Primary immunodeficiency

Primary immunodeficiency - congenital disorders of the immune system associated with genetic defects of one or more components of the immune system, namely cellular and humoral immunity, phagocytosis, and the complement system. Primary immunodeficiency states (IDS) include only cases of persistent impairment of the final effector function of the damaged 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, with some forms having an increased incidence of allergies, autoimmune diseases and the development of some malignant tumors. Sometimes primary immunodeficiency can be asymptomatic for a long time.

Epidemiology

Genetic defects of the immune system are rare, according to the most common estimates of about 1 in 10,000 births. At the same time, the prevalence of various forms of PIDS is not the same. An idea of the frequency of various forms of PIDS can be obtained by reviewing numerous registries of primary immunodeficiencies maintained in different countries and even regions. Humoral primary immunodeficiency is the most common, which is associated with both the ease of diagnosis and the better survival of such patients. On the contrary, in the group of severe combined immune deficiency, most patients die in the first months of life, often without receiving a lifetime diagnosis. Primary immunodeficiency with other major defects often has bright extraimmune clinical and laboratory markers that facilitate diagnosis, combined immune deficiency with ataxia-telangiectasia, Wiskott-Aldrich syndrome, chronic mucocutaneous candidiasis.

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Causes primary immunodeficiency

Currently, more than 140 precise molecular genetic defects leading to persistent immune dysfunctions have been deciphered. Defective genes have been mapped, abnormal products associated with them and affected cells of various forms of primary immunodeficiency have been identified.

Due to the limited availability of molecular genetic diagnostics of primary immunodeficiency, the phenotypic approach based on external immunological and clinical parameters of various forms of IDS prevails in everyday clinical practice.

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Symptoms primary immunodeficiency

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

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

Allergic lesions are obligatory for Wiskott-Aldrich syndrome and hyper-IgE syndrome and are more frequent in selective deficiency (atopic dermatitis, bronchial asthma) - they occur in 40%, having a normal course. On average, allergic manifestations occur in 17% of patients. It is very important for understanding the nature of allergic reactions to observe that allergic lesions in most of the most severe forms of primary immune deficiency (ID) are absent along with the loss of the ability to produce IgE and develop delayed-type hypersensitivity reactions; pseudoallergic (parallergic) reactions (toxicoderma, exanthema in drug and food intolerance) are possible in any forms of ID, including the deepest ones.

Autoimmune lesions are found in 6% of patients, which is much more common than in the normal pediatric population, but their frequency is very uneven. Rheumatoid arthritis, scleroderma-like syndrome, hemolytic anemia, autoimmune endocrinopathies are found with increased frequency in some primary immunodeficiencies, such as chronic mucocutaneous candidiasis, common variable immunodeficiency, selective IgA deficiency. Pseudoautoimmune lesions (reactive arthritis, infectious cytopenia, viral hepatitis) can be observed in any form of primary immunodeficiency.

The same applies to malignant diseases, which occur with increased frequency only in some forms of primary immunodeficiency. Almost all cases of malignant neoplasia are ataxia-telangiectasia, Wiskott-Aldrich syndrome, and common variable immunodeficiency.

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

• chronic or recurrent course, tendency to progression;
• polytopicity (multiple lesions of various organs and tissues);
• polyetiology (susceptibility to many pathogens simultaneously);
• incomplete cleansing of the body from pathogens or incomplete effect of treatment (lack of normal health-disease-health cycle).

Forms

Phenotypic classification of primary immunodeficiency:

• antibody deficiency syndromes (humoral primary immunodeficiency):
• predominantly cellular (lymphoid) immune defects;
• severe combined immunodeficiency syndromes (SCID),
• phagocytosis defects;
• complement deficiency;
• primary immunodeficiency disorder (PID) associated with other major defects (other well-defined PID).

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Diagnostics primary immunodeficiency

Primary immunodeficiency has a characteristic set of clinical and anamnestic signs that allow one to suspect one or another form of primary immune deficiency.

T-cell predominant primary immunodeficiency

• Early onset, delayed physical development.
• Oral candidiasis.
• Skin rashes, thinning hair.
• Prolonged diarrhea.
• Opportunistic infections: Pneurnocystis carinii, CMV, Epstein-Barr virus infection (lymphoproliferative syndrome), post-vaccination systemic BCG infection, severe candidiasis.
• Graft-versus-host disease (GVHD).
• Bone anomalies: adenosine deaminase deficiency, dwarfism due to short limbs.
• Hepatosplenomegaly (Omenn syndrome)
• Malignant neoplasms

Predominant B-cell primary immunodeficiency

• Onset of the disease after the disappearance of maternal antibodies from circulation.
• Recurrent respiratory infections: caused by gram-positive or gram-negative bacteria, mycoplasma; otitis media, mastoiditis, chronic sinusitis, bronchopneumonia and lobar pneumonia, bronchiectasis, pulmonary infiltrates, granulomas (common variable immunodeficiency); 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 (CVID, X-linked hyper-IgM syndrome); nodular lymphoid hyperplasia, ileitis, colitis (CVID).
• Musculoskeletal disorders: arthritis (bacterial, mycoplasmal, non-infectious), dermatomyositis or fasciitis caused by enteroviruses (X-linked agammaglobulinemia).
• CNS lesions: enterovirus-induced moningoencephalitis.
• Other signs: lymphadenopathy affecting the abdominal and thoracic lymph nodes (CVID); 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.
• Skin lesions (seborrheic dermatitis, impetigo) inflammation of loose tissue without pus (leukocyte adhesion defect).
• Late umbilical cord separation (leukocyte adhesion defect).
• Lymph nodes (purulent lymphadenitis) (hyper-IgE-sicrom)
• Diseases of the respiratory system: pneumonia, abscesses, pneumatocele (hyper-IgE syndrome).
• Oral lesions (periodontitis, ulcers, abscesses)
• Gastrointestinal diseases: Crohn's disease, gastric antral obstruction, liver abscesses.
• Bone lesion: osteomyelitis.
• Urinary tract diseases: bladder obstruction.

Complement defects

• The disease can begin at any age.
• Increased susceptibility to infections associated with deficiency of C1q, C1r/C1s, C4, C2, C3 (streptococcal, neisserial infectious diseases); C5-C9 (neisserial infectious diseases), factor D (recurrent infectious diseases); factor B, factor I, properdin (neisserial infectious diseases).
• Rheumatoid disorders (most often with deficiency of early components.
• Systemic lupus erythematosus, discoid lupus, dermatomyositis, scleroderma, vasculitis, membranoproliferative glomerulonephritis associated with deficiency of: C1q, C1r/C1s, C4, C2; C6 and C7 (rare) (systemic lupus erythematosus); C3, factor F (glomerulonephritis).
• C1 esterase inhibitor deficiency (angioedema, systemic lupus erythematosus).

Laboratory research

Laboratory diagnostics of primary immunodeficiency requires the combined use of both widely used methods for assessing immunity and complex, expensive studies that are generally only available to specialized medical research centers.

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

• clinical blood test:
• study of serum concentration of immunoglobulins M, G, A; HIV infection test (added later in connection with the development of the HIV pandemic).

It is difficult to overestimate the role of determining the serum concentration of IgM, IgG, IgA (total) in diagnosing a condition such as primary immunodeficiency. These studies account for up to 70% of cases where they turned out to be leading for establishing a diagnosis. At the same time, the information content of determining IgG subclasses is relatively low. Complete loss of individual subclasses is almost never encountered, but a relative decrease in their share was found in a variety of clinical conditions, including those far from the symptom complex of immunodeficiency states. An in-depth assessment of B-cell immunity may require determining the antibody response to vaccination (diphtheria-tetanus or pneumococcal vaccine), determining IgG synthesis in vitro in a culture of peripheral lymphocytes upon stimulation with mitogens and the presence of anti-CD40 and lymphokines, studying the proliferative response of B cells in vitro to anti-CD40 and interleukin-4.

The currently used expanded program of immune assessment includes 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);
• Memory T cells (CD45RO).

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Treatment primary immunodeficiency

Primary immunodeficiency is most often detected in children, usually in early childhood. Some forms of primary immunodeficiency (for example, selective IgA deficiency) are well compensated in a significant proportion of patients, so they can be detected for the first time in adults both against the background of clinical manifestations and as an accidental finding. Unfortunately, primary immunodeficiency is extremely dangerous, poorly amenable to therapy, and therefore a significant, and in some nosologies the predominant part of such patients do not survive to adulthood and remain known mainly 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, survive to adulthood.

Primary immunodeficiency is treated by using methods of isolation (separation) of patients from sources of infection. The required degree of separation varies from an abacterial (gnotobiological) block to a general regime ward, depending on the form of primary immunodeficiency. During the period of compensation of the immune defect and outside of exacerbation of infectious manifestations, strict restrictive measures are not required for most forms of primary immunodeficiency: children should go to school and participate in games with their peers, including sports. At the same time, it is very important to raise them as non-smokers and not expose them to passive smoking, and especially not to drug use. Skin and mucous membrane hygiene and the widespread use of physical methods of suppressing infection are extremely important.

Patients with primary immunodeficiency with all forms of severe total antibody deficiency and profound cellular immunodeficiency cannot be vaccinated with live vaccines against poliomyelitis, measles, mumps, rubella, chickenpox, tuberculosis due to the risk of developing vaccine-induced infections. Paralytic poliomyelitis, chronic encephalitis, prolonged excretion of poliovirus have been repeatedly described with accidental administration of live vaccines to such patients. In the home environment of such patients, only inactivated polio vaccine should also be used. Observations of HIV-infected children have shown that at a CD4 cell level above 200 per µl, the use of live vaccines is safe. However, 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 in case of selective IgA deficiency, mucocutaneous candidiasis in patients with primary immunodeficiency with preserved cellular immunity to other antigens, with defects in phagocytosis (except for the BCG vaccine) and complement. Patients with a sufficient antibody response (for example, with insufficiency of IgG subclasses, ataxia-telangiectasia) can be prescribed inactivated vaccines.

General principles of antimicrobial therapy of patients with primary immunodeficiency are as follows: early prescription of broad-spectrum antibiotics or combined sulfonamides if there is a risk of infection; early change of drug if it is ineffective, but long-term (up to 3-4 weeks or more) use if a specific drug has a positive effect; wide parenteral, intravenous and intralesional administration of drugs; simultaneous prescription of antifungal and, if indicated, antimycobacterial, antiviral and antiprotozoal agents. The duration of antimicrobial therapy of patients with primary immunodeficiency, depending on clinical manifestations and tolerability of treatment, can be long-term, lifelong; periodic anti-relapse or episodic. Antiviral therapy is successfully used for many immunodeficiencies. For influenza, amantadine, rimantadine or neuraminidase inhibitors, zanamivir and oseltamivir are used. In severe episodes of Herpes simplex, chickenpox, and shingles, acyclovir is prescribed; in parainfluenza and respiratory syncytial infection, ribavirin is prescribed. Local administration of cidofovir can be used to treat a severe episode of molluscum contagiosum infection. Preventive administration of antibiotics is also recommended before dental and surgical interventions. Long-term prophylactic administration of antibiotics is used in immunodeficiency syndromes with rapid development of infectious complications in complement deficiencies, in splenectomized patients with Wiskott-Aldrich syndrome, severe phagocytic defects, and in patients with antibody deficiency to developing infections despite immunoglobulin replacement therapy. The most commonly prescribed regimen is amoxicillin or dicloxacillin at 0.5–1.0 g per day: another fairly effective regimen 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 weeks. In severe primary or secondary T-cell immunodeficiencies, prophylaxis of Pneumocystis pneumonia (caused by Pneumocystis carinii or jiraveci) is recommended if the CD4 lymphocyte level falls below 200 cells/μl in children over 5 years of age, less than 500 cells/μl from 2 to 5 years of age, less than 750 cells/μl from 1 year to 2 years of age, and less than 1500 cells/μl for children under 1 year of age. Prevention is carried out with trimethoprimsulfamethoxazole at the rate of 160 mg/m2 of body area for trimethoprim or 750 mg/m2 for sulfamethoxazole per day. The daily dose is divided into 2 doses and given on the first three days of each week.

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

1. Immunoreconstruction - that is, the restoration of immunity, usually by transplantation of living pluripotent hematopoietic stem cells
2. Replacement therapy - replenishment of missing immune factors.
3. Immunomodulatory therapy is an effect on the impaired immune status of the body through regulatory mechanisms using immunomodulators, drugs that can stimulate or suppress the immune system as a whole or its individual components.

Immunoreconstruction methods are based mainly on transplantation of bone marrow or stem cells obtained from umbilical cord blood.

The goal of bone marrow transplantation in patients with primary immunodeficiencies is to provide the recipient with normal hematopoietic cells capable of correcting the genetic defect of the immune system.

Since the first bone marrow transplants in patients with primary immunodeficiency in 1968, more than 800 such transplants have been performed worldwide in patients with SCID alone; approximately 80% of recipients of HLA-identical unfractionated bone marrow and 55% of recipients of haploidentical T-cell-depleted bone marrow have survived. In addition to SCID, 45 patients with Omein syndrome have received bone marrow transplants; 75% of patients who received HLA-identical bone marrow from sibling donors survived, and 41% of patients who received HLA-identical bone marrow survived. Forty of 56 patients with X-linked hyper-IgM syndrome (CD40 ligand deficiency) who received BMT also survived.

The most common option for replacement therapy for patients with primary immunodeficiency is the use of allogeneic immunoglobulins. Initially, immunoglobulins were created for intramuscular administration, and in recent years, the use of immunoglobulins for intravenous administration has become dominant. These drugs do not contain ballast proteins, are highly concentrated, which allows you to easily and quickly achieve the desired level of IgG in the patient, are relatively painless, safe for hemorrhagic syndrome, have a normal half-life of IgG, and rarely cause side effects. A significant drawback is the high cost and complex technology for preparing these drugs. Abroad, methods of slow subcutaneous infusions of 10-16% immunoglobulin, originally developed for intramuscular administration, have become widespread; such drugs should not contain thimerosal. Primary immunodeficiency, for which immunoglobulin therapy is indicated, is listed below.

Primary immunodeficiencies for which immunoglobulin therapy is indicated

• Antibody deficiency syndromes
• X-linked and autosomal recessive atammaglobulinemia.
• CVID, including deficiency of ICOS, Baff receptors, CD19, TACI.
• Hyper IgM syndrome (X-linked and autosomal recessive forms).
• Transient infantile hypogammaglobulinemia.
• Deficiency of IgG subclasses with or without deficiency of IgA.
• Antibody deficiency with normal immunoglobulin levels
• Combined primary immunodeficiency