Immunodeficiencies: diagnosis and immunotherapy. Primary immunodeficiencies in children (with predominantly antibody deficiency) Primary immunodeficiencies immunology

RCHRH (Republican Center for Healthcare Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2015

Other immunodeficiencies with predominantly antibody defect (D80.8), Other common variable immunodeficiencies (D83.8), Selective deficiency of immunoglobulin g subclasses (D80.3), Immunodeficiency with predominant antibody defect, unspecified (D80.9), Hereditary hypogammaglobulinemia (D80. 0), Nonfamilial hypogammaglobulinemia (D80.1), Common variable immunodeficiency, unspecified (D83.9), Common variable immunodeficiency with predominant abnormalities in the number and functional activity of b-cells (D83.0)

Orphan diseases, Pediatrics

general information

Short description

Recommended
Expert Council
RSE on REM "Republican
health development center "
Ministry of Health
and social development
Republic of Kazakhstan
dated November 30, 2015
Minutes No. 18

Definition:

Immunodeficiencies with a predominant lack of antibodies are primary immunodeficiency with a shortage or low level of immunoglobulins, which, as a result, leads to an increased susceptibility of the body to respiratory and gastrointestinal infections.
Patients in this group often require lifelong human immunoglobulin (IgG) replacement therapy to prevent or reduce the severity of infections.
X-linked agammaglobulinemia (CSA) and common variable immunodeficiency (CVID) are characterized by low serum IgG and IgA levels, and often also IgM. Patients with CSA or CVID are prone to recurrent infections, both in the upper and lower respiratory tract. There were also frequent cases of septic arthritis, encephalitis, the development of malignant tumors (lymphoma, stomach cancer), granulomatous interstitial lung disease, intestinal lesions in the form of Crohn's disease and ulcerative colitis, the development of granulomatous hepatitis, autoimmune thrombocytopenia and autoimmune hemolytic hemolytic anemia. The prevalence of PID is 1.2-5.0 per 100,000 people.
Low serum IgG1 and / or immunoglobulin IgG2 levels are associated with ineffective defense against bacteria, which further causes recurrent respiratory infections

Protocol name: Primary immunodeficiencies in children (with predominantly antibody deficiency)

Protocol code:

ICD-10 code (s):
D80 Immunodeficiencies with predominantly antibody deficiency
D80.0 Hereditary hypogammaglobulinemia
D80.1 Nonfamilial hypogammaglobulinemia
D80.3 Selective deficiency of immunoglobulin g subclasses
D80.8 Other immunodeficiencies with predominantly antibody deficiency
D80.9 Immunodeficiency with predominantly antibody deficiency, unspecified
D83 Common variable immunodeficiency
D83.0 General variable immunodeficiency with predominant abnormalities in the number and functional activity of β-cells
D83.8 Other common variable immunodeficiencies
D83.9 Common variable immunodeficiency, unspecified

Abbreviations, designations used in the protocol:

ALT- Alanine aminotransferase AST- Asparaaminotransferase TANK- blood chemistry IVIG- intravenous immunoglobulins HIV- AIDS virus; GP- general doctor VEB- Epstein-Barr virus GKS- glucocorticosteroids CT scan- CT scan ICD- international classification of diseases NSG- neurosonography of the brain NST- nitro blue tetrazolium UAC- general blood analysis; PID- primary immunodeficiency CRB- C-reactive protein TKIN- severe combined immunological deficiency UZDG- ultrasound dopplerography of the vessels of the head and neck Ultrasound- ultrasound examination of internal organs; CMV- cytomegalovirus CMV- Cytomegalovirus CNS- central nervous system ECG- electrocardiography.

Development date: 2015 year.

Protocol users: pediatricians, neonatologists, GPs, infectious disease specialists, immunologists, neuropathologists, otolaryngologists, hematologists.

Classification

Clinical classification (1):

The international classification adopted in 2006 is used. Insufficiency of humoral immunity (50-60% of all primary immunodeficiencies) is a violation of the formation of antibodies.
I. Lack of humoral immunity - Primary deficiency of antibody production (B-cell immunodeficiency):
Agammaglobulinemia (agammaglobulinemia linked to the X chromosome);
· Common variable immunodeficiency;
· Selective deficiency of immunoglobulins A (dysimmunoglobulinemia);
Deficiency of subclasses of immunoglobulin G
· Transient hypogammaglobulinemia in children (slow immunological start).
Hyperimmunoglobulinemia syndrome M

Diagnostics

List of basic and additional diagnostic measures:
Basic (mandatory) diagnostic examinations carried out at the outpatient level:
· General blood test with expanded leukoformula;
· general urine analysis;
Biochemical blood test: (determination of alanine aminotransferase, aspartate aminotransferase, total protein, total and direct bilirubin, urea, creatinine, serum glucose)

Additional diagnostic examinations carried out on an outpatient basis:
Immunoglobulins A, M, G.
· Blood test for HIV by ELISA method;
· Determination of blood group and Rh factor;
· Smears from foci of infection;
· Diagnostic fluorography of the chest organs (from 12 years old) / plain chest X-ray.

The minimum list of examinations that must be carried out when referring to a planned hospitalization: in accordance with the internal regulations of the hospital, taking into account the current order of the authorized body in the field of health.

Basic (mandatory) diagnostic examinations carried out at the inpatient level during emergency hospitalization and after more than 10 days from the date of testing in accordance with the order of the Ministry of Defense:
· Determination of the main cellular subpopulations of lymphocytes by flow cytometry, (CD3 +, CD4 +, CD8 +, CD16 + / 56 +, CD19 +, CD20 +, CD3 + HLADR, CD3-HLADR), to identify the absolute and relative deficiency of T and B- lymphocytes;

Additional diagnostic examinations carried out at the inpatient level during emergency hospitalization and after more than 10 days from the date of testing in accordance with the order of the Ministry of Defense:
· Definition of ANA, RF, ANCA; C3, C4 complement proteins for the diagnosis of autoimmune complications.
· Study of the titer of antibodies to the corresponding antigens of the blood group (isohemagglutinins);
Serological blood test to detect post-vaccination (tetanus, diphtheria) antibodies to detect their sharp decrease or complete absence;
· To determine the functional activity of lymphocytes - determination of the proliferative activity of T-lymphocytes under the influence of mitogens (phytohemagglutinins) or bacterial antigens - their sharp decrease or absence.
Determination of the phagocytic activity of leukocytes for the purpose of differential diagnosis with other forms of PID:
· Relative and absolute determination of the number of neutrophils and monocytes;
· Determination of phagocytosis, phagocytic activity.
· Pressure research of all forms of PID to identify mutations (in order to confirm the diagnosis) of one or more genes.
· Study of the myelogram in the presence of prolonged cytopenia, anemia, thrombocytopenia of unknown origin, to identify a block of maturation of blood cells, reticular dysgenesis.
· Histological examination of lymph nodes - to detect their dysplasia and germinal centers (not developed or absent), infiltration by abnormal cells similar to Langerhans cells, T-lymphocytes and erythrocytes.
· Cultural studies of various loci and various biological material to identify the pathogen and assess its sensitivity to antibiotics;
· Study of biological material of various loci for the presence of pathogenic infectious microorganisms by the method of polymerase chain reaction (PCR);
· Research of blood culture with persistent, prolonged increase in body temperature.

Diagnostic criteria for making a diagnosis**:
Complaints and anamnesis.
Complaints: on purulent discharge from the external auditory canal, the appearance of plaque on the oral mucosa, decreased appetite, vomiting, frequent loose stools, prolonged cough, prolonged increase in temperature.
The variety of complaints is dictated by the variety of clinical manifestations of PID complications.
Anamnesis:
· Lagging behind a child under the age of 1 year in weight and height;
· Post-vaccination complications (BCGitis disseminated, paralytic poliomyelitis, etc.);
Deep infections transferred at least 2 times, such as: meningitis (inflammation of the membranes of the brain), osteomyelitis (inflammation in the bones), cellulitis (inflammation of the subcutaneous tissue), sepsis (systemic inflammation that occurs when an infection enters the bloodstream).
· Frequent purulent otitis media (inflammation inside the ear) - at least 3-4 times within one year.
Persistent thrush in children over one year old and fungal skin lesions;
Purulent inflammation of the paranasal sinuses (cavities in the bones of the facial skull) 2 or more times during the year;
· Recurrent purulent skin lesions;
Recurrent typical bacterial infections of the respiratory tract, occurring in a severe form, with the need to use multiple courses of antibiotics (up to 2 months or longer).
· Opportunistic infections (caused by Pneumocystic carini), herpes viruses, fungi.
Persistent viral infections, more often than expected for the patient's age:
a) for preschool children - 9 times or more,
b) for schoolchildren - 5-6 times a year or more;
c) adolescents - 3-4 times a year.
· Recurrent (repeated) diarrhea;
· The presence of ataxia and telangiectasia;
· Enlarged lymph nodes and spleen.
· Atopic dermatitis, widespread, severe continuously recurrent course;
· The presence in the family of patients with PID;
· A family history of the death of a young child with a clinical picture of an infectious process;
Changes in the blood, such as: a decrease in the number of platelets (blood cells that are involved in stopping bleeding) - thrombocytopenia, a decrease in the number of red blood cells (blood cells that carry oxygen) - anemia, accompanied by hemorrhagic syndrome (bleeding from the umbilical wound, melena, petechiae on the skin and mucous membranes, ecchymosis, hematuria, persistent nosebleeds).

Physical examination:
Physical examination data:
· skin and subcutaneous tissue: damage to the hair / teeth structure, eczema, erythroderma of newborns, albinism (partial), pale skin, pigment incontinence, nail dystrophy, condylomas / molluscs widespread, congenital alopecia, vitiligo, petechiae (early development / chronic), congestion, telangiectasia, lack of sweating;
· oral cavity: gingivostomatitis (severe), periodontitis, aphthae (recurrent), giant oral ulcers, thrush, crowded teeth, conical incisors, enamel hypoplasia, persistent milk teeth;
· in the eye area: retinal lesions, telangiectasia;
· assessment of the parameters of physical development: weight loss, stunted growth, disproportionate height and growth.
Neurological signs:
Ataxia;
Microcephaly;
Macrocephaly.
Palpation:
· Absence of lymph nodes: cervical, axillary, inguinal and pharyngeal tonsils.
Lymphadenopathy (excessive);
Asplenia, organomegaly (liver, spleen).

Laboratory research:
General blood analysis expanded, allows you to identify anemia, thrombocytopenia, leukopenia, hypereosinophilia, granulocytopenia or neutrophilia, lymphopenia:
· Detection of Howell-Jolly bodies (small round violet-red inclusions 1 - 2 microns in size, occur 1 (less often 2 - 3) in one erythrocyte. They represent the remainder of the nucleus);
· Detection of giant granules in phagocytes or the absence of granules;
· Identification of lymphocytes with basophilic cytoplasm;
Blood chemistry :
Total protein and protein fractions - a significant decrease in the γ-fraction of globulins on the electrophoregram of total protein, indicates a violation of the synthesis of immunoglobulins
· Determination of the level of calcium in the blood, its decrease characterizes the hypofunction of the parathyroid glands and is a condition for the development of tetany.
· Determination of triglycerides, to detect hyperlipidemia, characteristic of diseases of immune regulation (familial hemophagocytic lymphohistiocytosis);
· Determination of ferritin for differential diagnosis with hemophagocytic syndrome.
Determination of proteins of inflammatory reactions: CRP - a low level of CRP and other inflammatory parameters in the infectious process with PID is characteristic
· Quantitative determination of immunoglobulins A, M, G to detect a decrease (hypogammaglobulinemia) or complete absence (agammaglobulinemia).
· Determination of immunoglobulins of classes E (Ig E) in blood serum in order to detect its significant increase.

Immunological blood test:
Table 1 - immunological and genetic laboratory parameters for verification of the PID form

Deficiency of antibody production (B-cell immunodeficiencies)
form of immunodeficiency	laboratory parameters	genetic testing
Agammaglobulinization with deep deficiency or complete absence of B cells	CD19	Gene XLA, μ - heavy chain, λ5 light chain,Igα, Igβ, BLNK, Btk
Common variable immune deficiency	CD19, CD81, SD40, CD27, SD 28-V7, IL-12	Genes ICOS, TNFRSF13B, TACI, BAFF-R
Hyper-IgM syndromes with a decrease in the content of IgG, IgA and a normal number of B-lymphocytes	CD40L, AID, CD40, UNG, (CD154)	Genes XHGM, AICDA, UNG
Isolated deficiency of IgG subclasses	Subclasses IgG : IgG1, IgG2, IgG3, IgG4,
Selective IgA deficiency	Selective IgA, in biological fluids? IL-5, IL-10, CD40-CD40L
Hyper-IgE syndrome	-	STAT3, DOCK8, TYK2

Note: Molecular genetic research. It is carried out when a specific immunodeficiency is suspected. The presence / absence of a certain genetic defect is determined in the patient's blood cells. Only after the detection of such a defect, the diagnosis of primary immunodeficiency is considered confirmed.

Instrumental studies ( are carried out according to indications in order to identify complications of primary immunodeficiencies, to justify anti-inflammatory therapy and examination by narrow specialists):
X-ray of the chest in two projections: according to the results of this examination, it is possible to reveal an increase in the thoracic lymph nodes, detect pneumonia or abscess, exclude a tumor, determine the size of the thymus gland (aplasia / hypoplasia of the thymus).

Specialist consultations: all consultations of narrow specialists are carried out according to the indications, taking into account the complications of PID.
· Consultation of an ophthalmologist - in the presence of purulent discharge from the eyes, to detect telangiectasia;
· Consultation with a pulmonologist - in the presence of a chronic productive cough, symptoms of shortness of breath, persistent physical changes in the lungs (constant wheezing or weakening of breathing), hemoptysis.
Otolaryngologist consultation in the presence of recurrent otitis media, recurrent sinusitis and detection of hearing loss,
· Consultation with a cardiologist - in the presence of cardiac arrhythmias (persistent tachycardia, bradyarrhythmia, arrhythmia), when specifying the genesis of articular pathology.
· Consultation with an infectious disease specialist - with prolonged hyperthermia, meningeal symptoms.
· Consultation with a gastroenterologist - in the presence of recurrent abdominal pain, dyspeptic symptoms, stool disorders, persistent diarrhea, gastrointestinal bleeding.
· Consultation with a neuropathologist - in the presence of edema, urinary retention, changes in urine tests.

Differential diagnosis

Differential diagnosis:
For the purpose of clarifying the nature of the immunological breakdown, see Algorithm 1.
With other types of immunodeficiency states, genetic defects, infectious complications, see algorithm 2.

Table - 2. Differential diagnosis of primary immunodeficiency.

№	Clinical manifestation	Identified pathogens	Distinctive features	Non-immunological differential diagnosis	Presumptive diagnosis
1	Decreased weight gain and growth retardation in young children (including intractable diarrhea, severe eczema). Few of these children have PID, but the delay in diagnosis and treatment with stem cell transplantation significantly reduces survival. It is necessary to conduct immunological tests in parallel with the identification of other reasons for the decrease in weight gain and growth retardation.	Mainly viruses (CMV, EBV, VZV, HSV, adenovirus, EBV8, HPV, molluscum contagiosum, RSV), fungi (Candida superficial, Aspergillus, Cryptococcus, Histoplasma, Pheumocystisjiroveciium / carinii), protozoa (toxoropid bacteria such as Mycobacteriumspp. and Salmonella.	Intractable diarrhea with or without a specific pathogen. Rare infections or very severe infections, opportunistic infections. Graft-versus-host reactions from maternal T-lymphocytes or from transfusion of non-irradiated blood components. Severe eczema. Light sensitivity.	Various gastrointestinal, renal, cardiopulmonary, endocrine, neurological, metabolic and congenital causes. Malignant tumors. Chronic lead poisoning. Perinatal infections. Severe malnutrition (see relevant guidelines).	AIDS and SCID
2	Recurrent purulent infections (including granulomatous inflammation, poor wound healing). Defects in phagocytic function are rare and rarely become immediately life-threatening. | Neutropenia is the most common and easily diagnosed condition	Mainly Staphylococcusaureus, sometimes Klebsiella, Escherichiacoli, Enterobacter, Serratia, Pseudomonas, Salmonella, violaceum Chromobacterium, Burkholderia species. Invasive fungal infections (Candida disseminated, Aspergillus, Nocardia)	Infections in areas of the body surface (skin, mouth, mucous membranes), abscesses of internal organs (lungs, liver, lymph nodes, intestines) and bones. Unexplained granulomatous inflammation. Poor wound healing. Aphthae. Granulomatous colitis with severe rectal involvement. Delayed clamping of the umbilical cord (> 4 weeks).	Drug-induced neutropenia; alloimmune, autoimmune, hematological malignant tumors, aplastic anemia. Transient neutropenia followed by (viral) infection. Vitamin B12 / folate deficiency. Damage to the skin (eczema, burn inflammation).	Neutropenia
3	Rare infections or infections with a very severe course (unexplained - recurrent fever, see 6). Rare symptoms of common diseases are more common than rare diseases (such as immunodeficiency). Conduct; immunological examination, tests at an early stage, as the underlying immunodeficiency can be life-threatening	Mostly intracellular bacteria such as Mycobacteriumspp. and Salmonella, viruses (CMV, EBV, VZV, HSV, JC, HPV), fungi (Candida, Aspergillus, Cryptococcus, Histoplasma, Pheumocystisjir oveci / carinii) and protozoa (Toxoplasma, Microsporidia, Cryptosporidium).	Symptoms may appear later. Early onset, combination of several symptoms; unusual resistance to treatment; opportunistic infections.	Virulent strain of the pathogen, deterioration of the general condition of the patient, leading to secondary immunodeficiency (malignant tumors, malnutrition, chronic diseases). Immunosuppressive therapy. HIV.	AIDS and SCID
4	Recurrent infections with the same pathogen. Many patients do not have PID, but recurrent infections can be life-threatening. Screening required.	Intracellular bacteria such as Salmonella, Mycobacteriaceae Neisseriae such as Neisseria meningitidis. Yeast, fungi such as Candida. Encapsulated bacteria such as pneumococci. Viruses	There are usually no recurrent infections. No / delayed fever / increased CRP level: Deficiency of NF-kV signals (deficiency of IRAK4, NEMO-ID, 1xBα). Sepsis due to encapsulated bacteria: asplenia. Excessive warts: warty epidermodysplasia, WHIM syndrome, DOCK8. Herpes virus: NK cell deficiency. X-linked lymphoproliferative syndrome	Increased impact, coincidence. Improper treatment of the first infection. Anatomical defects (eg, fistula). Colonization. Latent infections that act as a reserve (eg, endocarditis, abscess). Asplenia.	Intracellular bacteria: exclude (interaction of T-lymphocytes and macrophages for the production of cytokines, autoantibodies to IFN-γ). Neisseria: exclude (compliment deficiency, sometimes antibody deficiency). Yeast, fungi: exclude (T-lymphocyte deficiency, CMC, MPO). Encapsulated bacteria: exclude (antibody deficiency, IRAK4 deficiency, compliment deficiency). Viruses: AIDS SCID
5	Autoimmune or chronic inflammatory diseases; lymphoproliferation. In most cases, autoimmune diseases, chronic inflammatory diseases, and lymphoproliferation are not associated with recurrent infections. If a combination of diseases occurs, if the disease is atypical or at an age not typical for it, the presence of immunodeficiency is most likely.	For a combination of clinical manifestations, see here. Autoinflammatory disorders do not pose a serious infectious problem.	Various combinations of clinical conditions, including autoimmune diseases, rheumatic tests, lymphoproliferation. Identified by clinical signs. Atypical HUS. Unexplained hemolysis.	(See related guides).	Any PID possible

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Treatment

Treatment goals:
· Achievement of normalization of indicators of immune status and level of immunoglobulins;
· Prevention of infectious complications;
· Early detection and treatment of infectious manifestations.

Treatment tactics:
· Lifelong replacement therapy (intravenous or subcutaneous administration of immunoglobulins). Intravenous administration of immunoglobulin "G" should be started as early as possible. Subcutaneous immunoglobulins are given weekly as an alternative to intravenous administration;
· Treatment of infectious complications - according to the protocols of therapy of the corresponding nosologies. Prophylactic antibiotic therapy is used when there is insufficient response to optimal immunoglobulin replacement therapy;
· Treatment of autoimmune and neoplastic pathology as complications of PID - use appropriate protocols for the disease;
· Transplantation of hematopoietic cells in hyperimmunoglobulinemia "M".

Drug treatment

Table - 2. Drug therapy for various forms of PID

№	The name of the group of drugs	Release form Dose, frequency
1	normal human immunoglobulin for intravenous administration (IVIG) (with an IgG content of at least 95%)	saturation therapy 1.2-1.5 g / kg of body weight per month, intravenously, 4-5 injections every 5-7 days until the normal age-related concentration of serum IgG is reached; further, the standard dose of immunoglobulins for maintenance therapy is 0.4 g / kg once IV every 3-4 weeks. The maintenance dose is applied for life
2	human immunoglobulin normal for subcutaneous administration	applied at an average dose of 0.1 g / kg once a week subcutaneously
3	corticosteroid therapy prednisone	used for granulomatous diseases 1 - 2 mg / kg. Duration of treatment is 6 weeks. In the presence of autoimmune complications, first of all - hemocytopenia, prednisolone is indicated at a dose of 1-2 mg / kg of body weight until hematological remission is obtained, followed by a gradual decrease in the dose to minimal supportive.

Other treatments: no.
Surgery
Surgical intervention provided at the inpatient level: It is carried out due to complications of PID (lymphadenitis, abscesses of the liver, kidneys, skin, paraproctitis).

Further management:
In patients with hypogammaglobulinemia, nonspecific replacement therapy with normal human immunoglobulin preparations for intravenous administration - monthly, at the rate of 0.4 - 0.5 g / kg - monthly;
· In patients with hypogammaglobulinemia, control of the IgG level before each prophylactic administration of immunoglobulins;
· In children with chronic foci of infection, microbiological (bacteriological cultures with determination of antibiotic sensitivity) studies from inflammation loci should be carried out every 6 months. When assessing the results of crops, one should not forget that opportunistic flora is also pathogenic for children with primary immunodeficiencies and causes the development of a severe infectious process;
· For relief of bacterial infections and treatment of complications of any localization, antibiotic therapy is carried out for 2 - 4 weeks according to generally accepted principles. Empirical antibiotic prescribing involves broad spectrum antibiotics.

Treatment effectiveness indicators:
· Normalization of immunological parameters;
· Decrease in the severity of symptoms / their elimination in case of exacerbation of infectious pathology;
· Prevention of the development of exacerbations;
· Reducing the need for the use of drugs;
· Reducing the risk of developing a side effect of treatment.

Preparations (active ingredients) used in the treatment

Hospitalization

Indications for hospitalization with an indication of the type of hospitalization: Indications for planned hospitalization:
· Initial diagnosis in the presence of symptoms characteristic of PID;
· Carrying out replacement therapy with iv immunoglobulins, in the absence of them;
Exacerbation of recurrent purulent-inflammatory diseases of the bronchopulmonary system, skin, ENT organs;
· Autoimmune complications or the development of cancer on the background of PID.

Indications for emergency hospitalization:
· Conditions that threaten life and require emergency medical care: hemorrhagic syndrome, cardiovascular, respiratory failure, malignant fever.

Prophylaxis

Preventive actions:
· Diet, in the absence of malabsorption syndrome, diet is not required. The diet must meet the need for proteins, vitamins and minerals and be high in calories to support normal growth and development. Insufficient nutrition with immunodeficiency can lead to even greater suppression of immunity.
· In children with recurrent and chronic otitis media, hearing tests are regularly performed for early detection and treatment of hearing loss.
· Avoid contact with solar radiation.
· Monitoring of the infectious status. Remediation of chronic foci of infection with the use of antibacterial therapy, antifungal and antiviral drugs.
· Before surgical or dental interventions, it is imperative to prescribe antibiotics to prevent infectious complications.
· Vaccination is not carried out with live vaccines (BCG, vaccination against measles, rubella, mumps, oral poliomyelitis, chickenpox, rotavirus infection).
Refusal of contact with people who have a cold, exclusion of presence in crowded places

Information

Sources and Literature

1. Minutes of the meetings of the Expert Council of the RCHRH MHSD RK, 2015
   1. List of used literature: 1). I. V. Kondratenko, A. A. Bologov Primary immunodeficiencies. M .: Medpraktika-M, 2005.2). Allergology and Immunology. National leadership (Editors-in-chief of Academician RAS and RAMS Khaitov RM, prof. Ilyina NI 397 p). 1) Childhood Immunology (under the editorship of Prof. A.Yu. Shcherbina and Prof. E.D. Pashanov) - M .: ID MEDPRAKTIKA-M, 2006, 432 p. 2) Drannik G.N. Clinical immunology and allergology. - К .: LLC "Polygraph plus", 2006. - 482 p. 3) Shcherbina A.Yu., Kosacheva T.G., Rumyantsev A.G. Primary immunodeficiency states: issues of diagnosis and treatment // Issues of hematology, oncology and immunopathology in pediatrics. - 2010. - T. 9, No. 2. - S. 23-31. 4) Yartsev M.N., Yakovleva K.P. Immune deficiency: clinical and laboratory assessment of immunity in children // Immunology. - 2005. - T. 26, No. 1. - S. 36-44. 5) Kondratenko I.V., Litvina M.M., Reznik I.B., Yarilin A.A. Violations of T-cell immunity in patients with general variable immune deficiency. Pediatrics 2001; 4: 18-22. 6) Sidorenko I.V. Leshkevich I.A., Kondratenko I.V., Gomes L.A., Reznik I.B. "Diagnostics and treatment of primary immunodeficiencies". Methodical recommendations for doctors of the Health Committee of the Moscow Government. M., 2000. 7) Khaitov R.M. Physiology of the immune system. M., 2001, 223 p. 8. AS Yurasova, OE Paschenko, IV Sidorenko, IV Kondratenko Non-infectious manifestations of primary immunodeficiencies. In the book. Advances in Clinical Immunology and Allergology, 2002; 3: 59-79. 8) Effective pharmacotherapy 2012 № 1 pp. 46 - 54. 9) Rich Robert R. et all. Clinical Immunology. - 2008, Elsevier Limited. 10) Geha R.S. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee / RSGeha, LDNotarangelo, JLCasanova, H. Chapel, MEConley, A. Fischer, L. Hammarström, S. Nonoyama, HDOchs, JMPuck, C. Roifman, R. Seger, J. Wedgwood; International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee // J. Allergy Clin. Immunol. - 2007. - Vol. 120, No. 4. - P. 776-794.

Information

List of protocol developers:
1) Marshalkina Tatyana Vasilievna - candidate of medical sciences, doctor of the highest qualification category, head of the department. complex somatic pathology and rehabilitation of the RSE on the REM "NCP and DH".
2) Isabekova Alma Aytahanovana - candidate of medical sciences, doctor of the highest qualification category, Department of Pediatric Neurology with a course of medical genetics of KazMUNO, associate professor.
3) Manzhuova Lyazat Nurbapaevna - candidate of medical sciences, doctor of the highest qualification category, head of the department of hematology, NCP and DH.
4) Bulegenova Minira Guseinovna - Doctor of Medical Sciences, Head. laboratory NCP and DH.
5) Gurtskaya Gulnar Marsovna - Candidate of Medical Sciences of JSC "Astana Medical University" Associate Professor of the Department of General Pharmacology, clinical pharmacologist.

No Conflict of Interest Statement: No

Reviewers:
Kovzel Elena Fedorovna - Doctor of Medical Sciences, Head of the Department of Allergology, Pulmonology and Orphan Diseases, Allergologist, Immunologist of the highest qualification category of the Republican Diagnostic Center JSC.

Indication of the conditions for revision of the protocol: Revision of the protocol 3 years after its publication and from the date of its entry into force or if there are new methods with a level of evidence.

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Everyone has an immune system designed to recognize and protect the body from foreign substances. The ultimate goal of immunity is to destroy microorganisms, atypical cells that cause a negative impact on human health. Depending on the origin, primary and secondary immunodeficiencies are distinguished. With immunodeficiency, all infections and diseases are more complicated, more often they become chronic and have complications.

What is primary immune deficiency?

Primary immunodeficiency is a hereditary or acquired condition during fetal development, in which there are problems in the functioning of the immune system. In other words, a child is born without the ability to defend against any infections and viruses. Primary immunodeficiency in children is diagnosed at an early age. Severely ill patients usually die. In some forms of the disease, the first symptoms can be detected already in adulthood. This occurs when the patient has good compensation for a certain form of the disease. The clinical picture is expressed by repeated and chronic infectious processes. It often affects the bronchopulmonary system, ENT organs, skin and mucous membranes. Primary immunodeficiency can lead to the development of purulent lymphadenitis, abscess, osteomyelitis, meningitis and sepsis.

Some forms are manifested by allergies, autoimmune diseases, and can provoke the development of malignant tumors. Immunology will help to recognize primary immunodeficiencies - a science that studies the mechanisms of the body's self-defense against any harmful substances.

Congenital immunodeficiencies are difficult to diagnose. Early diagnosis is essential for the following reasons:

• a timely diagnosis and correctly prescribed therapy contribute to the preservation of a high quality of life in patients for many years;
• diagnosis of primary immune deficiency and recognition of defective genes makes it possible to explain to family members in an accessible form the results of a medical genetic report and to carry out intrauterine diagnostics.

Primary immunodeficiencies: classification

Immunodeficiency refers to a persistent change in the immune system caused by a defect in one or more of the immune response mechanisms. There are four types of it:

1. Age-related, arising in early childhood or old age.
2. Purchased.
3. Infectious, provoked by a virus.
4. Congenital (primary immunodeficiencies).

The classification of primary immune deficiency is as follows:

1. Immune deficiency associated with damage to several types of cells:

   ● Reticular dysgenesis - characterized by the complete absence of stem cells. This form of the disease is incompatible with life.
   ● Severe combined immunodeficiency caused by defects in both T-lymphocytes and B-lymphocytes.

2. Immune deficiency, due to the defeat of mainly T-cells: Di George syndrome, which is characterized by the absence or underdevelopment of the thymus (thymus gland) and parathyroid glands, congenital heart defects, deformities in the structure of the face. The disease may be accompanied by abnormalities in the development of the skeleton, kidneys, and nervous system.
3. Immune deficiency, with predominant damage to B cells.
4. The defeat of myeloid cells provokes primary immunodeficiency. Chronic granulomatous disease has a pronounced defect in the production of reactive oxygen species. As a result, there are chronic infections provoked by bacteria or fungi.
5. Immunodeficiencies associated with defects in the complement system. These defects lead to a lack or complete absence of various complement constituents.

There are also cellular, cellular-humoral and primary humoral immunodeficiencies. The cellular form of immune deficiency includes defects associated with a deficiency of lymphocytes, macrophages, plasma cells. The humoral form is due to a deficiency of antibodies.

What is secondary immunodeficiency?

This type of immunodeficiency is not a hereditary disease. It is acquired throughout life. Its development can be caused by the influence of factors of a biological, chemical and ecological nature. People who lead an unhealthy lifestyle, malnourished food, and are in a constant state of stress are not protected from secondary immunodeficiency. Most often adults are ill.

Classification of secondary immunodeficiencies

Among the secondary states of immune deficiency, I distinguish three forms:

• acquired, an example of which is AIDS, provoked by a defeat of the immune system by the human immunodeficiency virus;
• induced, resulting from exposure to specific stimuli in the form of x-rays, the use of corticosteroids, trauma and surgery;
• spontaneous, characterized by the absence of an obvious cause leading to the onset of immune deficiency.

Secondary immunodeficiencies are also divided into reversible and irreversible. Fasting and the associated deficiency of vital components can be a variant of reversible immune deficiency. HIV infection is an example of an irreversible form of immunodeficiency.

Signs of immunodeficiency

The main symptom of the disease is a person's predisposition to frequent infectious diseases. Primary immunodeficiency disease is characterized by recurrent respiratory infections. Here it is necessary to clearly distinguish between people with immunodeficiency and weakened immunity.

A more characteristic symptom of this disease is the occurrence of infections of a bacterial nature, with frequent relapses. This manifests itself in recurrent sore throat, itching in the nose, which leads to the development of chronic sinusitis, bronchitis and otitis media. The body in the process of treatment is not able to completely get rid of the causative agent of the disease, and therefore relapses occur. Primary immunodeficiency in children can lead to the development of autoimmune diseases such as autoimmune endocrinopathy, hemolytic anemia, rheumatoid arthritis. Children in this condition are susceptible to several infectious agents at once. Also typical for this condition is a disorder of the digestive system. Primary immunodeficiency in adults can be manifested by the presence of a large number of warts and papillomas on the body.

Diagnosis of primary immune deficiency

Diagnosis of the disease begins with the collection of anamnesis. The doctor should look at the family history, especially if a child with the primary form is diagnosed. The patient should be examined, the condition of the mucous membrane and skin, the size of the liver and spleen should be assessed. For such a diagnosis, manifestations in the form of eye inflammation, swelling of the nostrils, and chronic lingering cough are also characteristic.

For an accurate diagnosis, a detailed blood test should be performed, which will show the number of different cells in the body, the level of immunoglobulin. An analysis is mandatory, which will show the content of proteins in the blood, which indicates the body's ability to resist various infections.

Prenatal diagnosis

It has been established that primary immunodeficiency is a hereditary disease and not as rare as it was thought. To date, it has become possible to identify the carriage of the mutated gene and counsel families who plan to give birth to a child at risk of the disease. If the family already has a child with this condition, he undergoes a mutation analysis, after which a diagnostic study of the embryo is performed. For this, a molecular analysis of the amniotic fluid, which contains the cells of the fetus, is performed.

Complications after immunodeficiency

Primary and secondary immunodeficiencies can lead to complications in the form of severe infectious diseases such as sepsis, pneumonia and abscesses. In view of a fairly wide variety of diseases caused by immunodeficiency, possible complications must be determined individually.

Immunodeficiency treatment

Primary immunodeficiency, the treatment of which is a complex and lengthy process, requires a healthy lifestyle and avoidance of any infections. Before prescribing a complex treatment, an accurate diagnosis should be established by identifying the impaired link in the immune defense system. If a lack of immunoglobulin is detected, replacement therapy with sera containing antibodies is carried out throughout life. The complications that have arisen in infectious diseases are treated with antibiotics, antiviral and antifungal drugs. In some cases, primary immunodeficiency is treated with immunoglobulin given subcutaneously or intravenously.

Immunocorrection is also carried out through bone marrow transplantation and the use of immunomodulators.

Children with this condition should not be vaccinated with live vaccines. Adults living with a child are vaccinated only with inactivated polio vaccine.

Secondary immunodeficiency has less pronounced disorders in the functioning of the immune system.

This disease is provoked by disorders in the hematopoietic system, which can be both congenital and acquired. The bone marrow simply stops making blood cells. A deficiency in erythrocytes, platelets and leukocytes is revealed.

The occurrence can be triggered by individual intolerance, in particular to certain drugs. The reason for this sensitivity is not always clear, but may be associated with a genetic defect in hematopoietic cells.

Other causes of occurrence can also be:

Signs of aplastic anemia

Symptoms of this condition include:

• constant fatigue and weakness;
• irregular heart rate;
• pallor of the skin;
• frequent nosebleeds;
• prolonged bleeding after cuts;
• bleeding gums;
• frequent infectious diseases;
• dizziness and migraine.

Aplastic anemia treatment

Mild cases of the disease require only constant monitoring of the patient. In more complex conditions, blood transfusions, bone marrow transplants, and special drugs that stimulate hematopoietic cells are used. Immunosuppressants are often used in treatment to help weaken the body's immune response by causing the cells of the immune system to not respond to bone tissue. In recent years, more and more often, doctors are inclined to an early bone marrow transplant, which avoids many complications.

Prevention of primary immune deficiency

Primary immunodeficiency syndrome is a hereditary disease, and, accordingly, there are no preventive measures for it. In order to avoid manifestations of an immunodeficiency state, it is necessary to determine the possible carrier of the defective gene in the family, where the history is positive. For such a pathology as severe combined immunodeficiency, intrauterine diagnosis is possible.

To prevent the occurrence of secondary immunodeficiencies, one should lead a correct lifestyle, have moderate physical activity, and avoid getting HIV infection into the body. And for this you need to avoid unprotected sexual relations and make sure that sterile medical instruments are used. Diseases triggered by immune deficiency are complex and insidious in any form. A careful attitude to one's health, an integrated approach and timely access to doctors will help to save our future - our children.

TO HELP A PRACTICAL DOCTOR

UDC 612.216-112

Received April 31, 2008

L.M. KARZAKOVA, O. M. MUCHUKOVA,
N.L. STORIES

PRIMARY AND SECONDARY IMMUNODEFICIENCIES

Republican Clinical Hospital,

Children's City Hospital No. 3, Cheboksary

The principles of diagnostics and treatment of immunodeficiency states are considered. Much attention is paid to primary immunodeficiency diseases. Given composed sponsored Register primary immunodeficiencies Chuvashia.

Here are the principles of diagnoctic and treatment of immuno-deficient states. The great attention is attracted to primary immuno-deficient diseases. It contains the list of the primary immuno-deficient diseases in Chuvashia, made by the authors.

Immunodeficiencies, disorders of the immune response, are divided into two large groups - primary (congenital) and secondary (acquired), caused by various endogenous (diseases) and exogenous influences (for example, negative environmental factors). Primary immunodeficiencies (PIDs), as a rule, are caused by genetic defects and only sometimes non-hereditary ones that have arisen during the embryonic period. A typical manifestation of PID is a violation of anti-infectious resistance with the development of recurrent and / or chronic infections of various localization. The type of infectious pathogens to which the body is hypersensitive depends on a defect in one or another link of the immune response. Thus, a defect in antibody production (insufficiency of the humoral link of the immune response) leads to a decrease in resistance mainly against bacteria (staphylococcus, streptococcus, pneumococcus, Escherichia coli, Proteus, Klebsiella) and enteroviruses. An increased susceptibility to viral, protozoal infections, tuberculosis, cryptococcosis, leishmaniasis is characteristic of the violation of the cellular link of the immune response. With defects in phagocytosis, the most common cause of the infectious syndrome are microorganisms that produce catalase (staphylococci, E. coli, Serratia marcescens, Nocardia, Aspergillus, etc.), most gram-negative bacteria and fungi (Candida albicans, Aspergillus). A defect in the complement system is manifested by infections caused by the coccal flora and Neisseria. With a combined violation of the immune response (combined immunodeficiency), the infectious syndrome is caused by both bacteria and viruses, fungi, protozoa.

In some cases, the infectious syndrome is combined with non-immunological manifestations - with well-defined symptoms from other organs and systems. So, DiGeorge's syndrome manifests itself not only in a violation of the cellular link of immunity, but also in aplasia or hypoplasia of the thymus with agenesis of the parathyroid glands, malformations of the heart and large vessels, stigma of dysembryogenesis (cleft palate, absence of ear lobes, etc.). In Louis-Bar syndrome, combined immune deficiency (a decrease in the number of T-lymphocytes, a decrease in the IgA level) is combined with cerebellar ataxia and telangiectasia on the skin and sclera of the eyes. A combined immune defect (a decrease in the number of T-lymphocytes, a decrease in IgM levels) in combination with eczema and thrombocytopenia occurs in Wiskott-Aldrich syndrome.

Primary immunodeficiencies

The first case of a congenital immunodeficiency state (agammaglobulinemia due to a genetically determined violation of the production of immunoglobulins) was described by Bruton in 1952. Since then, more than 100 different primary defects of the immune system have been recognized. Some PIDs are quite common. For example, the frequency of selective IgA deficiency reaches 1: 500. For most other PIDs, this figure is 1:50,000 - 1: 100,000. According to numerous publications, there is a clear underdiagnosis and a lag in the timing of PID diagnostics in the world. At the initiative of the Jeffrey Model Foundation (USA) and ESID (European Society for the Study of Immunodeficiencies), criteria have been developed to suspect PID in patients.

PID criteria:

1. Frequent diseases of otitis media (6-8 times a year).

2. Frequent diseases of sinusitis (4-6 times a year).

3. More than two confirmed pneumonia.

4.Repeated deep abscesses of the skin and internal organs.

5. The need for long-term therapy (more than 2 months) with antibiotics to stop the infection.

6. The need for intravenous antibiotics to stop the infection.

7. More than two severe infections (meningitis, osteomyelitis, sepsis).

8. Lagging of an infant in height and weight.

9. Persistent fungal infection of the skin over the age of 1 year.

10. Relatives have PID, early deaths from severe infections, or one of the listed symptoms.

Detection of more than one of the listed symptoms in a patient should alert PID and be a signal for an immunological study. The role and place of PID in the structure of morbidity and mortality in the world is of great importance, which led to the creation of national PID registers in Western Europe, America, Australia. Analysis of the data included in the registers makes it possible to judge the frequency of occurrence of PID in various parts of the world, ethnic populations, to establish the prevailing forms of pathology and thereby create the prerequisites for improving the quality of diagnosis of rare forms of diseases by comparing new cases with analogs available in the register. Since 1992, Russia has also maintained a PID register based on data from an analysis of hospitalizations and patients' referrals to the departments of the State Research Center of the Russian Federation “Institute of Immunology”. However, many cases of PID diagnosed in the regions remain unaccounted for. The formation of any register should be based on a unified classification of diseases. Due to the brevity of the history of the study of PID, its classification is still not final. The WHO scientific group publishes reports and recommendations on the PID systematics every 2-3 years, while as modern diagnostic methods are introduced, the number of described forms of the disease and the order of their classification change significantly . In accordance with the latest WHO classification (2004), PID is divided into the following groups:

1. PID with predominantly antibody defects (humoral immunodeficiencies):

Agammaglobulinemia linked to the X chromosome (CVAGG);

· General variable immune deficiency (CVID);

Agammaglobulinemia with normal or elevated IgM levels;

· Selective deficiency of IgA;

· Transient hypogammaglobulinemia of infancy (late immunological start).

2.PID with predominantly T-cell defects:

• primary deficiency of CD4 + cells;
• deficiency of IL-2;
• multiple cytokine deficiency;
• signal transduction defect + myopathy;
• defect in calcium influx with myopathy.

3. Combined immunodeficiency states:

• severe combined immunodeficiencies (SCID);
• Wiskott-Aldrich syndrome;
• ataxia - aleangiectasia (Louis-Bar syndrome).

4. Defects of phagocytosis:

• chronic granulomatous disease;
• Chédiak-Higashi syndrome.

5. Defects of the complement system.

6. Immunodeficiencies associated with other major defects outside the immune system:

• hyper-IgE syndrome (Job's syndrome);
• chronic mucocutaneous candidiasis;
• intestinal lymphangiectasia;
• enteropathic acrodermatitis.

7. Immunodeficiencies associated with lymphoproliferative processes.

The most common forms of PID are as follows.

X-linked agammaglobulinemia, or Bruton's disease (1:50 000), is observed in boys at the 5-9th month of life, when there is a depletion of transplanted maternal immunoglobulins. The disease is manifested by recurrent pyogenic infections (pneumonia, sinusitis, mesotympanitis, meningitis). An important diagnostic symptom is the lymph nodes, the spleen do not respond with an increase in the inflammatory process. An immunolaboratory study reveals: 1) a decrease or absence of γ-globulins in the blood serum; 2) a decrease in the level of serum IgG (less than 2 g / l) in the absence or a sharp decrease in the levels of IgM and IgA; 3) the absence or a sharp decrease in the number of B-lymphocytes (CD19 + or CD20 +) in the circulation of less than 2%; 4) the absence or hypoplasia of the tonsils; 5) small size of lymph nodes; 6) preserved function of T-lymphocytes.

CVID (1:10 000 - 1:50 000) is a heterogeneous group of diseases with a defect in antibody production and a different type of inheritance. The term "variable" means the manifestation of the disease at different ages (childhood, adolescence, adult) with individual variations in the type and severity of immunodeficiency. According to the clinical picture, CVID resembles Bruton's disease, the main difference is in the timing of the manifestation of the disease: the average age of the clinical manifestation of CVID is 25, the diagnosis is 28 years. Survival of patients depends on the degree of decrease in the level of IgG and inadequacy of the cellular component of the immune response: the more pronounced they are, the earlier patients with CVID die. This form of PID affects both men and women equally. Like all humoral immunodeficiencies, CVID is clinically manifested by recurrent and chronic pneumonia, sinusitis, otitis media, bronchiectasis is often formed, in half of the cases the gastrointestinal tract is affected with symptoms of malabsorption, weight loss, diarrhea, hypoalbuminemia, and vitamin deficiency. Characterized by chronic inflammatory processes in the intestine (enterovirus infections) with the development of nodular lymphoid hyperplasia. About one third of patients have splenomegaly and / or diffuse lymphadenopathy. In 22% of cases, autoimmune manifestations develop (pernicious or hemolytic anemia, thrombocytopenia, neutropenia, rheumatoid arthritis, thyroid dysfunction). An immunolaboratory study reveals: 1) a normal or slightly reduced number of circulating B-lymphocytes; 2) a decrease in the levels of serum IgG and IgA, to a lesser extent - the level of IgM; decrease in the total concentration of IgG + IgA + IgM less than 3 g / l; 3) the total number of T-cells is normal or slightly reduced due to a decrease in the number of T-helper subpopulations; 4) reduced immunoregulatory index CD4 + / CD8 +.

Selective IgA deficiency (1: 700 in Caucasians; 1:18 500 in Japanese) is characterized by a decrease in serum IgA levels to 0.05 g / l and below (quite often to 0) with normal levels of other classes of immunoglobulins. If the IgA concentration is higher than 0.05 g / l, but below 0.2 g / l, then a diagnosis of "partial (partial) IgA deficiency" should be made. In most cases, IgA deficiency is asymptomatic, however, in some individuals it manifests itself as synopulmonary infections in combination with allergic manifestations (atopic dermatitis, hay fever, bronchial asthma, Quincke's edema, etc.) and autoimmune (scleroderma, rheumatoid arthritis, vitiligo), thyroiditis.

Transient hypogammaglobulinemia in children ("slow immunological start") is characterized by low levels of immunoglobulins. The onset of the disease is from 5-6 months, when the child suddenly, for no apparent reason, begins to get sick with recurrent pyogenic infections of the kidneys and respiratory tract. This is due to the fact that the maternal IgG received by the child transplantation is catabolized by this age, and the production of its own IgG, usually starting from the 4th month, is delayed. With this form of immunodeficiency, the levels of IgG and IgA are often reduced, while the level of IgM is within the normal range or even increased. B-lymphocytes, lymph nodes and tonsils are not changed. This transient immunodeficiency condition occurs in 5–8% of infants (usually premature babies or children from immunocompromised families) and usually resolves without treatment by 1.5–4 years of age.

Hyper-IgE syndrome (Job's syndrome). The diagnosis of "Job's syndrome" is based on a repeated (at least two-fold) increase in the serum concentration of total IgE above 1000 IU / ml in the presence of dermatitis and repeated deep purulent infections with a "cold" course: abscesses of the skin, subcutaneous tissue, lymph nodes, otitis media. Of particular danger are severe episodes of acute pneumonia, including destructive episodes with an outcome in pneumocele, liver abscesses. Characterized by skeletal anomalies, spontaneous fractures of tubular bones, gross dysplastic facial features. The pathogenetic mechanism of the disease is that Th1 is unable to produce interferon-γ. This leads to an increase in Th2 activity, which is manifested in increased IgE production. The latter causes the release of histamine, which blocks the development of the inflammatory response (the formation of cold abscesses is associated with this). In addition, histamine inhibits neutrophil chemotaxis.

Chronic mucocutaneous candidiasis. It is characterized by candidal lesions of the skin, mucous membranes, nails, scalp. The disease is based on a unique defect in T-lymphocytes, which is that these cells are unable to develop a normal response, in particular, to produce a factor that inhibits the migration of macrophages (MIF) to the Candida albicans antigen. The skin test of HRTT for this antigen is also negative. At the same time, patients have a normal number of T-lymphocytes, and their response to other antigens is not impaired. The humoral response to the Candida antigen is not changed. The syndrome is associated with autoimmune polyglandular endocrinopathy. Symptomatic antifungal therapy is used in the treatment.

Chronic granulomatous disease (CGD). It is a congenital form of phagocytosis defect. Neutrophils have normal chemotaxis, absorption activity, but the formation of the "respiratory explosion" is impaired. Catalase-positive microorganisms (Staphylococcus aureus, E. coli, Klebsiella, Serratia marcescens, Salmonella, Aspergillus fungi) form granulomas in the lymph nodes, liver, lungs, and gastrointestinal tract. The development of recurrent lymphadenitis, abscesses (hepatic, pulmonary, perirectal), osteomyelitis, ulcerative stomatitis, rhinitis, conjunctivitis is characteristic. Some patients diagnosed with CGD in childhood live up to 30 years of age. The diagnosis is confirmed by the NBT test (nitro blue tetrazolium recovery test), which has zero values ​​for the pathology under consideration. Treatment: daily prophylactic intake of antistaphylococcal antibiotics, subcutaneous interferon-γ 3 times a week.

On the basis of observations, we have created the PID Register of Chuvashia, which includes 19 patients with 7 forms of immune deficiency (Table 1).

Table 1

Register of primary immunodeficiencies of Chuvashia

Out of more than 100 known verified PID forms, we have established 7. 19 PID forms are described in the national register of Russia. Attention is drawn to the fact that 15 of the PIDs presented in the register were diagnosed only after the patients transferred to the adult network of the medical service. The register does not include children with transient hypogammaglobulinemia at an early age. This is due to the lack of clear diagnostic criteria for this form of PID and the difficulties in differentiating with secondary immunodeficiency states in children under 3 years of age. In addition, there are no SCIDs in the register, which are known to be caused by defects in both the humoral and cellular mechanisms of the immune response, and leading to the death of children at a very early age. They are usually diagnosed retrospectively at autopsy by clinical and pathological comparison. Unfortunately, in our republic, pathological bureaus do not register SCID, writing off the deaths of cases of pronounced defects of the immune system for certain severe infections (sepsis, meningitis, etc.). The republican rate of incidence of selective IgA deficiency is also not true. According to many authors, the prevalence of this form of PID is 1: 500. For example, in the PID register of the South Ural region, this disease ranks first in terms of frequency of occurrence, and the overwhelming majority with selective IgA deficiency are children. Only adult patients with the considered PID are included in our republican register. The low detection rate of selective IgA deficiency is most likely associated with the variability of the clinical manifestations of the immunological defect, which are often very mild. A significant number of patients with immunopathology have an increased incidence of respiratory viral infections. It is significant that the increased frequency of infections, often noted in early childhood, decreases significantly in subsequent years. More than 20% of patients with selective IgA deficiency suffer from allergic and autoimmune diseases. In some patients, the immunological defect is not clinically manifested. Probably, the low frequency of selective IgA deficiency in the republican register is due to its insufficient detection by specialists. An example of a well-detected PID in Chuvashia is CVID, which is located in the national register of the Russian Federation in second place in terms of prevalence after selective IgA deficiency. The reason for the effective detection of CVID is the good awareness of the doctors of the adult network about the diagnostic criteria for this pathology due to the repeated demonstration of patients at clinical analyzes and conferences of the Association of Physicians of Chuvashia.

Thus, in Chuvashia, the detection rate of combined immunodeficiencies, selective IgA deficiency is low, which is apparently due to the lack of basic knowledge of clinical immunology among doctors of various specialties (including on issues related to clinical manifestations, diagnosis of PID), as well as with insufficient use of immunological diagnostic methods by doctors.

Secondary immunodeficiencies. Secondary immunodeficiency states are predominantly common among the adult contingent. Acquired defects in the cellular immune response are more often observed, less often in the humoral one. The reason for this, apparently, is that T cells are more sensitive to apoptogenic factors than B cells protected from apoptotic death by the pro-oncogene Bcl antigen expressed on their membrane, and apoptosis is known to be the main mechanism of cell death of the immune system and development immune deficiency. Any factors that can induce the processes of T-cell apoptosis (ionizing radiation, stress, increased levels of glucocorticosteroids and ethanol, infection, etc.) can play a causal role in the occurrence of secondary T-cell immunodeficiency. Secondary insufficiency of the humoral immune response, as a rule, develops against the background of already existing serious diseases. The main conditions causing acquired deficiency of the humoral mechanism of adaptive immunity are as follows:

1) protein deficiency associated with malabsorption syndrome, chronic pancreatitis, celiac disease, burn disease (the synthesis of immunoglobulin molecules is impaired due to a lack of "building material" - amino acids);

2) conditions leading to the loss of immunoglobulins and immunocompetent cells - nephrotic syndrome (with glomerulonephritis, the glomerular filter is passable not only for low molecular weight proteins, but also high molecular weight - globulins, including immunoglobulins), bleeding, lymphorrhea, burns;

3) multiple myeloma (myeloma is an abnormal clone of B-lymphocytes that has acquired the properties of unrestrained growth, producing immunoglobulins of the same class, one specificity, growing myeloma replaces normal clones of B-lymphocytes in the bone marrow, producing immunoglobulins of other, approximately 108, different specificities, during development IgA myeloma reduced levels of IgG and IgM, IgG myeloma is accompanied by a decrease in IgA and IgM, and in IgD myeloma and light chain disease, three main classes of immunoglobulins are reduced);

4) splenectomy syndrome (when the spleen is removed, the cellular immune response suffers to a lesser extent, but the humoral link is significantly inhibited, since the spleen is predominantly an organ of antibody production).

With these conditions, a decrease in the content of antibodies to the level of hypo-, agammaglobulinemia can be observed. In contrast to congenital forms with a secondary defect in the humoral mechanism of the immune response, the levels of immunoglobulins vary depending on the course and severity of the main process, their content can be normalized (without replacement therapy with immunoglobulin drugs) during the period of remission of the underlying disease.

Guided by the data of WHO experts, the following should be named as etiopathogenic factors of secondary insufficiency of the cellular immune response:

1) exposure to physical and chemical factors:

• physical (ionizing radiation, microwave, high or low air temperature in arid climatic zones, etc.);
• chemical (immunosuppressants, chemotherapy, corticosteroids, drugs, herbicides, pesticides, technogenic pollution of the environment with salts of heavy metals);

2) the modern way of human life (physical inactivity, an excess of information with the development of "information" disease);

3) malnutrition (deficiency of essential micronutrients in the daily water-food ration - zinc, copper, iron, vitamins - retinol, ascorbic acid, alpha-tocopherol, folic acid; protein-energy malnutrition, depletion, cachexia, metabolic disorders, obesity);

3) viral infections:

• acute - measles, rubella, mumps, chickenpox, flu, hepatitis, herpes, etc.;
• persistent - chronic hepatitis B, subacute sclerosing panencephalitis, AIDS, etc.;
• congenital - cytomegaly, rubella (TORCH-complex);

4) protozoal invasions and helminthiases (malaria, toxoplasmosis, leishmaniasis, trichinosis, ascariasis, etc.);

5) bacterial infections (staphylococcal, pneumococcal, meningococcal, tuberculosis, etc.);

6) malignant tumors, especially lymphoproliferative;

7) autoimmune diseases;

1. conditions leading to the loss of immunocompetent cells (bleeding, lymphorrhea);
2. exogenous and endogenous intoxication (poisoning, thyrotoxicosis, decompensated diabetes mellitus);
3. violation of neurohormonal regulation (stressful effects - severe trauma, surgery, physical, including sports, overload, mental trauma);
4. natural immunodeficiencies - early childhood, gerontological age, pregnant women (first half of pregnancy).

Secondary immunodeficiencies are sharp(caused by an acute infectious disease, trauma, intoxication, stress, etc.) and chronic(developing against the background of chronic purulent-inflammatory diseases, tumors, chronic stress, immunosuppressive therapy, when living in regions with unfavorable ecological and geochemical conditions, etc.). Acute immunodeficiencies are diagnosed on the basis of detecting abnormalities in immunogram indicators - a decrease in the number of T-lymphocytes (CD3 +), T-helpers (CD4 +), a decrease in the immunoregulatory index (CD4 + / CD8 +). They, as a rule, are transient and gradually stop with a favorable course and adequate etiopathogenetic treatment of the underlying disease with the use of well-known, so-called fortifying drugs and agents (vitamins, adapagens, physiotherapeutic procedures, etc.), as well as energy metabolic therapy (wobenzym, coenzyme Q10) ... Chronic immunodeficiencies can occur in three variants: 1) with clinical and laboratory signs, 2) with clinical signs in the absence of laboratory abnormalities, 3) with a causal factor (for example, living in conditions of environmental disadvantage), the absence of clinical manifestations and the presence of immunological disorders ... The first type is more common. In the second type, when immunodeficiency is manifested only clinically, but no changes are found in a typical immunogram, a malfunction of the immune system at a more subtle level, which is not detected during routine research, is not excluded. Formally normal values ​​of indicators of the immune status, which are a reflection of the individual response of the immune system, can be "pathological" for a given individual, unable to provide a sufficiently high level of resistance of the organism. The third type, which reveals itself only as immunolaboratory signs of immunodeficiency, in essence, is a pre-illness, a risk factor for diseases associated with secondary immunodeficiency - infectious, autoimmune, oncological, etc. Often the third type of immunodeficiency is accompanied by signs of chronic fatigue syndrome.

Chronic Fatigue and Immune Dysfunction Syndrome (CFS). It was first described by A. Lloyd et al. In 1984 and characterized as chronic fatigue experienced by the patient, which does not disappear after rest and leads over time to a significant decrease in performance, both mental and physical. The detection of a pronounced imbalance of the immune system in patients with CFS was the basis for the transformation of the name of the disease into a syndrome of chronic fatigue and immune dysfunction. CFS is registered mainly in ecologically unfavorable regions with a high level of environmental pollution by chemically harmful substances or with an increased level of radiation. These factors negatively affect the state of the immune system (primarily, the cellular mechanism of adaptive immunity), which apparently supports the persistence of latent viruses with damage to the central nervous system and the activation of latent viruses (herpes virus, Epstein-Barr virus). The onset of clinical manifestations of CFS, as a rule, is associated with a previous cold illness, less often with emotional stress. The symptomatology of CFS consists of severe fatigue, muscle weakness that does not go away after a night's sleep, difficulty falling asleep, shallow sleep with nightmares, and recurrent states of depression. For patients with CFS, especially young people, sensitivity to respiratory viral infections is typical. Patients complain of pain and sore throat (non-exudative pharyngitis). In some patients, weight loss, pale skin color, and decreased turgor are noted. According to a number of researchers, the pathophysiological basis of CFS is immunological disorders. Indeed, in the majority of patients, a decrease in the number of T cells, a decrease in their proliferative activity, a decrease in the function of NK cells, and dysimmunoglobulinemia are found. Complex treatment of patients with CFS includes the appointment of tricyclic antidepressants, non-steroidal anti-inflammatory drugs, immunomodulators and adaptogens under the control of an immunogram.

Principles of correction of immunodeficiency states. Correction of humoral insufficiency includes the appointment of substitution immunotherapy and antibody production stimulants. Substitution immunotherapy is indicated when the total concentration of immunoglobulins decreases below 5 g / l. Immunoglobulin preparations (sandoglobulin, octagam, intraglobin or normal human immunoglobulin for intravenous administration) are administered intravenously 2 times a week at a dose of 0.1-0.2 g / kg in a monthly dose of up to 1.2 g / kg. Stimulants of antibody production are indicated for agammaglobulinemia of the type of CVID: myelopid 3 mg (0.3% solution of 1 ml) intramuscularly every other day 6-8 injections, sodium nucleinate - 0.2 g 3 times a day orally for 21 days or Derinat 1.5% solution 5 ml at intervals of 2-3 days 8-10 intramuscular injections.

In case of damage to the phagocytic link, apply: polyoxidonium 0.006-0.012 g for adults every other day the first 5 injections, then at intervals of 2-3 days, for a course of 7-10 intramuscular injections; lycopid 1 tablet once a day under the tongue for 10 days (tablet for adults - 0.01 g each); Derinat 0.25% solution - 2 drops in the nose 3-4 times a day for 10 days.

In case of defects in the cellular link of adaptive immunity, the following are used: 1) preparations of thymic origin (thymalin 0.010-0.020 g i / m at night 7-10 injections; thymogen 0.01% -1 ml i / m daily - 3-10 injections; immunofan 0.005% - 1.0 ml s / c or i / m 5-7 injections every other day or after 2-3 days, for a course of 8-10 injections); 2) interferon drugs (human leukocyte interferon 1,000,000 IU / m 2 times a week for up to 6 months; reaferon 3,000,000-5,000,000 IU / m 2 times a week for 4 weeks to 6 months); 3) a recombinant analogue of IL-2 - roncoleukin 500,000-1,000,000 IU IV drip or s / c with an interval of 48-72 hours 3-5-10 injections; 4) stimulants of endogenous interferonogenesis (amiksin 0.125 g - on the first day 2 tablets after meals, then every other day 1 tablet; cycloferon - 0.15 g tablets and 12.5% ​​injection solution - 2 ml, prescribed according to the basic scheme for 1 , 2, 4, 6, 8, 11, 14, 17, 20, 23, 26, 29 days).

BIBLIOGRAPHY

1. L. V. Kovalchuk, A. N. Cheredeev Apoptotic immunodeficiencies // Modern problems of allergology, clinical immunology and immunopharmacology: Abstracts. report 2nd nat. Congress of RAAKI. M., 1998.S. 615-619.
2. Reznik I.B. The current state of the question of primary immunodeficiency // Pediatrics. 1996. No. 2. S. 4-14.
3. Yartsev M.N., Yakovleva K.P. Register of primary immunodeficiency states of the Institute of Immunology of the Ministry of Health of the Russian Federation // Immunology. 2005. No. 3. S. 23-27.
4. Bruton O.C. Agammaglobulinemia // Pediatrics. 1952. Vol. 9.P. 722-726.
5. Cunningham-Rundles C. Clinical and immunological analysis of 103 patients with common variable immunodeficiency // J. Clin. Immunol. 1989. Vol. 9.P. 22-33.
6. Lloyd A.R. et al. Immunological abnormalities in the chronic fatigue syndrome // Med. J. Aust. 1989. Vol. 151. P. 122-124.
7. Matamoros F.N. et al... Primary immunodeficiency syndrome in Spain: first report of National Registry in children and adults // J. Clin. Immunol. 1997. Vol. 17.P. 333-339.

Section of immunology.

Primary (congenital) immunodeficiencies

The concept of primary immunodeficiency developed in the 60s of the XX century, although some hereditary diseases of the immune system were described earlier. From the very beginning, genetically determined immunodeficiencies were considered as "experiments of nature" (R. Good), the study of which helps to understand the immunological mechanisms. Indeed, in a number of cases, the analysis of the molecular basis of immunodeficiencies made it possible to reveal new details of the structure and functioning of the immune system; however, the nature of the defects underlying primary immunodeficiencies more often became known after the disclosure of general immunological laws, the clinical confirmation of which they turned out to be.

Primary immunodeficiencies are extremely rare diseases. Most of them are detected with a frequency of 1 in 10 5 -10 6, some - with a frequency of 1 in 10 4. Only for selective IgA deficiency has a frequency of 1 in 500-1000 been defined. The disease of this group is detected mainly in childhood, since many patients do not live up to 20 years, and in the rest, the defects are compensated to a certain extent. Thanks to successful treatment, the upper age threshold was found to be more blurred than before.

Due to the special severity of these pathological reactions, as well as the significant scientific interest that each specific case of the disease presents, primary immunodeficiencies attract the attention of not only immunologists. The World Health Organization publishes materials reflecting the state of this problem at regular intervals.

The bottom line, however, is that without lymphocytes, but with the complete preservation of leukocytes and complement, there is no immune response: alone, without lymphocytes, the mechanisms of pre-immune cellular and humoral resistance cannot cope with the real, constantly changing set of infectious microorganisms and helminths, as well as artificial food additives and drugs. Clinical symptoms and adequate laboratory tests make it possible to differentiate pathology at the level of lymphocytes and pathology at the level of non-lymphocytic mechanisms of destruction and release of Ar.

The incidence of PID in general is 1 case per 10-100 thousand live births. Selective IgA deficiency is much more common - 1 in 500-1500 inhabitants of the general population.

The main clinical defect in PID corresponds to the main natural function of the immune system and consists in infectious diseases. Since before the beginning of the second half of the XX century. Since humanity lived without antibiotics, infant mortality from infections was common, and against the background of high infant mortality from infections, doctors did not isolate PID, and immunology was underdeveloped. Only between 1920 and 1930. in the medical literature, descriptions of diseases began to appear for the first time, which were later understood as PID. The first nosology was identified in 1952 by the English physician Bruton, who, upon electrophoresis of the blood serum of a sick child, revealed a complete absence of g-globulins (i.e., immunoglobulins). The disease is called Bruton's agammaglobulinemia. Later it became clear that the pathology is linked to the X chromosome, its modern name is X-linked Bruton's agammaglobulinemia.

Classification of primary immunodeficiencies:

1. Syndromes with AT deficiency.

2. Syndromes with deficiency of T-lymphocytes.

3. Combined T- and B-deficiencies.

4. Syndromes with deficiency of complement components.

5. Syndromes with defects in the NK.

6. Syndromes with phagocyte defects.

7. Syndromes with defects in adhesion molecules.

The main clinical "face" of PID is the so-called infectious syndrome - increased susceptibility to infections in general, recurrent course of infectious diseases, unusually severe clinical course, atypical pathogens (often opportunistic). Most PIDs manifest in early childhood. PID is suspected if a small child suffers from infectious diseases more than 10 times a year. In children with PID, infections can be persistent. Attention should be paid to the lag in age indicators of development, recurrent sinusitis, otitis media, pneumonia, diarrhea, malabsorption, candidiasis. Fical examination reveals the absence of lymph nodes and tonsils.

If clinical evidence suggests PID, the following laboratory tests are performed:

1.analysis for HIV infection,

2.determination of blood count,

3.determination of levels of IgG, IgA, IgM in blood serum,

4.skin tests of HRT for commonplace Ar (Ar tetanus, diphtheria, streptococcal, tuberculin, Proteus mirabilis, Trichophyton mentagrophytes, Candida albicans),

5.if necessary - counting subpopulations of T- and B-lymphocytes,

6. for special clinical indications, analysis for the content of complement components (starting with C3 and C4),

7. for special indications, analysis of the state of phagocytes (the simplest and most informative analysis is the test for the restoration of terazolium blue dye),

8. Molecular genetic research, if it makes sense (ie specific prospects for gene therapy) and means.

Analyzes are not performed all at once, but step by step, as the doctor manages or fails to recognize the nosology. All analyzes are expensive, and it is not customary to do "superfluous" tests.

Primary Immunodeficiencies with Immunoglobulin Defects

X-linked Bruton agammaglobulinemia

Boys are sick whose mothers are carriers of the defective X chromosome. Defectan has one gene on the X chromosome (Xq22); encoding a B-lymphocyte-specific protein tyrosine kinase (designated in Bruton's honor as Btk), homologous to members of the Tes tyrosine kinase family.

Laboratory data. There are no peripheral B-lymphocytes. The bone marrow contains pre-B cells with an m-chain in the cytoplasm. IgM and IgA are not detected in serum, IgG may be present, but not enough (40-100 mg / dl). Analysis for antibodies to the corresponding Ar blood groups and antibodies to vaccine Ar (tetanus toxin, diphtheria toxin, etc.) shows their absence. T-lymphocyte count and T-lymphocyte function tests are normal.

The clinical picture. If the family history is unknown, the diagnosis is, on average, evident by the age of 3.5 years. The disease is characterized by severe pyogenic infections, infections of the upper (sinusitis, otitis) and lower (bronchitis, pneumonia) respiratory tract, there may be gastroenteritis, pyoderma, septic arthritis (bacterial or chlamydial), septicemia, meningitis, encephalitis. Respiratory tract infections are most often caused by Haemophilus influenza, Streptococcus pneumonia, Staphylococcus aureus. Diarrhea is caused by intestinal bacteria or Giardia lambia. Typical viral infections are those with the neurotropic viruses ECHO-19, which cause persistent meningoencephalitis. In sick children, when immunized with live poliovacine, as a rule, there is a prolonged leaching of the polio virus through the mucous membranes, and with restored and increasing virulence (i.e., in the children's collective, there is a real danger of infection of healthy children with poliomyelitis as a result of contact with a vaccinated immunodeficient child). When examining such children, attention is paid to growth retardation, fingers in the form of drumsticks, changes in the shape of the chest, characteristic of diseases of the lower respiratory tract, hypoplasia of the lymph nodes and tonsils. Histological examination of lymphoid tissue shows the absence of germinal centers and plasma cells.

1. Antimicrobial chemotherapy.

2. Substitution therapy: intravenous infusion of donor serum immunoglobulin preparations every 3-4 weeks for life. Doses of immunoglobulin preparations are selected so as to create a concentration of immunoglobulins in the patient's serum that overlaps the lower limit of the age norm.

3. The possibility of genetic therapy is being discussed. The Btk gene has been cloned, but there is evidence that hyperexcretion of this gene is associated with malignant transformation of hematopoietic tissue.

X-linked agammaglobulinemia with hyperimmunoglobulinemia syndrome M

Boys whose mothers are carriers of the defect are sick. The molecular defect, with some degree of suspicion, concerns the CD40 lagnda gene. Insufficient expression of CD40L in T-lymphocytes leads to the impossibility of switching the synthesis of classes of immunoglobulins in B-lymphocytes from M to all other isotypes.

Laboratory data. IgG, IgA, IgE are undetectable or there are very few of them. The IgM level is increased, it can be significantly. As a rule, IgV is polyclonal, sometimes monoclonal. There are no germinal centers in the lymphoid tissue, but there are plasma cells.

The clinical picture. Recurrent bacterial and flexible infections, including oppuronic (Pneumocustis carinii). There may be lyfadenopathy and splenomegaly. A similar clinical picture is described for the presumably autosomal type of inheritance of the pathology, as well as for some cases of pathology in children who have undergone intrauterine infection with the rubella virus.

Treatment. Similar to the treatment of Bruton's agammaglobulinemia, i.e. antimicrobial chemotherapy and regular lifelong infusions of donor serum immunoglobulin preparations.

The full text of the lecture is presented on the slides.