Primary immunodeficiency

Primary immunodeficiency - congenital disorders of the immunity system associated with genetic defects of one or more components of the immunity system, namely cellular and humoral immunity, phagocytosis, complement system. The primary immunodeficiency states (IDS) are only cases of persistent disruption of the end effector function of the injured link, characterized by stability and reproducible laboratory characteristics.

What is primary immunodeficiency?

The clinical picture of primary immunodeficiency states is characterized by repeated and chronic infectious diseases, in some forms the frequency of allergy, autoimmune diseases and development of some malignant tumors is increased. Sometimes the primary immunodeficiency can for a long time be asymptomatic.

Epidemiology

Genetic defects of the immune system are infrequent, according to the most common estimates, about 1 per 10,000 births. However, the prevalence of different forms of PIDS is not the same. Representations about the frequency of various forms of PIDD can be obtained by getting acquainted with the numerous registers of primary immunodeficiencies, which are conducted in different countries and even regions. The most common humoral primary immunodeficiency, which is associated with both the simplicity of diagnosis and the better survival of such patients. In contrast, in the group of severe combined immune deficiency, most patients die in the first months of life, often without a life-long diagnosis. Primary immunodeficiency with other major defects often has bright, nonimmune clinical and laboratory markers that facilitate diagnosis, combined immune deficiency with ataxia-telangiectasia, Wiskott-Aldrich syndrome, chronic cutaneous mucocutaneous candidiasis.

[1], [2], [3], [4], [5], [6]

Causes of the primary immunodeficiency

Currently, more than 140 precise molecular-genetic defects that lead to persistent immune dysfunctions have been deciphered. Defective genes have been mapped, associated abnormal products and affected cells of various forms of primary immunodeficiency have been established.

In connection with the limited availability of molecular genetic diagnosis of primary immunodeficiency, a phenotypic approach predominates in everyday clinical practice, based on external immunological and clinical parameters of various forms of IDS.

[7], [8], [9], [10], [11], [12], [13]

Symptoms of the primary immunodeficiency

Despite the pronounced heterogeneity of both clinical and immunological manifestations, it is possible to single out common features characteristic of all forms of primary immunodeficiency.

Primary immunodeficiency has a basic feature - inadequate susceptibility to infections, while other manifestations of immune deficiency; The increased frequency of allergies and autoimmune manifestations, as well as the propensity for neoplasia, are relatively small and extremely uneven.

Allergic lesions are mandatory for Wiskott-Aldrich syndrome and hyper-IgE syndrome and are frequent in selective failure (atopic dermatitis, bronchial asthma) - occur in 40%, with the usual nature of the course. On average, allergic manifestations occur in 17% of patients. Very important for understanding the nature of allergic reactions is the observation that allergic lesions in most of the most severe forms of primary immune deficiency (IN) are absent along with the loss of the ability to produce IgE and develop hypersensitivity reactions of delayed type pseudoallergic (paralgic) reactions (toxicodermia, exanthems in drug and food intolerance ) are possible for any forms of IN, including the deepest ones.

Autoimmune lesions show up in 6% of patients, which is much more frequent than in a normal child population, but their frequency is very uneven. Rheumatoid arthritis, scleroderm-like syndrome, hemolytic anemia, autoimmune endocrinopathies occur with increased frequency in some primary immunodeficiencies, such as chronic cutaneous mucocutaneous candidiasis, general variable immune deficiency, selective IgA deficiency. Pseudoautoimmune lesions (reactive arthritis, infectious cytopenia, viral hepatitis) can be observed in any form of primary immunodeficiency.

The same is true of malignant diseases, which occur with increased frequency only with some forms of primary immunodeficiency. Almost all cases of malignant neoplasia account for ataxia-telangiectasia, Wiskott-Aldrich syndrome and general variable immune deficiency.

The infections that accompany primary immunodeficiency have a number of distinctive features. They are characterized by:

• chronic or recurrent course, propensity to progress;
• polytopic (multiple lesions of various organs and tissues);
• polyethiologic (susceptibility to many pathogens at the same time);
• incompleteness of purification of the organism from pathogens or incomplete treatment effect (lack of normal cyclicity of health-illness health).

Forms

Phenotypic classification of primary immunodeficiency:

• syndromes of insufficiency of antibodies (humoral primary immunodeficiency):
• mainly cellular (lymphoid) defects of immunity;
• syndromes of severe combined immune deficiency (SCID),
• defects of phagocytosis;
• deficiency of complement;
• primary immunodeficiency (PIDC) associated with other major defects (others clearly delineated by PIDC).

[14],

Diagnostics of the primary immunodeficiency

Primary immunodeficiency has a characteristic set of clinical and anamnestic signs, which allow one to suspect some form of primary immune deficiency.

Prevailing T-cell primary immunodeficiency

• Early onset, lagging behind in physical development.
• Candidiasis of the mouth.
• Skin rashes, sparse hair.
• Prolonged diarrhea.
• Opportunistic infections: Pneurnocystis carinii, CMV, infection caused by the Epstein-Barr virus (lymphoproliferative syndrome), postvaccinal systemic BCG infection, expressed candidiasis.
• Graft-versus-host reactions (GVHD).
• Bone abnormalities: deficiency of adenosine deaminase, dwarfism due to short extremities.
• Hepatosplenomegaly (Omenna syndrome)
• Malignant neoplasms

Prevailing B-cell primary immunodeficiency

• The onset of the disease after the disappearance from the circulation of maternal antibodies.
• Repeated respiratory infections: caused by gram-positive or gram-negative bacteria, mycoplasma; otitis media, mastoiditis, chronic sinusitis, bronchopneumonia and lobar pneumonia, bronchiectasis, pulmonary infiltrates, granulomas (general variable immune deficiency); pneumonia caused by Pneumocystis carinii (X-linked hyper-IgM syndrome).
• Lesions of the digestive system: malabsorption syndromes, diseases caused by Giardia Cryptosporidia (X-linked hyper-IgM syndrome), Campylobacter; cholangitis (X-linked hyper-IgM syndrome, splenomegaly (OVIN, X-linked hyper-IgM syndrome), nodular lymphoid hyperplasia, ileitis, colitis (CVID).
• Musculoskeletal: arthritis (bacterial, mycoplasmic, non-infectious), dermatomyositis or fasciitis caused by enteroviruses (X-linked agammaglobulinemia).
• CNS lesions: moningoencephalitis caused by enteroviruses.
• Other signs: lymphadenopathy affecting the abdominal, thoracic lymph nodes (OVIN); neutropenia.

Defects of phagocytosis

• Early onset of the disease.
• Diseases caused by gram-positive and gram-negative bacteria, catalase-positive organisms (chronic granulomatous disease).
• Staphylococcus, Serralia marcescens, Klebsiella, Burkhoideria cepacia, Nocardia.
• Lesions of the skin (seborrheic dermatitis, impetigo) inflammation of loose fiber without pus (defect of adhesion of leukocytes).
• Later, the prolapse of the umbilical cord (defect of adhesion of leukocytes).
• Lymph nodes (purulent lymphadenitis) (hyper-IgE-sitzcr)
• Diseases of the respiratory system: pneumonia, abscesses, pneumatology (hyper-IgE-syndrome).
• Oral cavity damage (periodontitis, ulcers, abscesses)
• Diseases of the gastrointestinal tract: Crohn's disease, obstruction of the antral part of the stomach, liver abscess.
• Lesion of bones: osteomyelitis.
• Diseases of the urinary tract: obstruction of the bladder.

Defects of complement

• The onset of the disease at any age.
• Increased susceptibility to infections due to lack of C1q, C1r / C1s, C4, C2, C3 (streptococcal, neisserial infectious diseases); C5-C9 (neisserial infectious diseases), factor D (repeated infectious diseases); factor B, factor I, properdine (neisserial infectious diseases).
• Rheumatoid disorders (most often with deficiency of early components.
• Systemic lupus erythematosus, discoid lupus, dermatomyositis, scleroderma, vasculitis, membranous-proliferative glomerulonephritis associated with a deficiency: C1q, C1r / C1s, C4, C2; C6 and C7 (rarely) (systemic lupus erythematosus); C3, factor F (glomerulonephritis).
• Deficiency of C1-esterase inhibitor (angioedema, systemic lupus erythematosus).

Laboratory research

Laboratory diagnosis of primary immunodeficiency requires the combined use of widely used methods of assessing immunity, as well as complex expensive studies, usually available only to specialized medical research centers.

In the early 80-ies of the last century, L.V. Kovalchuk and A.N. Cheredeev singled out screening tests for assessing the immune system and suggested calling them tests of level 1. These include:

• clinical blood test:
• study of the serum concentration of immunoglobulins M, G, A; a test for HIV infection (added later due to the development of the HIV pandemic).

It is difficult to overestimate the role of the determination of serum concentrations of IgM, IgG, IgA (total) in the diagnosis of a condition such as primary immunodeficiency. These studies account for up to 70% of cases when they were leading to establish a diagnosis. At the same time, the information content of the definition of IgG subclasses is relatively small. Complete loss of individual subclasses is practically not found, but a relative decrease in their proportion was found in a variety of clinical conditions, including those far from the symptom complex of immunodeficiency states. An in-depth evaluation of B-cell immunity may require the determination of an antibody response to vaccination (diphtheria-tetanus or pneumococcal vaccine), the determination of IgG synthesis in vitro in peripheral lymphocyte culture, mitogen stimulation and the presence of anti-CD40 and lymphokines, in vitro proliferative response of B cells on anti-CD40 and interleukin-4.

The now expanded program of immunity assessment includes a cytofluorometric determination of CD-antigens of peripheral blood lymphocytes in patients with primary immunodeficiency:

• T cells (CD3)
• T-helpers (CD4)
• T-killers (CD8)
• NK cells (CD16 / CD56)
• B-lymphocytes (CD19.20);
• T-cell memory (CD45RO).

[15], [16], [17]

Treatment of the primary immunodeficiency

Primary immunodeficiency is most often detected in children, usually already in early childhood. Some forms of primary immunodeficiency (for example, selective deficiency of IgA) in a significant part of patients are well compensated, so they can be first detected in adults both on the background of clinical manifestations and as a random finding. Unfortunately, the primary immunodeficiency is extremely dangerous, poorly amenable to therapy, and therefore significant, and for some nosologies, most of these patients do not survive to adulthood and remain predominantly known to pediatricians (severe combined immune deficiency, ataxia-telangiectasia, Wiskott Aldrich syndrome, hyper-IgE syndrome, etc.). Nevertheless, the successes achieved in treatment, and in some cases other individual factors, lead to the fact that an increasing number of patients, even with severe forms of primary immunodeficiency, live to the adult state.

Primary immunodeficiency is treated against the background of using methods of isolation (dissociation) of patients with sources of infection. The necessary degree of dissociation varies from the abacterial (gnotobiological) block to the general mode ward, depending on the form of primary immunodeficiency. During the period of compensating for an immune defect and without exacerbation of infectious manifestations, in most forms of primary immunodeficiency, strict restrictive measures are not required: children should go to school and participate in games with peers, including sports. At the same time, it is very important to educate them non-smokers and not to subject them to passive smoking, much less to the use of drugs. It is extremely important to have skin and mucous membranes toilet, wide application of physical methods of suppression of infection.

Patients on primary immunodeficiency with all forms of severe total antibody deficiency and deep cellular immunodeficiency can not be vaccinated with live vaccines against poliomyelitis, measles, mumps, rubella, varicella, tuberculosis due to the risk of developing vaccine infections. Paralytic poliomyelitis, chronic encephalitis, long-term release of poliovirus are described many times with the random assignment of live vaccines to such patients. In the home environment of such patients, it is also necessary to use only inactivated polio vaccine. Observations of HIV-infected children have shown that at a CD4 cell count above 200 in μL, the use of live vaccines is safe. Nevertheless, children with primary immunodeficiency are not capable of an antibody response, so attempts to vaccinate them are ineffective. The use of live vaccines is safe with selective deficiency of IgA, mucocutaneous candidiasis in patients with primary immunodeficiency with preserved cellular immunity to other antigens, with defects of phagocytosis (except BCG vaccine) and complement. Patients with a sufficient antibody response (eg, if IgG subclasses are deficient, ataxia-telangiectasia) can be assigned inactivated vaccines.

The general principles of antimicrobial therapy of patients for primary immunodeficiency are as follows: early administration of broad-spectrum antibiotics or combined sulfanilamides in the event of infection; early change of the drug with its ineffectiveness, but long-term (up to 3-4 weeks or more) application with a positive effect of a particular drug; wide parenteral, intravenous and intramuscular administration of drugs; simultaneous administration of antifungal and, according to indications, antimycobacterial, antiviral and antiprotozoal medium. The duration of antimicrobial therapy of patients for primary immunodeficiency, depending on the clinical manifestations and the tolerability of treatment, can be long-term, lifelong; periodic or anti-recurrent or episodic. Antiviral therapy is successfully used in many immunodeficiencies. When the flu is used, amantadine, remantadine or neuraminidase inhibitors, zanamivir and oseltamivir. In severe episodes of Herpes simplex diseases, chickenpox, herpes zoster, acyclovir is prescribed, with parainfluenza and respiratory syncytial infection - ribavirin. To treat a serious episode of infection with molluscum contagiosum, local administration of cidofovir can be used. Preventive prescription of antibiotics is recommended before dental and surgical interventions. Prolonged preventive prescription of antibiotics is used in immunodeficient syndromes with rapid development of infectious complications with complement deficiencies, in splenectomized patients with Wiskott-Aldrich syndrome, severe phagocytic defects, and in patients with a deficiency of antibodies to developing infections, despite immunoglobulin replacement therapy. The most commonly prescribed amoxicillin or dicloxacillin is 0.5 1.0 g and day: another rather effective scheme is based on taking azithromycin at a daily dose of 5 mg / kg, but not more than 250 mg given in one dose, the first three consecutive days every 2 ned. Serious primary or secondary T-cell immunodeficiencies are recommended to prevent pneumocystis pneumonia (Pneumocystis carinii or jiraveci pathogen) if the CD4 level of lymphocytes falls below 200 cells / mm3 in children older than 5 years, less than 500 cells / μl from 2 to 5 years, less than 750 cells / μl from 1 year to 2 years and less than 1500 cells / mm for children under 1 year. Preventive maintenance is carried out with trimethoprimsulfomethacosol from the calculation of 160 mg / m2 of the body area according to trimethoprim or 750 mg / m2 by sulphometacosol and day. The daily dose is divided into 2 doses and given the first three days of each week.

Correction of immune deficiency (immunocorrection) can be achieved only by using special methods of treatment. Methods of immunocorrection can be divided into 3 groups:

1. Immunorekonstruktsiya - that is, the restoration of immunity, as a rule, transplantation of live polypotent hematopoietic stem cells
2. Substitution therapy - the replacement of the missing immunity factors.
3. Immunomodulatory therapy is an effect on the immune status of an organism that is disturbed through regulatory mechanisms with the help of immunomodulators of drugs capable of stimulating or inhibiting immunity and the whole or its individual components.

Methods of immunorefection are based mainly on bone marrow transplantation or stem cells derived from umbilical cord blood.

The purpose of bone marrow transplantation in patients with primary immunodeficiency is to provide the recipient with normal hematopoietic cells that can correct the genetic defect of the immune system.

Since the first bone marrow transplantation for patients with primary immunodeficiency in 1968, more than 800 such transplants have been performed in the world only to patients with SCID, about 80% of HLA-identical unfractionated bone marrow recipients and 55% of Haploidentical bone marrow recipients depleted from T cells survived. In addition to SCI, 45 patients with Omein syndrome received bone marrow transplantation, 75% of patients who received HLA-identical bone marrow of donor siblings and 41% of patients who received HLA-identical bone marrow survived. Survived also 40 of 56 patients who received TCM X-linked hyper-IgM syndrome (deficiency of CD40 ligand).

The most common variant of substitution therapy for patients with primary immunodeficiency is the use of allogeneic immunoglobulin. Initially, immunoglobulins were created for intramuscular injection, and in recent years the use of immunoglobulins for intravenous administration has become dominant. These drugs do not contain ballast proteins, they are highly concentrated, which makes it possible to reach the required level of IgG in a patient easily and quickly, relatively painless, safe with hemorrhagic syndrome, have a normal half-life of IgG, rarely cause side effects. A significant disadvantage is the high cost and complex technology of preparation of these drugs. Abroad, methods of slow hypodermic infusions of 10-16% of immunoglobulin, originally developed for intramuscular injection, were widely used; similar preparations should not contain merziolate. Primary immunodeficiency, in which immunoglobulin therapy is indicated, is indicated below.

Primary immunodeficiencies, in which therapy with immunoglobulins is indicated

• Antibody deficiency syndromes
• X-linked and autosomal recessive atamaglobulinemia.
• OVIN, which includes deficiency of ICOS, Baff receptors, CD19, TACI.
• Hyper IgM syndrome (X-linked and autosomal recessive forms).
• Transient infant hypogammaglobulinemia.
• Deficiency of IgG subclasses with or without IgA deficiency.
• Deficiency of antibodies at normal levels of immunoglobulins
• Combined primary immunodeficiency