency can often be eliminated by eliminating the cause that caused it and with an adequately selected basic treatment for the underlying disease. The treatment of such patients is primarily based on a correctly diagnosed diagnosis, on the correction of concomitant pathology, and on the account of the side effects of pharmacotherapy aimed at eliminating the leading to immunodeficiency.

Spontaneous secondary immunodeficiency is characterized by the absence of an obvious cause, which caused a violation in the immune system. The clinical manifestation of this form is chronic, often recurrent infectious and inflammatory diseases of the bronchopulmonary apparatus, paranasal sinuses, genitourinary and digestive systems, eyes, skin, soft tissues caused by opportunistic or conditionally pathogenic microorganisms. Patients with a spontaneous form of secondary immunodeficiency are a heterogeneous group, and many believe that at the root of these diseases there must be some causes that we have not determined at the moment. It can be assumed that the cause of secondary immunodeficiencies is the congenital insufficiency of some component of the immune system, compensated to a certain time due to their normal high functional activity of other links in this system. Such failure can not be identified due to various reasons: an inadequate methodological approach, the use of inappropriate material for research, or the inability to identify a violation at this stage in the development of science. If a defect is detected in the immune system, some patients may later find themselves in the PID group. Thus, the boundary between the concepts of primary and secondary immunodeficiencies (especially in spontaneous form) can be conditional. The decisive role in determining the form of immunodeficiency is played by hereditary factors and induced effects. On the other hand, very often patients undergo insufficient research, and therefore the cause of the development of immunodeficiency remains unspecified. The more carefully the examination is performed in patients with spontaneous form of secondary immunodeficiency, the less this group becomes.

In quantitative terms, induced secondary immunodeficiency predominates. It is necessary to avoid the main error in the management of patients and practical health care, when the severe and torpid current of an infectious inflammatory disease is due not to a defect in the immune system, but to incorrectly arranged accents of cause and effect, as well as errors in the diagnosis.

Since at the present stage, in the condition in which the diagnostic base of clinical immunology is located, it is not always possible to determine laboratory markers of immunodeficient conditions, the diagnosis of "secondary immunodeficiency" is primarily a clinical concept. The main clinical sign of secondary immunodeficiency is the atypical course of acute and chronic infectious inflammatory processes, torpid to adequate treatment.

When it is possible to suspect a secondary immunodeficiency?

The most common diseases that can accompany both the congenital and acquired form of immunodeficiency and which require mandatory imminological examination:

• generalized infections: sepsis, purulent meningitis, etc .;
• chronic bronchitis with frequent relapses and pneumonia in a history of combination with diseases of the ENT organs (purulent sinusitis, otitis, lymphadenitis), torpid to standard therapy;
• often recurrent pneumonia and bronchopleuropneumonia;
• bronchiectatic disease;
• chronic bacterial infections of the skin and subcutaneous tissue (pyoderma, furunculosis, abscesses, phlegmon, septic granuloma, recurrent paraproctitis in adults);
• chronic fungal lesions of the skin and mucous membranes, candidiasis, parasitic diseases;
• recurrent aphthous stomatitis in combination with increased incidence of ARVI;
• recurrent herpes-viral infection of different localization;
• gastroenteropathy with chronic diarrhea of unclear etiology, intestinal dysbiosis;
• lymphadenopathy, repeated lymphadenitis;
• long subfebrile condition, LNG.

These diseases can occur against the background of already existing somatic pathologies, the course and treatment of which predisposes to the formation of immunodeficiency with a decrease in tolerance to infections (diabetes, autoimmune, oncological diseases, etc.).

How is secondary immunodeficiency manifested?

Symptoms of secondary immunodeficiency are nonspecific and multifaceted. In ICD-10 there is no diagnosis of "secondary immunodeficiency", except acquired immunodeficiency (AIDS). In the same classification in adults, there is no diagnosis of PID (as opposed to the infantile classification of diseases). Therefore, there is a legitimate question of reconciling the diagnosis of "secondary immunodeficiency" with ICD-10. Some suggest the following solution to this issue: when changes in the immune status are irreversible and lead to the formation of the disease, then the diagnosis should bear the detected immunological defect, since this presupposes a definite and permanent set of therapeutic measures, for example, AIDS; AO with violation and complement system; the main diagnosis is a brain tumor; condition after radiation therapy and chemotherapy - hypogammaglobulinemia; chronic purulent maxillary sinusitis

When the change and immune status of them is reversible and accompanied by somatic diseases or might be the result of a pharmacological or other method of treatment, the identified transitory laboratory disorders can not be diagnosed. Diagnosis is established for the underlying disease and associated pathology, for example: the main diagnosis is type II diabetes, severe course, insulin-dependent variant, decompensation phase; complications - chronic recurrent furunculosis, exacerbation.

How to recognize secondary immunodeficiency?

Screening immunological laboratory tests (1 level) are available, appropriate and can be carried out in many hospitals and clinics where there is a clinical diagnostic laboratory. These tests include studies of the following indicators:

• absolute number of leukocytes, neutrophils, lymphocytes and platelets;
• level of protein and y-fraction;
• level of serum immunoglobulins IgG, IgA, IgM, IgE;
• hemolytic activity of complement;
• hypersensitivity of delayed type (skin tests).

In-depth analysis can be carried out only in a specialized treatment and prophylactic institution, which has a modern laboratory of clinical immunology.

Investigations of the immune status in immunodeficiencies should include the study of the amount and functional activity of the main components of the immune system that play a major role in the anti-infection protection of the body. They include phagocytic system, complement system, subpopulations of T- and B-lymphocytes. The methods used to assess the functioning of the immune system are conditionally divided by RV. Petrov and co-workers. In 1984 on tests of the 1 st and 2 nd at the level. Tests of the 1st level are indicative; they are aimed at identifying gross defects in the immune system, which determine the reduction of anti-infective protection.

Tests of the second level - additional, aimed at identifying a specific violation in the immune system. They substantially supplement information on the functioning of the corresponding immunity system

Tests of the 1st level of phagocytic evaluation:

• determination of the absolute number of neutrophils and monocytes;
• establishment of the intensity of neutralization of microorganisms by neutrophils and monocytes;
• determination of the content of reactive oxygen species.

Tests of the 1st level of evaluation of the B-system of immunity:

• determination of IgG, IgA, IgM and IgE levels in blood serum;
• setting the percentage and the absolute number of B-lymphocytes (CD19, CD20) in the peripheral blood.

Determination of the level of immunoglobulins is an important and reliable method that allows to evaluate the functions of the B-system of immunity. It can be considered the main method of diagnosing all forms of immunodeficiencies associated with a violation of the synthesis of antibodies. This type of violations are noted most often. It can accompany many somatic diseases and acute conditions associated with increased catabolism or impaired synthesis of immunoglobulins.

Tests of the 1st level of evaluation of the T-system of immunity:

• determination of the total number of lymphocytes;
• establishment of the percentage and absolute number of mature T-lymphocytes (CD3 and their two main subpopulations: helper cells (CD4 and killers (CD8));
• revealing the proliferative response of T-lymphocytes to mitogens (phytohemagglutinan and concanavalin A).

Tests of the second level are aimed at an in-depth study of the immune status, identification of the causes that cause disorders and defects of the immune system at the cellular, molecular and molecular-genetic levels.

Tests of the 2nd level of phagocytosis evaluation:

• determination of intensity of chemotaxis of phagocytes:
• establishment of expression of adhesion molecules (CD11a, CD11b, CD11c, CD18) on the surface membrane of neutrophils;
• Determination of the completeness of phagocytosis by seeding or flow cytometry.

Tests of the 2nd level of evaluation of the B-system of immunity:

• determination of the content of subclasses of immunoglobulins (especially IgG):
• determination of secretory IgA;
• establishing the ratio of kappa- and lamp-chains:
• determination of the content of specific antibodies to protein and polysaccharide antigens;
• the establishment of the ability of lymphocytes to respond to proliferation by mitogens: B cells - staphylococcus, lipopolysaccharide enterobacteria; T and B cells mitogen of the lakonos.

The determination of subclasses of IgG is of definite diagnostic value, since at normal levels of IgG, a deficiency can occur in subclasses of immunoglobulins. In such cases, in some cases, secondary immunodeficiency is observed in the form of a weakening of the anti-infective protection of IgG2, a subclass of IgG, which mainly contains antibodies against polysaccharides of encapsulated bacteria (Haemophilus influlenzae, Streptococcus pneumoniae). Important information on the state of humoral immunity determines the level of antibodies to bacterial protein and polysaccharide antigens, since the degree of protection of the organism from this particular infection depends on the total level of immunoglobulins, and on the amount of antibodies to its causative agent. Therefore, the absence of specific IgG antibodies to the transferred infection is always a prognostically favorable sign. Valuable information on the state of humoral immunity can also be obtained by studying their functional properties. To them, in the first place, should be attributed to the property of antibodies, as affinity, on which the strength of the interaction of antibodies with the antigen largely depends. The production of low-affinity antibodies may lead to insufficient protection from infection.

The B-system of immunity can be assessed by the level and quality of the functional activity of immunoglobulins, since they are the main end product of these cells. Such an approach is still difficult to implement with respect to the T-system of immunity, since the main end-product of activation of T-lymphocytes is cytokines, and systems for their determination are still not widely available in practical public health. Nevertheless, the evaluation of the functional activity of the T-system of immunity is of utmost importance, since this activity can be significantly reduced with a normal number of T cells and the ratio of their subpopulations. Methods for assessing the functional activity of T-lymphocytes are rather complicated. The simplest of them is the reaction of blast transformation with the use of two major T-mitogens: phytohemagglutinin and concanavalin A. Proliferative T-lymphocyte response to mitogens is reduced in almost all chronic infectious inflammatory processes, malignant diseases (especially hematopoiesis); with all types of immunosuppressive treatment, AIDS and all types of primary T-cell immunodeficiency.

The determination of the production of cytokines by lymphocytes and macrophages is still of great importance. The role of the determination of such cytokines as TNF, IL-1 and IF-y in the etiopathogenesis of various acute and chronic inflammatory processes is not only infectious but also autoimmune. Their increased education is the main cause of septic shock.

It should be noted that cytokines are mediators of cellular interaction, they determine only the severity of both infectious and non-infectious inflammation,

The study of the expression of activation molecules and adhesion molecules on the surface of lymphocytes provides important information on the degree of their activation. A violation of the expression of the receptor for IL-2 is observed in many malignant blood diseases (T-cell leukemia, hairy cell leukemia, lymphogranulomatosis, etc.) and autoimmune processes (rheumatoid arthritis, systemic lupus erythematosus, aplastic anemia, scleroderma, Crohn's disease, sarcoidosis, diabetes mellitus and etc.).

On the recommendation of foreign experts and in accordance with the recommendations of WHO experts, skin testing in the diagnosis of T-cell immunodeficiency is used as screening tests or tests of the 1st level. Skin tests - the simplest and at the same time informative tests, allowing to evaluate the functional activity of T-lymphocytes. Positive skin toasts with some microbial antigens are very likely to exclude the presence of T-cell immunodeficiency in a patient. A number of western firms have developed standardized systems for the formulation of skin tests, which include the main antigens for determining T-cell immunity. This allows in strictly controlled conditions to evaluate the functional activity of the T-system of immunity. Unfortunately, skin test systems for evaluation of the T-system of immunity in Russia are absent and, therefore, they are practically not used.

Scheme of examination of various parts of the immune system

Humoral immunity:

• the main classes and subclasses of immunoglobulins: IgG (IgG1, IgG2, IgG3, IgG4) IgA, IgM, IgE; antigen-specific IgA, IgM, IgG, IgE; circulating immune complexes;
• complement system: СЗ, С4, С5, С1-inhibitor;
• affinity of antibodies.

Phagocytosis:

• phagocytic index of neutrophils and monocytes;
• opsonic index;
• intracellular bactericidal and phagocytic fungicides;
• Formation of reactive oxygen species in luminol and lucetinin-dependent spontaneous and induced chemiluminescence.

Immunophenotyping:

• CD19, CD3, CD3 CD4, CD3 CD8, CD3-HLA-DR, CD3-HLA-DR;
• CD3 CD16 / 56. CD4 CD25.

Functional activity of lymphocytes:

• Proliferative response to T- and B-mitogens;
• Cytotoxic activity of RL cells;
• Determination of the cytokine profile (IL 1, IL-2, IL-4, IL-6, etc.).

Interferon profile:

• determination of IFN-a on serum and in supernatant fluid suspensions of leukocytes activated by the virus of Newcastle disease;
• determination of IFN-y in the blood serum and in the supernatant of suspensions of lymphocytes activated by phytohemagglutinin.

By the nature of changes in patients diagnosed during immunological examination, secondary immunodeficiency can be divided into three groups:

• patients with clinical signs of immune deficiency and identified changes in the parameters of immune status;
• patients with only clinical signs of immune deficiency and normal indices of immune status;
• patients with a lack of clinical manifestations of immune deficiency, but with the revealed changes in the parameters of the immune status.

For groups 1 and 2, immunotropic treatment should be selected. The third group requires observation and monitoring of the immunologist to exclude the artifact of the study, as well as an in-depth clinical examination of the clarification of the causes that led to immunological changes.

Treatment of secondary immunodeficiency

The main tool for treating patients with secondary immunodeficiency is immunotropic treatment. It has three directions:

1. active immunization (vaccination);
2. substitution treatment (preparations of the sprinkling: plasma, immunoglobulins, leukocyte mass, etc.);
3. preparations of immunotropic action (immunostimulants, granulocyte-macrophage colony-stimulating factors, immunomodulators of exogenous and endogenous origin, chemically pure and synthesized)

The choice of immunotropic treatment depends on the severity of the infectious inflammatory process and the detected immunological defect.

Vaccinotherapy

Vaccinotherapy is used for prophylactic purposes only during remission of both infectious and somatic diseases. Each of the drugs used has its own indications, contraindications and patterns of use.

Substitution treatment of secondary immunodeficiency

Can be used at any stage of the infectious-inflammatory process. Drugs of substitution treatment are the drugs of choice in an acute situation. The most commonly used intravenous immunoglobulins. The main active components of these drugs are specific antibodies, I drink from a large number of donors. Currently, intravenous immunoglobulin preparations are used to prevent infectious processes and treat diseases in which the pathogenesis of defects of humoral immunity. Substitution treatment is used to fill the deficit of antibodies in a number of acute and chronic diseases with secondary immunodeficiency, accompanied by hypogammaglobulinemia, which is caused either by the increase in the catabolism of immunoglobulins or by a violation of their synthesis.

The increase of catabolism of immunoglobulins is observed in nephrotic syndrome, enteropathy of various etiology, burn disease, fasting, paraproteinemia, sepsis and other conditions. Disturbance of the synthesis of immunoglobulins occurs in primary tumors of the lymphoid tissue against the background of treatment with cytostatics, glucocorticoids and radiation therapy, as well as in diseases accompanied by toxicosis (renal failure, thyrotoxicosis, severe generalized infections of various etiologies).

The multiplicity of the administration and dose of intravenous immunoglobulins depends on the clinical situation, the initial level of IgG, the severity and prevalence of the infectious-inflammatory process. The most widely used preparations of intravenous immunoglobulins containing only IgG: gabriglobin (human immunoglobulin normal), octagam (human immunoglobulin normal), intraglobin (human immunoglobulin is normal). Intravenous immunoglobulin containing all three classes of immunoglobulins (IgA, IgM, IgG) is analogous to plasma - pentaglobin (human immunoglobulin normal IgG + IgA + IgM)) has been introduced into standards for the treatment of septic patients. Immunoglobulins with an elevated IgG titer to specific antigens, such as cytotecs (anti-cytomegalovirus immunoglobulin) with an elevated titre of antibodies to cytomegelovirus infection and neogepatec (immunoglobulin against human hepatitis B) to hepatitis B, are used much less often. It must be remembered that preparations containing IgA (pentaglobin, plasma) are contraindicated in patients with selective immunodeficiency A.

Immunotropic treatment of secondary immunodeficiency

And now there is no doubt that the use of immunomodulators of various origins in the complex treatment of infectious and inflammatory processes increases the effectiveness of antimicrobial treatment. Immunomodulators are widely used in patients with secondary immunodeficiency.

General principles of the use of immunomodulators in patients with insufficient anti-infective protection.

• Immunomodulators are prescribed in combination with etiotropic treatment of the infectious process. Monotherapy is permissible only for the stage of remission of the infectious process,
• The choice of the immunomodulator and the scheme of its use are determined depending on the severity of the infectious inflammatory process, its cause, the detected immune defect, taking into account somatic diseases and inducer effects.
• The main criteria for the appointment of immunomodulating drugs - clinical manifestations of immunodeficiency (the presence of an infectious inflammatory process, torpid to adequate etiotropic treatment).
• Doses, schedules and duration of treatment should be consistent with the drug's instructions; correction of the use of the drug should only be carried out by an experienced clinical immunologist.
• If there is a corresponding material and technical base in the medical and prophylactic establishment, the use of immunomodulators should be carried out against the background of immunological monitoring, which should be carried out independently of the initial changes in immunological parameters.
• In the presence of any parameter of immunity, revealed by immunodiagnostic examination in a practically healthy person, can not be the reason for prescribing immunomodulatory treatment for him. Such patients should undergo an additional examination and be under the supervision of an immunologist.

Despite the fact that the action of immunomodulating drugs in different directions, each of them has its own advantages. When the cells of the monocyte-macrophagal system are affected, polyoxidonium (azoxime), galavite (sodium aminodihydrophthalazinedione), bronchomunal, ribomunil are used. At defects of a cellular link of immunity it is expedient to appoint or nominate polyoxidonium (azoksimer), tactivin (a thymus

Extract), thymotene (alpha-glutamyl-tryptophan), thymalin (thymus extract), imunophane (arginyl-aspartyl-lysyl-valyl-tyrosyl-arginine). When the synthesis of antibodies by B-lymphocytes is violated and the affinity of antibodies to the general antigenic determinant is broken, galavite (aminodihydrophthalazinedione sodium) and myelopid are indicated. Changes in the indices of interferon status are corrected with the help of drugs - inducers of interferon or substitution treatment with the use of natural or recombinant IF.

Care must be taken to prescribe immunomodulators in the acute phase of the infectious process. For example, preparations of microbial origin are not recommended for use in this period in connection with the possible development of polyclonal activation of cells of the immune system. When using cytokines, it must be remembered that the indications for their use are leukopenia, lymphopenia and low spontaneous activation of neutrophils; otherwise they can provoke a severe systemic inflammatory response, which can lead to septic shock. The most safe immunomodulator in such cases is polyoxidonium, which, in addition to immunomodulating effect, has detoxifying, antioxidant and chelating properties.

Immunostimulants

Preparations of granulocyte-macrophage colony-stimulating factor are used only in severe leukopenia and agranudocytosis under daily control of a clinical blood test.

Thus, due to the multifactoriality of the etiological factors involved in the formation of such a disease as secondary immunodeficiency, the success of the treatment of such patients depends on the professionalism of the immunologist who correctly places the accents in the cause-effect relationship, adequately assesses the results of the immunological study and selects immunotropic medication, which will shorten the time hospitalization, lengthen remission in chronic infectious-inflammatory processes, and in some cases save the patient's life.

Among systemic immunomodulators, the use of interferon inducer preparations, including Lavomax, coated tablets (active ingredient tilorone 0.125 g) deserves attention. Lavomax triggers the synthesis of all three types of interferons by the body itself, activates cellular immune mechanisms that collectively interrupt the multiplication of viruses and other intracellular agents and infected cells or cause death and contribute to the elimination of the virus. Synthesis of interferons with the introduction of Lavomax in the blood is determined 20-24 hours after taking the drug. Distinctive feature of Lavomax as an inducer of interferon is the ability to cause a prolonged circulation in the blood of therapeutic doses of IFN, which prevent infection of uninfected cells and create a barrier antiviral state, suppress the synthesis of virus-specific proteins and intracellular multiplication of HPV. Moreover, induction of endogenous IFN can be considered as a physiological mechanism of IFN-genesis. Scheme of application: the first two days of 1 tablet, then 1 tablet every other day. The course dose is 10-20 tablets.