Secondary immunodeficiency

Significant prevalence of chronic infectious and inflammatory diseases in the population, sluggish to conventional treatment and accompanying many somatic diseases; severe course of acute infectious diseases, sometimes ending fatally; septic complications after surgical interventions, severe injuries, stress, burns; infectious complications against the background of chemoradiation therapy; high prevalence of frequently and long-term ill people, causing up to 40% of all labor losses; the emergence of such an infectious disease of the immune system as AIDS, determined the emergence 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 any genetic defect. They have a heterogeneous mechanism of origin, leading to increased infectious morbidity; atypical course of the infectious and inflammatory process of various localizations and etiologies, torpid to adequately selected etiotropic treatment. Secondary immunodeficiency is characterized by the obligatory presence of 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, radiation therapy, various stress situations, injuries, etc.) a failure of the immune response may develop, leading to the development of both transient and irreversible changes in the immune response. These changes may be the cause of weakening of the anti-infective defense.

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What causes secondary immunodeficiency?

The most widespread and accepted classification of secondary immunodeficiencies was proposed by RM Khaiton. They distinguish three forms of secondary immunodeficiencies.

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

Induced secondary immunodeficiency occurs as a result of external causes that caused its appearance: infections, X-rays, cytostatic treatment, use of glucocorticoids, injuries and surgical interventions. Also, the induced form includes immune disorders that develop secondary to the main disease (diabetes, liver disease, kidney disease, malignant neoplasms). In the presence of a specific cause leading to an irreversible defect in the immune system, secondary immunodeficiency is formed with characteristic clinical manifestations and treatment principles. For example, against the background 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 treatment principles resemble patients with PID with damage to the humoral link of immunity. In the 20th century, humanity first encountered the HIV viral infection, in which the virus irreversibly damages the cells of the immune system, resulting in the development of a severe infectious disease AIDS. This disease is characterized by a high mortality rate, its own epidemiological features, its own set of clinical manifestations and treatment principles. In this case, the inducer of the development of immunodeficiency is an immunotropic virus that irreversibly damages lymphocytes, causing secondary immunodeficiency. Considering the direct irreversible damage of the virus to immunocompetent cells (T-lymphocytes), as well as the severity and epidemic features of the course of this disease, it was isolated into a separate group of genetically non-determined immunodeficiency, namely secondary acquired immunodeficiency - AIDS.

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

Spontaneous secondary immunodeficiency is characterized by the absence of an obvious cause that caused a disorder in the immune system. The clinical manifestation of this form is chronic, often recurring infectious and inflammatory diseases of the bronchopulmonary apparatus, paranasal sinuses, genitourinary and digestive systems, eyes, skin, soft tissues, caused by opportunistic or opportunistic microorganisms. Patients with spontaneous secondary immunodeficiencies are a heterogeneous group, and many believe that these diseases must be based on some causes that we have not yet determined. It can be assumed that the cause of secondary immunodeficiencies is a congenital deficiency of some component of the immune system, compensated for a certain time due to the normal high functional activity of other links of this system. Such deficiency cannot be identified due to various reasons: inadequate methodological approach, use of inappropriate material for research or impossibility to identify the disorder at this stage of scientific development. When a defect in the immune system is identified, some patients may later end up in the group with PID. Thus, the boundary between the concepts of primary and secondary immunodeficiencies (especially in the spontaneous form) may be conditional. Hereditary factors and induced effects play a decisive role in determining the form of immunodeficiency. On the other hand, very often patients are given insufficient research, and therefore the cause of immunodeficiency remains unspecified. The more thoroughly the examination of patients with spontaneous secondary immunodeficiency is carried out, the smaller this group becomes.

In quantitative terms, induced secondary immunodeficiency dominates. It is necessary to avoid the main error in patient management and practical health care, when the severe and sluggish course of an infectious inflammatory disease is caused not by a defect in the immune system, but by incorrectly placed accents of causes and effects, as well as by an error in diagnosis.

Since at the present stage, given the state of the diagnostic base of clinical immunology, it is not always possible to determine laboratory markers of immunodeficiency states, 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 that are torpid to adequate treatment.

When can secondary immunodeficiency be suspected?

The most common diseases that can accompany both congenital and acquired forms of immunodeficiency and which require mandatory immunological examination:

• generalized infections: sepsis, purulent meningitis, etc.;
• chronic bronchitis with frequent relapses and a history of pneumonia and combination with ENT diseases (purulent sinusitis, otitis, lymphadenitis), resistant to standard therapy;
• frequently recurring pneumonia and bronchopleuropneumonia;
• bronchiectasis;
• chronic bacterial infections of the skin and subcutaneous tissue (pyoderma, furunculosis, abscesses, phlegmon, septic granulomas, recurrent paraproctitis in adults);
• chronic fungal infections of the skin and mucous membranes, candidiasis, parasitic diseases;
• recurrent aphthous stomatitis in combination with increased incidence of acute respiratory viral infections;
• recurrent herpes virus infection of various localizations;
• gastroenteropathy with chronic diarrhea of unknown etiology, intestinal dysbacteriosis;
• lymphadenopathy, recurrent lymphadenitis;
• prolonged subfebrile temperature, LNG.

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

How does secondary immunodeficiency manifest itself?

Symptoms of secondary immunodeficiency are non-specific and multifaceted. ICD-10 does not have a diagnosis of "secondary immunodeficiency" except for acquired immunodeficiency (AIDS). In this classification, adults do not have a diagnosis of PID (unlike the pediatric classification of diseases). Therefore, a legitimate question arises about coordinating 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 a disease, then the diagnosis should be made of the identified immunological defect, since this implies a certain and permanent complex of therapeutic measures, for example, AIDS; AO with a violation of the complement system; the main diagnosis is a brain tumor; the condition after radiation therapy and chemotherapy is hypogammaglobulinemia; chronic purulent sinusitis

When changes in the immune status are reversible and accompany somatic diseases or can be the result of pharmacological or other treatment methods, then the transient laboratory abnormalities determined are not included in the diagnosis. The diagnosis is established based on the underlying disease and concomitant pathology, for example: the main diagnosis is type II diabetes mellitus, severe course, insulin-dependent variant, decompensation phase; complications are chronic recurrent furunculosis, exacerbation.

How to recognize secondary immunodeficiency?

Screening immunological laboratory tests (Level 1) are available, appropriate and can be performed in many hospitals and clinics where a clinical diagnostic laboratory is available. Such tests include studies of the following indicators:

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

An in-depth analysis can only be carried out in a specialized medical and preventive institution with a modern clinical immunology laboratory.

Studies of the immune status in immunodeficiencies should include the study of the quantity and functional activity of the main components of the immune system that play a major role in the body's anti-infective defense. These include the phagocytic system, the complement system, and subpopulations of T- and B-lymphocytes. The methods used to assess the functioning of the immune system were conditionally divided by R.V. Petrov et al. back in 1984 into tests of the 1st and 2nd levels. Tests of the 1st level are indicative; they are aimed at identifying gross defects in the immune system that determine a decrease in anti-infective defense.

Level 2 tests are additional tests aimed at identifying a specific disorder in the immune system. They significantly supplement information about the functioning of the corresponding immune system.

Level 1 tests for assessing the phagocytic link:

• determination of the absolute number of neutrophils and monocytes;
• determination of the intensity of neutralization of microorganisms by neutrophils and monocytes;
• determination of the content of active oxygen forms.

Level 1 tests for assessing the B-system of immunity:

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

Determination of the immunoglobulin level is an important and reliable method for assessing the functions of the B-system of immunity. It can be considered the main method for diagnosing all forms of immunodeficiencies associated with impaired antibody synthesis. This type of disorder is noted most often. It can accompany many somatic diseases and acute conditions associated with increased catabolism or impaired immunoglobulin synthesis.

Level 1 tests for assessing the T-system of immunity:

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

Level 2 tests are aimed at an in-depth study of the immune status, identification of the causes of disorders and defects of the immune system at the cellular, molecular and molecular-genetic levels.

Level 2 tests for phagocytosis assessment:

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

Level 2 tests for assessing the B-system of immunity:

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

Determination of IgG subclasses has a certain diagnostic value, since a deficiency in immunoglobulin subclasses may occur with a normal IgG level. In some cases, such people have secondary immunodeficiency in the form of weakened anti-infective protection IgG2 - a subclass of IgG, which mainly contains antibodies against polysaccharides of encapsulated bacteria (Haemophilus influenzae, Streptococcus pneumoniae). Important information about the state of humoral immunity is provided by determining the level of antibodies to bacterial protein and polysaccharide antigens, since the degree of protection of the body from a particular infection depends on the general level of immunoglobulins, and on the number of antibodies to its pathogen. Therefore, the absence of specific IgG antibodies to a past infection is always a prognostically favorable sign. Valuable information about the state of humoral immunity can also be obtained by studying their functional properties. First of all, this includes such a 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 can lead to insufficient protection against infection.

The B-immune system 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 in relation to the T-immune system, since the main end product of T-lymphocyte activation is cytokines, and systems for their determination are still poorly available in practical healthcare. Nevertheless, the assessment of the functional activity of the T-immune system is an extremely important task, since this activity can be significantly reduced with a normal number of T-cells and the ratio of their subpopulations. The methods for assessing the functional activity of T-lymphocytes are quite complex. The simplest of them is the blast transformation reaction using two main T-mitogens: phytohemagglutinin and concanavalin A. The proliferative response of T-lymphocytes to mitogens is reduced in almost all chronic infectious inflammatory processes, malignant diseases (especially of the hematopoietic system); in all types of immunosuppressive treatment, AIDS and all types of primary T-cell immunodeficiency.

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

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

Studying the expression of activation molecules and adhesion molecules on the surface of lymphocytes provides important information on the degree of their activation. Impaired expression of the IL-2 receptor 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, etc.).

According to recommendations of foreign specialists and in accordance with recommendations of WHO experts, skin testing in diagnostics of T-cell immunodeficiencies is used as screening tests or tests of the 1st level. Skin tests are the simplest and at the same time informative tests that allow to evaluate the functional activity of T-lymphocytes. Positive skin tests with some microbial antigens with a high probability allow to exclude the presence of T-cell immunodeficiency in the patient. A number of Western companies have developed standardized systems for setting skin tests that include the main antigens for determining T-cell immunity. This allows to evaluate the functional activity of the T-system of immunity in strictly controlled conditions. Unfortunately, skin test systems for evaluating the T-system of immunity are absent in Russia and, therefore, they are practically not used.

Scheme of examination of various links of the immune system

Humoral immunity:

• 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: C3, C4, C5, C1 inhibitor;
• antibody affinity.

Phagocytosis:

• phagocytic index of neutrophils and monocytes;
• opsonic index;
• intracellular bactericidal and fungicidal activity of phagocytes;
• formation of reactive oxygen species in luminol- and lucentinin-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 cytokine profile (IL I, IL-2, IL-4, IL-6, etc.).

Interferon profile:

• determination of IF-a in blood serum and in the supernatant of leukocyte suspensions activated by the Newcastle disease virus;
• determination of IF-γ in blood serum and in the supernatant of lymphocyte suspensions activated by phytohemagglutinin.

Based on the nature of the changes identified during immunological examination, patients with secondary immunodeficiency can be divided into three groups:

• patients with clinical signs of immune deficiency and identified changes in immune status parameters;
• patients with only clinical signs of immune deficiency and normal immune status indicators;
• patients with no clinical manifestations of immune deficiency, but with identified changes in immune status parameters.

For groups 1 and 2, it is necessary to select immunotropic treatment. Group 3 requires observation and control examination by an immunologist to exclude research artifact, as well as an in-depth clinical examination to clarify 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. replacement therapy (blood preparations: plasma, immunoglobulins, leukocyte mass, etc.);
3. immunotropic drugs (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 and inflammatory process and the identified immunological defect.

Vaccine therapy

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

Replacement therapy for secondary immunodeficiency

It can be used at any stage of the infectious and inflammatory process. Substitution therapy drugs are the drugs of choice in an acute situation. Intravenous immunoglobulins are most often used. The main active components of these drugs are specific antibodies, which are obtained from a large number of donors. Currently, intravenous immunoglobulin drugs are used to prevent infectious processes and treat diseases in the pathogenesis of which there are defects in humoral immunity. Substitution therapy is carried out to replenish the deficiency of antibodies in a number of acute and chronic diseases with secondary immunodeficiency, accompanied by hypogammaglobulinemia, which is caused by either increased catabolism of immunoglobulins or a violation of their synthesis.

Increased immunoglobulin catabolism is observed in nephrotic syndrome, enteropathies of various etiologies, burn disease, starvation, paraproteinemia, sepsis and other conditions. Disruption of immunoglobulin synthesis occurs in primary tumors of 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 frequency of administration and doses of intravenous immunoglobulins depend on the clinical situation, the initial level of IgG, the severity and prevalence of the infectious and inflammatory process. The most widely used intravenous immunoglobulin preparations contain only IgG: gabriglobin (normal human immunoglobulin), octagam (normal human immunoglobulin), intraglobin (normal human immunoglobulin). Intravenous immunoglobulin containing all three classes of immunoglobulins (IgA, IgM, IgG) similar to plasma - pentaglobin (normal human immunoglobulin |lgG+IgA+IgM]) is included in the standards for the treatment of septic patients. Immunoglobulins with an increased IgG titer to specific antigens, such as cytotec (anti-cytomegalovirus immunoglobulin) with an increased titer of antibodies to cytomegalovirus infection and neohepatec (immunoglobulin against human hepatitis B) to hepatitis B, are used much less frequently. It is necessary to remember that preparations containing IgA (pentaglobin, plasma) are contraindicated for patients with selective immunodeficiency A.

Immunotropic treatment of secondary immunodeficiency

And at present 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 using immunomodulators in patients with insufficient anti-infective protection.

• Immunomodulators are prescribed in combination with etiotropic treatment of the infectious process. Monotherapy is only permissible at the stage of remission of the infectious process,
• The choice of immunomodulator and the scheme of its use are determined depending on the severity of the infectious inflammatory process, its cause, the identified immune defect, taking into account somatic diseases and inductive effects.
• The main criteria for prescribing immunomodulatory drugs are clinical manifestations of immunodeficiency (the presence of an infectious inflammatory process that is resistant to adequate etiotropic treatment).
• Doses, regimens and duration of treatment should be in accordance with the instructions for the drug; adjustment of drug use regimens should be carried out only by an experienced clinical immunologist.
• If the given medical and preventive institution has the appropriate material and technical base, it is advisable to use immunomodulators against the background of immunological monitoring, which should be carried out regardless of the initially identified changes in immunological parameters.
• The presence of any immunity parameter detected during an immunodiagnostic study in a practically healthy person cannot be the basis for prescribing immunomodulatory treatment. Such patients should undergo additional examination and be under the supervision of an immunologist.

Despite the fact that the action of immunomodulatory drugs is multidirectional, each of them has its own advantages. In case of damage to cells of the monocyte-macrophage system, polyoxidonium (azoximer), galavit (sodium aminodihydrophthalazinedione), bronchomunal, ribomunil are used. In case of defects of the cellular link of immunity, it is advisable to prescribe polyoxidonium (azoximer), taktivin (thymus

Extract), thymoten (alpha-glutamyl-tryptophan), thymalin (thymus extract), imunofan (arginyl-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine). In case of impaired antibody synthesis by B-lymphocytes and impaired affinity of antibodies to the common antigen determinant, galavit (sodium aminodihydrophthalazinedione) and myelopid are indicated. Changes in interferon status indicators are corrected using interferon inducer drugs or replacement therapy using natural or recombinant IF.

It is necessary to be careful when prescribing immunomodulators in the acute phase of the infectious process. For example, preparations of microbial origin are not recommended for use in this period due to the possible development of polyclonal activation of immune system cells. When using cytokines, it is necessary to remember 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 safest immunomodulator in such cases is polyoxidonium, which, in addition to the immunomodulatory effect, has detoxifying, antioxidant and chelating properties.

Immunostimulants

Granulocyte-macrophage colony-stimulating factor preparations are used only in cases of severe leukopenia and agranudocytosis under daily monitoring of clinical blood tests.

Thus, due to the multifactorial nature of the etiological factors involved in the formation of such a disease as secondary immunodeficiency, the success of treating such patients depends on the professionalism of the immunologist, who will correctly place emphasis in cause-and-effect relationships, adequately assess the results of the immunological study and select immunotropic treatment, which will reduce the duration of hospitalization, prolong remission in chronic infectious and inflammatory processes, and in some cases save the patient's life.

Among systemic immunomodulators, the use of interferon inducer drugs deserves attention, which include Lavomaks, film-coated tablets (active substance tiloron 0.125 g). Lavomaks causes the synthesis of all three types of interferons by the organ itself, activates cellular immune mechanisms, which together interrupt the reproduction of viruses and other intracellular agents in infected cells or cause death and promote the elimination of the virus. Interferon synthesis in the blood after Lavomaks administration is determined 20-24 hours after taking the drug. A distinctive feature of Lavomaks as an interferon inducer is the ability to cause long-term 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 reproduction of HPV. Moreover, the induction of endogenous IFN can be considered as a physiological mechanism of IFN genesis. Application scheme: 1 tablet for the first two days, then 1 tablet every other day. The course dose is 10-20 tablets.